U.S. Army Medical Department, Office of Medical History
Skip Navigation, go to content

HISTORY OF THE OFFICE OF MEDICAL HISTORY

AMEDD BIOGRAPHIES

AMEDD CORPS HISTORY

BOOKS AND DOCUMENTS

HISTORICAL ART WORK & IMAGES

MEDICAL MEMOIRS

AMEDD MEDAL OF HONOR RECIPIENTS External Link, Opens in New Window

ORGANIZATIONAL HISTORIES

THE SURGEONS GENERAL

ANNUAL REPORTS OF THE SURGEON GENERAL

AMEDD UNIT PATCHES AND LINEAGE

THE AMEDD HISTORIAN NEWSLETTER

Section 4

The Histories of the Commissions - Contents

Commission on Streptococcal and Staphylococcal Diseases


Foreword

Rheumatic fever ranks historically among the top diseases in terms of causing lingering illness leading to crippling cardiac disability and death. The ability to control and significantly limit the spread of streptococcal infections played a large and important role in the demise of rheumatic fever and nephritis in developed countries. Improved standards of health and the advent of specific chemotherapy were important aspects of this favorable turn of events. When basic guidelines and defined principles of surveillance and application of preventive methods are discarded, streptococcal infections and rheumatic fever are likely to reappear.

The history of the Commission on Streptococcal and Staphylococcal Diseases is a story of heroic success. The Commission began humbly but firmly in 1941 as a part of the Armed Forces Epidemiological Board (AFEB) program mission and, with the exception of 2 years from 1946 to 1948, contributed ceaselessly until its termination in 1973. In the medical community, such persons as Drs. John Dingle, Charles H. Rammelkamp, I. Lowell Rantz, Maclyn McCarty, Rebecca Lancefield, Richard M. Krause, William S. Tillett, Floyd W. Denny, Jr., Lewis W. Wannamaker, Harold B. Houser, Gene H. Stollerman, Armine T. Wilson, and others are really household names.

Drs. Denny and Houser have described the remarkable activities of the Commission that sponsored work on streptococcal and staphylococcal diseases. The record has been one of excellence from its meager beginnings to the Warren Air Force Base, Wyoming, to Cleveland, Ohio; Chapel Hill, North Carolina; Minneapolis, Minnesota; San Francisco, California; and elsewhere, to its termination in 1973.

New knowledge of the means of spread of streptococci and staphylococci, how to detect and classify them, clarification of the mechanisms causing illness and how to control them, particularly streptococci, are all now matters of his torical record. Problems remain, but the basic principles are soundly grounded. The AFEB has always looked with pride toward the contributions of its Commissions, including this one. Denny and Houser have my sincerest thanks and appreciation for bringing this important report to fruition. We are all in their debt, including those dedicated and talented persons who helped make these events possible.

- Theodore E. Woodward, M. D.


History of the Commission on Streptococcal and Staphylococcal Diseases

Floyd W. Denny, Jr., M.D.
and
Harold B. Houser, M.D.

PREFACE

When we were contacted by Dr. Theodore E. Woodward, President of the Armed Forces Epidemiological Board (AFEB), and asked to write the history of the various streptococcus and staphylococcus commissions our first thought was: Why us? On brief reflection, we realized that all of the Commission directors were deceased. Had Charles H. Rammelkamp, Jr., or Lewis W Wannamaker been alive at the time, it is clear that the task would have been theirs. In their absence, however, we accepted the charge, although with some reluctance because of the enormity of the job.

Writing this history has been truly a "labor of love" and we have enjoyed it thoroughly. At times we had difficulty "keeping our noses to the grindstone" when we met for planning sessions because we kept reminiscing about the "good old days" and our many hours, days, and even weeks of experiences with the Commission. Probably the only thing that allowed us to finish was that we had to return inevitably to our offices in Cleveland, Ohio, and Chapel Hill, North Carolina.

The history of the Streptococcal Disease Laboratory occupies a large portion of this present work. This stems in part from the authors' intimate knowledge of the "strep lab" also from the prominent part the laboratory had in laying the groundwork for much of the streptococcal research supported by the Commission in the 1950s and 1960s. In his recollections of the Commission, Maclyn McCarty refers to the laboratory as "the star in its crown." Because the authors have great respect for Dr. McCarty, we make no efforts to rebut his description in this history.

We did not attempt to follow up on all of the Commission members, both because we thought it not necessary and because of the size of the task. We did try to contact all of the members of the professional staff of the Streptococcal Disease Laboratory. We were able to locate or determine the deaths of all of them. Seven of the staff are now dead: Robert J. Kohen, Earl C. Marple, William D. Perry, Charles H. Rammelkamp, Jr., Alan C. Siegel, Chandler A. Stetson, and Lewis W. Wannamaker. We communicated with the remaining staff; summaries or excerpts from the letters we received are included in Appendices V and VIII.

Almost all of the work of gathering the information for this history and writing the text was done by us. The greatest sources of material were our personal records or those of others involved in the Commission work. We did obtain valuable information from the files of the National Library of Medicine, the Smadel Library at the Walter Reed Army Institute of Research (WRAIR), and the National Archives. Unfortunately, many of the records that would have been helpful have been lost, misplaced, or destroyed. We do want to acknowledge the help given to us by the staff of the AFEB office, especially Jean Ward and Colonel Robert A. Wells. We also want to thank Dr. H. Sherwood Lawrence for writing his reminiscences of the saga of transfer factor and Dr. Fred Robbins for his memorial to Dr. Rammelkamp. Finally, we thank Mary Gardner of Cleveland and Kathy Cheek of Chapel Hill for their excellent help in bringing to light our thoughts and scribbles.


264

THE COMMISSION ON HEMOLYTIC STREPTOCOCCAL INFECTIONS—
6 FEBRUARY 1941 TO 30 JUNE 1946

The importance of hemolytic streptococcal infections, their complications, and sequelae were not generally recognized by the military services at the start of World War II. The important work of Lancefield1 and Griffith2 during the late 1920s and early 1930s resulted in classification schemes for hemolytic streptococci and established the group A β-hemolytic streptococcus as an important human pathogen. The work of Coburn3 during the same period provided strong epidemiological evidence for a direct association between group A hemolytic streptococcal respiratory infections and subsequent acute rheumatic fever. This information, not widely disseminated to the medical community at large, was not generally known and, when known, was not universally accepted. As late as December 1941 Paul accepted that ". . . hemolytic streptococcal infections have something to do with rheumatic fever " but still questioned whether the hemolytic streptococcus was the only infectious agent in rheumatic fever.4

At the beginning of World War II, the military services had no history to draw on for concern about group A hemolytic streptococcal infections. The streptococcal etiology of scarlet fever was not established until the early 1920s. A brief review by Rantz5 of the history of streptococcal infection and its sequelae in the military prior to World War II indicates that these infections were a major problem. Erysipelas and acute rheumatism were epidemic in the U.S. Army during the Civil War. Twenty-five thousand cases of acute articular rheumatism occurred during World War I, suggesting epidemic streptococcal disease (rheumatic fever is not mentioned in the official history of the Medical Department of the U.S. Army in World War I). Scarlet fever was 45th on the list of important diseases in the U.S. Army in World War I, based on admission to sick report.6 Streptococcal respiratory infections without a skin rash were not distinguished from other respiratory infections and any relation to subsequent rheumatic fever was not appreciated. It was against the above backdrop, that Rantz5 attributes the poor preparations of the Medical Department to cope with the problems of hemolytic streptococcal infections at the start of World War II.

At the time of the first meeting of the newly established Board for the Investigation and Control of Influenza and other Epidemic Diseases in the Army in February 1941, the paucity of information about the occurrence of streptococcal infection and sequelae during the prewar mobilization was recognized.5 Outbreaks of scarlet fever and rheumatic fever at Chanute Field and Scott Field in Illinois and at Fort Knox, Kentucky, in early 1941 emphasized the seriousness of the problem. The Board, at its first meeting, recommended that "'Commissions' of the Board be appointed to deal with important infectious diseases, each 'Commission' to have a 'Director' and such additional consultant personnel as necessary for the purposes of the Commission."7 The Commission on Hemolytic Streptococcal Infections was one of the seven recommended Commissions. The Board also recommended, as director of the Commission, Dr. Francis F. Schwentker of The Rockefeller Foundation, New York City. Dr. Schwentker declined the directorship because of anticipated absence from the United States. As a result, the Streptococcal Commission was not represented at the second meeting of the Board, 27 and 28 February 1941. At this meeting, Dr. Martin H. Dawson, College of Physicians and Surgeons, Columbia University, New York City, was appointed Director of the Commission.7 The Commission Director's responsibilities were to appoint an executive committee, arrange for meetings of the committee, and prepare field and interim research programs, budgets, and lists of additional personnel. The committee appointed by Dr. Dawson was comprised of Dr. Chester F. Keefer, Boston University School of Medicine; Dr. David Seegal, Research Division for Chronic Diseases, Welfare Island, New York City; Dr. William S. Tillett, New York University College of Medicine; and Dr. James Trask, Yale University College of Medicine, New Haven, Connecticut.

Dr. Dawson resigned as Director on 14 October 1942 owing to poor health and recommended Dr. Keefer as Director. Dr. Keefer accepted appointment and continued as Director until the Commission


265

was disbanded in 1946. Dawson remained a member of the Commission until his death in 1945. Dr. Trask died in May 1942. Most of the Commission members served through 1945. Drs. Ann G. Kuttner, John S. Lockwood, Wesley W. Spink, Homer F. Swift, Tillett, and Conrad Wesselhoeft were still members in 1946.

The Commission held its first meeting on 26 April 1941 at Columbia University, New York.8 All members of the Commission attended. Dr. Swift, Hospital of the Rockefeller Institute for Medical Research, New York, also attended as an unofficial consultant. The Commission's first order of business was to recommend appointment of an additional 13 members, 6 "clinicians" and 7 "bacteriologists":

Clinicians
George F. Dick, Chicago, Illinois
Conrad Wesselhoeft, Boston, Massachusetts
J. D. Lyttle, New York City
Champ Lyons, Boston, Massachusetts
John Lockwood, Philadelphia, Pennsylvania
Frank Meleney, New York City

Bacteriologists
Eleanor Bliss, Baltimore, Maryland
Ann Kuttner, Irvington, New York City
C. V. Seastone, Madison, Wisconsin
Harold Lyall, Albany, New York
Julia Coffey, Albany, New York
Harry Rose, New York City
P. L. Boisvert, New Haven, Connecticut

Dr. Swift and Dr. Rebecca C. Lancefield were to serve in an advisory capacity. Inspection of the geographic place of residence of the executive committee and the proposed 13 new members shows almost exclusively a Boston, New Haven, New York, east coast axis. This, perhaps, led to a recommendation for eight additional members, selected on a national basis. The nominated members who accepted appointment were

Arthur Bloomfield, San Francisco, California
Franklin Top, Detroit, Michigan
Wesley Spink, Minneapolis, Minnesota
Lowell Rantz, San Francisco, California
Jean Cook, St. Louis, Missouri
J. M. Sherman, Ithaca, New York
Lawrence Wells Smith, Philadelphia, Pennsylvania

The Commission made an operational classification of streptococcal infections and assigned primary responsibility for specific disease states as follows:

Scarlet fever: Trask
Upper respiratory tract: Keefer
Lower respiratory tract: Tillett
Rheumatic fever: Swift
Nephritis: Seegal

Not included in this list but in their classification were wound infections, anaerobic infections, and secondary streptococcal infections with measles and influenza. The Commission also emphasized close cooperation with other Commissions, particularly those on Epidemiological Survey, Measles, and Influenza. The functions of the Commission were defined as coordination of knowledge and offering of advice concerning hemolytic streptococcal infections, investigation of problems of an epidemiological nature, and assistance in control of epidemics. The Commission recognized the need to identify group A hemolytic streptococci and the specific types within group A if meaningful epidemiological studies were to be carried out. The initial recommendation was to rely primarily on agglutination typing, reserving the M precipitin method for special circumstances. Dr. Swift agreed to make the facilities at the Rockefeller Institute available for the latter method. The proposed budget of the Commission included $27,500 for 12,500 mL of grouping sera and 15,000 mL of typing sera. (The initial total budget for the Commission was $78,000.) According to Rantz,9 the slide agglutination method proved to be of little value in the field and the precipitin method of Drs. Swift, Wilson, and Lancefield10 was used for


266

the epidemiological studies carried out during the war. The identification of hemolytic streptococci by group and/or type and the study of their distributions and association with illness in large groups of persons were now possible for the first time. (The Board, still reflecting the soon to be outmoded state of knowledge, approved the use of typing sera in the field "provided outbreaks of one hundred to two hundred cases of scarlet fever occur." No record has been found that indicates when the Board accepted the importance of streptococcal sore throat without rash.)

Studies carried out by the Commission established the importance of streptococcal respiratory infections without rash both as a leading cause of morbidity, particularly in training camps, and as directly related to subsequent occurrence of rheumatic fever. The frequency with which rheumatic fever followed streptococcal infections (3.6% in studies at Fort Carson, Colorado) and the absence of rheumatic fever following nonstreptococcal respiratory infections were other seminal observations that solidified the group A hemolytic streptococcus-rheumatic fever relationship. Commission studies, particularly those at Fort Carson (see below), laid the groundwork for the studies by the Streptococcal Disease Laboratory at Warren Air Force Base, Cheyenne, Wyoming, beginning in 1949.

The activities of the Commission following its organization were rather limited for almost 2 years. This may owe in part to the limitation of the Commission activities to assistance in control of epidemics and investigation of problems of an epidemiological nature. The hemolytic streptococcus also was not reserved to the Commission. The Board had charged the Commission on Epidemiological Survey to conduct periodic surveys throughout the year to determine the prevalence of hemolytic streptococci and other bacterial diseases transmitted via the respiratory tract. Other Commissions also included the streptococcus in their investigations. The Commission on Cross-Infection in Hospitals, and its successor, the Commission on Air-borne Infections, evaluated the effect of ultraviolet light and propylene glycol vapor on dust-borne bacteria in hospitals and barracks. The Commission on Acute Respiratory Diseases (CARD) conducted field and laboratory studies of hemolytic streptococcal infections at Fort Bragg, North Carolina.

The first field study of the Commission was a 1-week survey by Drs. Trask, Schwentker, and Dawson in November 1941 at Scott and Chanute Fields and Fort Knox, all camps with large numbers of reported cases of rheumatic fever the previous year. As a result of the survey, a study was established at Chanute Field under the direction of Dr. Schwentker. During the period of 18 December 1941 to 25 March 1942, he conducted illness and carrier surveys at Chanute and also at Scott Field, Fort Knox, and Fort Francis E. Warren, Wyoming. A food-borne outbreak of septic sore throat at Camp Stoneman, California was investigated by Drs. Arthur L. Bloomfield and Rantz in July 1942, and a minor epidemic of scarlet fever at Santa Ana Army Air Base, California, in October 1942 was studied by Dr. Rantz. In the spring of 1943, large numbers of cases of rheumatic fever were reported from Fort Francis E. Warren and at Lowry Field, Buckley Field, and Camp Carson in Colorado. Drs. Keefer and Rantz visited these installations and for the first time the magnitude of the problem of streptococcal infection and rheumatic fever in the Army was acknowledged. (There were 18,339 admissions for acute rheumatic fever in the Army between 1942 and 1945, for a rate of 0.72 per year per 1,000 average strength.5) As a result, Dr. Rantz was asked to plan an extensive investigation directed to the natural history and control of the problem.9 The Commission on Air-borne Infections, Dr. O. H. Robertson, Director, was requested to participate with the Commission on Hemolytic Streptococcal Infections in the planning and conduct of the studies.

Camp Carson was selected as the site for the study that began in January 1944 and continued through the spring. Dr. Rantz was appointed Field Director and Dr. Morton Hamburger, Jr., was in charge of all field activities for the Commission on Air-borne Infection. The active members of the Commission on Hemolytic Streptococcal Infections and their technical and secretarial assistants are listed below with the dates on which they began and ended their service at Camp Carson:


267

Dr. Lowell A. Rantz, Field Director
29 November 1943 to 22 May 1944

Miss Loraine Kerr, Technician
30 November 1943 to 17 May 1944

Dr. Wesley W. Spink
1 January 1944 to 15 April 1944

Miss Viola Ferris, Technician
13 December 1943 to 15 May 1944

Dr. Paul J. Boisvert
1 February 1944 to 15 April 1944

Mrs. Helen Halm, Technician
25 March 1944 to 30 June 1944

Miss Elizabeth Randall, Technician
29 November 1943 to 17 May 1944

Mrs. Helen Rantz, Secretary
29 November 1943 to 22 May 1944

Without question, the studies at Camp Carson were the most definitive to that time relative to the relationship between the group A hemolytic streptococcus and rheumatic fever, the natural history of streptococcal infections, the effect of treatment with sulfadiazine and penicillin, and the antibody response to infection. The studies at Camp Carson by Dr. Hamburger complemented the work of Dr. Rantz and provided important information on the microepidemiology of streptococcal infections within barracks. The studies by Drs. Rantz and Hamburger served as models for the later studies at the Streptococcal Disease Laboratory. Dr. Rantz summarized the Camp Carson studies in his unpublished history of the Commission on Hemolytic Streptococcal Infections.9 Excerpts from his history follow:

The acute phase of hemolytic streptococcal respiratory disease has been demonstrated to be of a more variable nature than had been realized previously. Exudative tonsillitis was shown to be a characteristic manifestation of infection by these organisms, but large numbers of patients were seen in whom streptococcal infection was proved by the development of circulating antibodies and in whom no exudate was observed. Edema of the pharyngeal tissues, redness, and particularly anterior cervical adenitis were useful signs in the diagnosis of hemolytic streptococcal respiratory infection. The most important result was the establishment of the fact that rheumatic fever is invariably preceded by an infection with group A hemolytic streptococci.

Antifibrinolysin, antistreptolysin, and various precipitating antibody responses were determined in a large group of men infected by group A hemolytic streptococci. The results of these studies have not yet been completely analyzed but, as a result of this work and of serial Dick testings, it may be stated to have been proved conclusively that there are very great biological differences between various types or strains of these hemolytic streptococci. Thus, certain types failed to induce rash formation in Dick positive individuals. There were also great differences in the frequency and magnitude of the antistreptolysin and antifibrinolysin responses which followed infection by the various types.

Because the rheumatic state was invariably preceded by infection by hemolytic streptococci, and because evidence was obtained during the study that reinfection by new types of such organisms was likely to initiate the pathological process, it seemed reasonable to suppose that some fraction or product of the hemolytic streptococcus which is common to all types should be responsible for the development of these disorders. It also seemed probable that some immunological process was the immediate cause of the late, nonsuppurative complications of streptococcal disease.

The studies of the Commission have served to stress the fact that hemolytic streptococcal infections were much more prevalent in certain parts of the United States than others. This was especially true of the states on the eastern and western slopes of the Rocky Mountains (Wyoming, Colorado, Idaho, Utah). It was also true that the incidence of scarlet fever could not be relied upon as an index of the prevalence of hemolytic streptococcal infection in the adult population of any area. Outbreaks of hemolytic streptococcal infection only occasionally have their origin in food. The precise mode of the spread of these infections is not yet clear. There are reservoirs of streptococci in the dust, in blankets, in bed linen, in the nose and throat and in the air, and intimate contact between infected persons and susceptible individuals is extremely important, but it is not known at present what the most important factors are in the spread of the disease among the living subjects. These are matters of the greatest importance and must continue to receive attention until the commonest mode of spread is ascertained, if outbreaks are to be adequately controlled.


268

It is also plain from the studies of the Commission that if rheumatic fever is to be prevented, hemolytic streptococcal infection must be prevented. Once hemolytic streptococcal infection becomes established there are no clear cut methods available for preventing rheumatic fever and the incidence of the rheumatic state following hemolytic streptococcal infection is far more common than has been fully appreciated in the past. [Rantz had concluded that neither sulfonamide nor penicillin treatment of the acute streptococcal infection prevented subsequent rheumatic fever; his penicillin treatment studies involved relatively small doses of penicillin and a small number of subjects.] It is important that we learn to detect all cases as promptly as possible, so that adequate care may be provided and efforts made to limit the damage caused by the disease. The most urgent studies for the future should be directed toward methods of preventing hemolytic streptococcal infection and determining the manner in which hemolytic streptococci cause the rheumatic state.

Other activities under the auspices of the Commission were rather limited. The support of the laboratory at the Rockefeller Institute as a reference center for grouping and typing of streptococci was critical to the success of the studies at Camp Carson, but these were carried out by the Navy and the Army Air Force. Dr. Paul L. Boisvert at Yale studied erythrogenic toxin production of group A streptococci. Dr. Rantz continued for several years his study of bacteriologic and serum specimens collected at Camp Carson. As mentioned above, both the CARD and the Commission on Air-borne Infections carried out important work on the hemolytic streptococcus. The Navy, under the leadership of Dr. Alvin F. Coburn, made extensive observations on the geographical spread of streptococci and initiated mass chemoprophylaxis programs with sulfonamide that controlled epidemics until sulfonamide resistant strains became prevalent.11 Commander Armine T. Wilson, who later became a charter member of the new Commission on Streptococcal Diseases in 1948, was in charge of the Navy's streptococcal typing laboratory and developed the method for measuring sulfonamide resistance. The Army Air Force also carried out sulfadiazine prophylaxis studies12 and, when sulfonamide resistance appeared, requested The Surgeon General to recommend "to the appropriate committee of the Army Epidemiological Board or to the Committee on Medical Research of the Office of Scientific Research and Development that a clinical study be undertaken to determine the prophylactic effectiveness of oral penicillin against strains of hemolytic streptococci demonstrably resistant to the sulfonamides."13 The Medical Research Board "expressed deep interest" in the proposal and referred it to the Army Epidemiological Board.14

The Board considered the request and made the following recommendation:15

13. Use of Oral Penicillin for Prophylaxis of Streptococcal Infection

In compliance with the request of the Army Medical Research Board the question of the use of oral penicillin for prophylaxis of hemolytic streptococcal infections of the respiratory tract was considered at the Executive Session following earlier discussion at the meeting of Directors of Commissions and members of the Board on 26 April. The proposals contained in the undated letter from The Air Surgeon to The Surgeon General relative to the undertaking of a clinical study to determine the prophylactic effectiveness of oral penicillin against strains of hemolytic streptococci demonstrably resistant to the sulfonamide were discussed at length. In the course of the discussion it was brought out that widespread use of oral penicillin might result in the selection of penicillin resistant strains and that these strains might become the predominant infective organisms in hemolytic streptococci infections. This risk appeared to be so great that it seemed undesirable to undertake a widespread study at this time. On the other hand, as definite information on the value of oral penicillin as a prophylaxis of infection due to sulfonamide resistant streptococci is desired, it was felt that a small well controlled study would be appropriate. The Board did not contemplate setting up such a study by one of its Commissions at this time.

On motion to Dr. Dochez, seconded by Dr. Maxcy, it was voted to submit to The Surgeon General a statement of information and recommendation as indicated above.

This recommendation effectively curtailed studies of penicillin prophylaxis in the military and it was not until 6 years later that studies of penicillin prophylaxis were initiated at Francis E. Warren Air


269

Force Base by the Streptococcal Disease Laboratory16 and at Great Lakes Naval Training Station by the Naval Medical Research Unit (NAMRU-4).17 These studies showed the effectiveness of penicillin in controlling epidemic streptococcal disease without the appearance of penicillin-resistant strains. Mass prophylaxis with penicillin eventually became the cornerstone of rheumatic fever control in the military services as recounted in subsequent sections of this history. One can speculate that if effective penicillin prophylaxis had been demonstrated in 1945 and 1946 there would have been no pressure to create the Streptococcal Disease Laboratory in 1949.

Conspicuous by its absence during the time of the Commission on Hemolytic Streptococcal Infections is any reference to nephritis, except for the first meeting of the Commission when Dr. Seegal was assigned the responsibility for nephritis. The explanation for no mention of nephritis probably lies with the absence of nephritogenic streptococcal strains in the epidemic situations studied during World War II. It is unlikely that epidemics of nephritis would not have been identified even though the paramount interest was rheumatic fever.

The Board, at its annual meeting on 15 and 16 April 1946, reorganized its structure, effective 1 July 1946, and the Commission was not one of the six commissions of the new Board. The CARD subsumed the streptococcus; this Commission also continued to support the work of Dr. Rantz at Stanford University.

COMMISSION ON STREPTOCOCCAL DISEASES—1948 TO 1960
AND COMMISSION ON STREPTOCOCCAL AND STAPHYLOCOCCAL
DISEASES (CSSD)—1960-1973

The Army Epidemiological Board at its meeting in May 1948, authorized the formation of a new Commission on Streptococcal Diseases. Colin M. MacLeod, MD, President of the Board, recommended for Director, Dr. Tillett, who met MacLeod's requirement that the Director "have a thorough knowledge of bacteriology of streptococci as well as the diseases caused by this species."18 The reactivation of the CSSD was initiated by the continued problem of a high incidence of rheumatic fever in the Army camps in the Rocky Mountain area. Although the CARD included streptococcal infections in its charge, the magnitude of the problem was thought to require a new initiative. The Respiratory Disease Commission continued to play an important role in relation to streptococcal infections, however. Its joint sponsorship of the Streptococcal Disease Laboratory, the joint annual meetings of the two Commissions, and the sharing of members and associate members between the two illustrate the close association that existed over the years.

The new CSSD met for the first time in New York City, 26 and 27 February 1949. Dr. Tillett had accepted the directorship of the CSSD, whose members were Drs. Oswald T. Avery, C. Phillip Miller, Rammelkamp, and Wilson; Associate members were Drs. Joseph J. Bunim, Harry Eagle, Hamburger and W. Barry Wood. The purpose of the meeting was "to explore lines of study, either directly or indirectly related to the streptococcal field, that might seem profitable to pursue."19 Invited guests (Drs. David P Earle, Jr., Seegal, McCarty, Swift, G. E. Murphy, Horace Gezon, Miller, Benedict Massell, and Kuttner) led discussions on active immunity to streptococcal infections, clinical and immunological features of rheumatic fever, and penicillin and the hemolytic streptococcus. Dr. Rammelkamp presented the current status of the new Streptococcal Disease Laboratory. Two research projects were approved. Dr. Avery received $8,800 for experimental studies on active immunity to hemolytic streptococci, and Dr. Tillett, $11,400, for studies of "Passive Transfer in Humans of Cutaneous Reactivity to Hemolytic Streptococci and Their Products." The Tillett studies, under the active direction of Dr. Lawrence, were supported annually during the life of the Commission and the successor CSSD. Dr. Lawrence, out of his deep respect for him, always made certain that Dr. Tillett was designated as the contractor.


270

The second meeting of the Commission was held jointly with the CARD in Cleveland, Ohio, on 29 and 30 March 1950. The two funded contracts were continued and one new contract was approved for Dr. Hamburger to study the effect of streptokinase and streptodornase on experimental pneumococcal meningitis in monkeys.

The Commission held a special meeting 6 and 7 November 1950 at the Streptococcal Disease Laboratory, where detailed reports of the Laboratory's research activities were presented. Also at this meeting, the Commission awarded a contract to Dr. Lester O. Krampitz, Western Reserve University, Cleveland, Ohio to study the biosynthesis of streptococcal M protein.

The contract with Dr. Avery ended in 1951, and until 1953 the contracts of Drs. Hamburger, Krampitz, and Tillett were the only work supported directly by the Commission and, of these, only the work of Dr. Krampitz was related directly to the streptococcal problem. A contract was awarded in 1953 to Dr. Floyd Denny for study of type-specific streptococcal antibodies. The only action items of the Commission during this time dealt with the issue of mass prophylaxis of streptococcal infections. Drs. Bunim and Wood were added as members in 1950 and, Dr. Denny, as associate in 1952.

A new era of activity and productivity for the Commission began in 1954 with the appointment of Dr. Rammelkamp as Director. Five new members and seven new associate members were appointed. New members included Drs. Lancefield, Maclyn McCarty, Alan Bernheimer, Wannamaker, and Denny; Tillett and Wilson were reappointed. Associate members were Drs. Samuel S. Barkulis, Albert H. Coons, Melvin H. Kaplan, Krampitz, Chandler A. Stetson, Robert H. Ebert, and Houser.

Dr. Rammelkamp continued as Director until 1968 except for a 2-year period, 1957 to 1959, when he was replaced by Dr. Wilson. Dr. Wannamaker became Director in 1968 and continued in that position until the commission was disbanded in 1973.

The subsequent annual meetings of the Commission had presentations of the highest scientific caliber and were the national forum for clinical, epidemiological, and basic research related to the group A streptococcus. In addition to reports from contractors, invitations were extended to other scientists. In 1957, for example, the Commission sponsored a special symposium on the day following the regular annual meeting. The program of this meeting appears on page 271.

The continued occurrence of epidemic rheumatic fever in the early 1950s resulted in the appointment of an ad hoc Committee of the Commission in October 1953 to make recommendations to the military services for streptococcal prophylaxis programs. Members of the Committee were Drs. Rammelkamp (Chairman), Eagle, Houser, Gene H. Stollerman, Tillett, Wannamaker, and Wilson. The Committee recommended that prophylactic programs of 250,000 units of oral penicillin twice a day for 10 days, or as an alternative, 1.2 million units of benzathine penicillin, be initiated when epidemic streptococcal disease was present. This Committee evolved into the Committee on Prophylaxis of Streptococcal Infections in the Armed Forces (see below), that played a vital role in eventual control of epidemic streptococcal disease in the military. The committee recommendations were formalized in Department of the Army Technical Bulletin, TB Med 259 (NAVMED P-5052-17; AEP 160-5-24), Treatment and Prevention of Streptococcal Disease and its Sequelae.

Acute poststreptococcal nephritis received little attention from the Commission until an epidemic occurred at Bainbridge Naval Training Center, Maryland, in 1951 and 1952. Dr. Rammelkamp investigated this epidemic, which confirmed in his mind that certain types of group A streptococci were nephritogenic. The reports of an unusual clustering of kidney disease in Yugoslavia interested Dr., Rammelkamp, and the Commission supported his studies of Balkan nephropathy. The only other international studies supported by the Commission were penicillin treatment studies of acute rheumatic fever carried out by Dr. Rammelkamp in Chile.

During the mid 1950s, hospital epidemics of staphylococcal infections were common in the United States and created unusual concern. Problems in military hospitals were similar to those reported from civilian hospitals. The Board assigned the responsibility for study of staphylococcal infections to the Commission in 1958. Drs. Rene S. Dubos and David C. Rogers were appointed members and Robert Wise an associate member, in response to the added role of the Commission. Contracts for study of


271

Program

Symposium on Streptococcal Disease
University of Virginia
Charlottsville, Virginia
27 March 1957

1. Study of Prophylaxis of Rheumatic FeverH. Wood

2. Treatment of Rheumatic Fever with Penicillin Effect on Acute Phase of IllnessT. Mortimer

3. Further Studies on Streptococcal Infections in RabbitsR. Glaser

4. Evidence Supporting an Autoimmune Mechanism in the Pathogenesis of Rheumatic FeverM. Kaplan

5. Accessory Factors in Rabbit and Human Blood Involved in the Bactericidal Test for Type-Specific AntibodyG. Stollerman, F. Kantor, and B. Gordon

6. Studies of L Forms of Group A Streptococci for Polysaccharide Production and Some of the ImplicationsJ. Sharp

7. Chemical Basis for the Serological Specificity of Group A CarbohydrateM. McCarty

8. Streptococcal Bacteriophage; A Lytic Factor in Lysates in Addition to the Phage ParticleR. Krause

9. Properties of a Streptococcal Enzyme: Occurrence and Possible SignificanceA. Kellner and A. Bernheimer

10. Survival of Streptococci in LeucocytesA. Wilson and G. Wiley



272

staphylococcal infections and host reactivity were awarded to Leighton E. Cluff and, for staphylococcal virulence studies, to Richard Ekstedt. Drs. Wannamaker and Rammelkamp also added staphylococcal studies to their contracts.

The Board, at its Spring meeting on 16 and 17 May 1960, based on a recommendation by the Commission, redesignated the Commission as the Commission on Streptococcal and Staphylococcal Diseases (CSSD). Dr. Cluff, who had been appointed an associate member in 1959, was made a full member in 1960, replacing Dr. Dubos. Dr. Rogers remained a member of the CSSD through 1968, and Dr. Cluff through 1972. Drs. Wannamaker and Rammelkamp continued their staphylococcal research. Some research was carried out at an interface of streptococcal and staphylococcal infections, impetigo, by Drs. Cluff, Hugh C. Dillon, and Wannamaker. Other studies concerned the effect of staphylococcal products on group A streptococci. The staphylococcal work of the CSSD did not have the central focus that the streptococcal work had, ie, streptococcal sore throat and its sequelae. The latter were problems of great magnitude to the military and drove much of the effort of the CSSD, particularly in the early years.

The CSSD became somewhat eclectic in its membership and contract support during the second half of its 24 years. Gram-positive bacterial infections, in general, and host responses were represented by Drs. Wood, James G. Hirsch, Lewis Thomas, and Paul G. Quie. The last link to the original Commission on Hemolytic Streptococcal Infections ended in 1966 when Dr. Tillett retired from the Commission. The outstanding accomplishment of the CSSD during the latter years was the work of Drs. Wannamaker and Dillon in elucidating the epidemiology of impetigo and associated acute glomerulonephritis.

The last meeting of the CSSD held jointly, as usual, with the CARD, was at WRAIR 8-10 November 1972. The CSSD now was comprised of 13 members and 13 associate members. Dr. Tillett was still a responsible investigator for one of the eight contracts of the CSSD. The program reflected the shift from studies directly related to the military to studies of the biology of the streptococcus and staphylococcus and epidemiological studies in civilian populations, including those in Trinidad and Egypt. Of the 18 papers presented, 9 were by invited guests. The invited guests and members and associate members represented the major centers and individuals in the United States carrying out research on the group A streptococcus and its diseases. This emphasized the premier role the CSSD played in financial and intellectual support of streptococcal research, not only in the United States, but also to the rest of the world through the personal and scientific ties developed by members of the CSSD.

It seems appropriate to include the last paragraph of the last Annual Report by Dr. Wannamaker in its entirety because it demonstrates so well the milieu of the activities of the CSSD:

At the fall meeting of the Commission held jointly with the Commission on Acute Respiratory Diseases on Wednesday, 8 November through Friday, 10 November, 1972, reports of contractors and other scientific reports were heard (see agenda attached). Invited outside speakers included Dr. Karakawa, who reported on an unusual capsular antigen obtained from staphylococcal strains associated with infection in a military hospital; Dr. Judy Falk reported on HLA studies in rheumatic families. The spirit of the Commission was maintained to the end.

The tradition of the CSSD meetings did not end with the last meeting. An ad hoc committee of the CSSD composed of Drs. Richard M. Krause (Chairman), Dillon, Houser, and Wannamaker discussed ways to continue the tradition. The Committee proposed that a "Streptococcal Club" be formed and that an annual scientific session be held in conjunction with the meeting of the Infectious Diseases Society. The first meeting was held in Washington, D.C. on 16 September 1973. The "Club" became the Lancefield Society in 1978. Annual meetings have continued and membership grew from fewer than 50 persons in 1973 to over 150 in 1990.


273

REFERENCES

1. Lancefield, R. C. A serological differentiation of human and other groups of hemolytic streptococci. J. Exp. Med. 1933, 57, 571-595.

2.Griffith, F. The serological classification of Streptococcus pyogenes. J. Hyg. 1934, 34, 542-584.

3. Coburn, A. F. The Factor of Infection in the Rheumatic State. Baltimore, MD: Williams & Wilkins, 1931.

4. Paul, J. R., editor. The Epidemiology of Rheumatic Fever and Some of its Public Health Aspects: 2nd ed. New York: Metropolitan Life Insurance Press, 1943.

5. Rantz, L. A. "Hemolytic streptococcal infections." In: Coates, J. B., Jr., ed. Preventive Medicine in World War II. Vol. IV: Washington, D.C.: Office of The Surgeon General, Department of the Army, 1958, 229-257.

6. The Medical Department of the United States Army in the War. Vol. IX. Washington, D.C.: U.S. Government Printing Office 1928, p. 391.

7. Board for the Investigation and Control of Influenza and Other Diseases in the Army. Report to The Surgeon-General, U.S. Army. 30 June 1941.

8. MinutesMeeting of the Executive Committee of the Commission on Hemolytic Streptococcal Diseases in the Army, 26 April 1941.

9. Rantz, L. A. History of the Commission on Hemolytic Streptococcal Infections. Army Epidemiology Board. Stanhope Bayne-Jones Papers, MS.C 155 in the History of Medicine Division, National Library of Medicine.

10. Swift, H. F., Wilson, A. T., and Lancefield, R. C. Typing group A hemolytic streptococci by M precipitin reactions in capillary pipettes. J. Exp. Med. 1943, 78, 127-133

11. Coburn, A. F., and Young, D. C. The Epidemiology of Hemolytic Streptococcus During World War II in the United States Navy. Baltimore, MD: Williams & Wilkins, 1949.

12. Holbrook, W. P. The Army Air Forces rheumatic fever control program. J. Am. Med. Assoc. 1944, 126, 84-87.

13. Grant, D. N. W., Major General, USA, The Air Surgeon to Commanding General, Army Service Forces, Office of The Surgeon General, Washington 25, D.C. Undated letter.

14. Bayne-Jones, S., Brigadier General, USA, Deputy Chief, Preventive Medicine Service to the Air Surgeon, HQ. Army Air Force. Letter dated 24 April 1945.

15. Blake, F. G., MD, to Dr. Chester S. Keefer. Letter dated 4 May 1945.

16. Wannamaker, L. W., Denny, F. W., Perry, W. D., Rammekamp, C. H., Jr., Eckhardt, G. C., Houser, H. B., and Hahn, E. O. The effect of penicillin prophylaxis on streptococcal disease rates and the carrier state. N. Engl. J. Med. 1953, 249, 1-7.

17. Seal, J. R., Mogabgab, W. J., Friou, G. J., and Banta, J. E. Penicillin prophylaxis of epidemic streptococcal infections I. The epidemic and the effects of prophylaxis on the clinical manifestations of acute streptococcal and non-streptococcal respiratory infections. J. Lab. Clin. Med. 1954, 44, 727-753.

18. MacLeod, C. M., to Members of the Army Epidemiological Board. Letter dated 21 September 1948

19. Annual Report of the Streptococcus Commission, 1949.


274

The Commission on Streptococcal and Staphylococcal Diseases (CSSD), November 1972.

8-10 November 1972

Seated, left to right: Harold B. Houser, Richard M. Krause, Lewis W. Wannamaker (Commission director), Rebecca C. Lancefield, Charles H. Rammelkamp, Jr.

Standing, left to right: Edward A. Mortimer, Jr., Bascom F. Anthony, Emil C. Gotschlich, Kenneth L. Vosti, Gene H. Stollerman, John B. Robbins, Hugh C. Dillon, Jr., Elia M. Ayoub, Emanuel Wolinsky, Paul G. Quie, Robert C. Austrian.


275

THE STREPTOCOCCAL DISEASE LABORATORY

The history of events leading to the establishment of the Streptococcal Disease Laboratoryhenceforth called the Strep Labbegan in the late 1940s, probably sometime during 1947 or early 1948. At that time, very little was known about the treatment of streptococcal infections, and nothing was known about the prevention of rheumatic fever by treating streptococcal infections. As already mentioned in the earlier history of the CSSD, it had been demonstrated during World War II that sulfonamide treatment of streptococcal infections had very little effect on the course of the acute disease and did not prevent the subsequent occurrence of rheumatic fever.

When the Strep Lab was opened in January 1949, the effect of treatment with the newer antimicrobials on clinical disease and the prevention of rheumatic fever was largely unknown. The decision was made at that time that the use of untreated controls was not only ethical, it was scientifically necessary if these issues were to be decided conclusively. Several years after the results of the studies done at the Strep Lab appeared in the scientific literature, there was criticism of the use of untreated patients as controls in many of the early studies. This criticism proved to be an annoying problem for several months, but no serious after effects occurred. The authors decided that it would be appropriate to clarify at this stage of this history the ethical issues raised in the studies carried out by the Strep Lab so that the readers would not be confused by this issue. After more than 40 years since these studies began, the authors of this report still feel strongly that our studies were ethically warranted and in good taste. It is our hope that the readers of this report in the 1990s will review this report of the activities of the Strep Lab in the light of this observation.

Background of Formation

The first mention of renewed interest in special studies on streptococcal infections and rheumatic fever in the Armed Services appeared in the AFEB Annual Report of 17 April 1947 to 1 April 1948. Under the general heading of "Field Trips" is a report entitled "Study of a reported outbreak of streptococcal infections at Lowry Field and at Fort Francis E. Warren," which was carried out between 14 and 17 February 1948 by Drs. Rammelkamp, and William S. Jordan, Jr. The report described in detail the problem at Lowry Field and added a short paragraph to the effect that the problem was similar at Fort Warren. The final section of this report is reproduced below because it describes very well the current thinking that set the basis for the establishment of the Strep Lab and its relationship to Western Reserve University (now Case Western Reserve University):

Proposal for a continuous study of streptococcal infection. Little detailed information is available regarding the pathogenicity of various types of group A streptococci. It seems entirely possible that certain biological or chemical characteristics of specific types of streptococci may be of paramount importance. Thus a clue as to the substance or substances which are responsible for exudate, scarlet fever, rheumatic fever, pneumonia or empyema may be obtained from a long term study of the relation of the specific type to the disease process. Lowry Field would seem to be an ideal location for such a study. In the past, streptococcal infections have been prevalent in this area, and furthermore, some data concerning the types of streptococci in preceding years are available.

The proposed investigation would include epidemiological, clinical and laboratory studies. An attempt would be made to determine the cause for the high rates of streptococcal infections in the population. Records of new recruits would be maintained. At regular intervals culture surveys would be made on the normal population. All patients entering the hospital would be cultured, and those exhibiting beta-hemolytic streptococci would be bled for acute and convalescent serum specimens. Brief clinical records would be maintained on all patients harboring beta-hemolytic streptococci and their clinical manifestations classified. Streptococci isolated would be grouped and typed, and all group A strains forwarded to the laboratories at Western Reserve University for further study.


276

It is estimated that the personnel required for this project would include two physicians, two enlisted men and three technicians at Lowry Field. Additional technical help would be required at Western Reserve University.

The next mention of this project appears in the AFEB Quarterly Report ending 31 December 1948, with the following short paragraph:

A study of streptococcal infections has been instituted at Fort Francis E. Warren, under the joint auspices of the Commission on Acute Respiratory Diseases and the Commission on Streptococcal Diseases. Dr. Charles H. Rammelkamp, Jr. has been appointed as field director of this study. Alterations are being made in a ward building of the Post hospital to house the laboratory which will be ready for operation during January. Three army officers, Lts. William R. Brink, Floyd Denny and Lewis W. Wannamaker, have completed a training period at Western Reserve University and have been transferred to Fort Warren. Training of the technical staff has been started.

The AFEB Annual Report of 1 May 1948 to 1 April 1949 clarifies, at least in part, the choice of Fort Warren as the site for the Strep Lab, instead of Lowry Field as suggested first. It outlines briefly the events leading to the establishment of the Lab and describes the initial staff and early studies. This part of the Report is reproduced in its entirety because it gives the background for the laboratory activities, which are to follow:

Study of streptococcal infections at Fort Warren

In October, 1948, a survey of Fort Francis E. Warren, Lowry Field, and Camp Carson was made by Drs. MacLeod, Tillett, Dingle, Rammelkamp and Colonels Patton and Pleuncke, Major Kossuth, and Lt. Brink. It was decided that Fort Francis E. Warren offered an ideal location for a long term study of streptococcal infections and rheumatic fever because of the high incidence of these diseases and the extreme interest of Col. J.C.B. Elliott, Commanding Officer, and Col. J.K. Cullen, Post Surgeon.

Plans for the laboratory and lists of equipment were prepared and submitted to Col. J.C.B. Elliott by 1 December and by 24 January 1949 the laboratory, which is a renovated W-1 hospital ward, was sufficiently completed so that the study was instituted.

The staff consists of Dr. Edward Custer, Lts. Brink, Denny and Wannamaker, 4 technicians, a secretary and 2 dieners. In addition, 2 enlisted men were assigned to the laboratory. The 3 medical corps officers received preliminary training in the Department of Preventive Medicine at Western Reserve University for a period of approximately 6 months.

The various studies now being conducted at Fort Francis E. Warren may be divided into 3 broad categories: Epidemiological, Clinical and Laboratory.

It seems appropriate to elaborate on the events leading to the establishment of the Strep Lab at Fort Warren. Accordingly, three documents will be reproduced in their entirety below and a fourth will be presented in Appendix 2. The first document is a letter from Dr. MacLeod, President of the AFEB, to Colonel Thomas E. Patton, MC, Chief of the Preventive Medicine Division, Office of The Surgeon General, Department of the Army, requesting officially the establishment of the Lab:

Dear Colonel Patton

I am enclosing six copies of a brief report of our recent trip to Camp Carson, Lowry Field and Fort Francis E. Warren, which indicates, I believe, the reasons for choosing Fort Warren as the site for the study of streptococcal diseases and rheumatic fever in the Rocky Mountain area.


277

Following discussion with Dr. Tillett, Dr. Dingle and Dr. Rammelkamp, Major Kossuth and yourself, the consensus was that Fort Warren is the most suitable of the three posts visited. I wish, therefore, to make formal recommendation that the study be located at Fort Warren.

It is recommended further that the study be set up under the joint auspices of the Commission on Streptococcal Diseases and the Commission on Acute Respiratory Infections, and that the contract be drawn up with Western Reserve University. Details regarding the latter will be supplied by Dr. Dingle, and will require clearance by the Army. Epidemiological Board. In the opinion of both Dr. Dingle and myself, it is important that a letter of authority, originating on a high military level, be provided. Our respective experiences during World Ward II at Fort Bragg, N.C. and Sioux Falls Air Base, S.D., have emphasized the importance of such an authorization if a long term study is to be carried out successfully. Copies of these letters of authorization, are available, I believe in the files in Washington. That relating to Fort Bragg should be in the files of the A.E.B.; that relating to Sioux Falls in the Air Surgeon's Office.

It is our hope that this study can be got underway very promptly. Drs. Dingle and Rammelkamp will be responsible for the design and equipment of the laboratory and as soon as final Army and Air Force approval are obtained, sketches will be forwarded to Col. Elliott at Fort Warren, so that the appropriate alterations cart be begun. It is our hope that the study will be running smoothly by the time the high epidemicity of streptococcal diseases can be expected.

Sincerely yours,

Colin H. MacLeod, M.D., President

The report to The Surgeon General, Department of the Army (through Preventive Medicine Division), subject: Survey of sites for location of study of streptococcal diseases and rheumatic fever in the Rocky Mountain Area is in Appendix 2. Two supporting documents from Colonel John K. Cullen, MC Surgeon, Station Hospital Fort Francis E. Warren, and Colonel John C.B. Elliott Commanding Officer, Fort Warren, are as follows:

MEMORANDUM TO: Streptococcal Disease Commission
THRU: Commanding Officer
Fort Francis E. Warren
and
3450th Technical Training Wing
Fort Francis E. Warren, Wyoming

SUBJECT: Factors Pertinent to the Consideration of Establishing
a Research Laboratory at this Station.

1. Inasmuch as I will be unable to be present during your visit to this station, I wish to present the following resume of factors which are believed to be pertinent to the consideration of the possibility of establishing a laboratory at this station for basic research in streptococcal infections and respiratory disease:

a. The mission of this station is to train Air Force personnel in various administrative and technical specialties. This involves a continuous flow of personnel through this Base throughout the year. At the present time the military strength at this Base is approximately 9,000 of which approximately 5,200 are "Pipeline" personnel. The remainder are permanent party personnel or members of T/O and E organizations. The average turn-over of student personnel is 3-4 times per year. Thus, it can be seen that with the present personnel set-up the total number of individuals who might be exposed during the course of a year to whatever diseases there may be in this locality will approximate 20,000. If the strength of this Base is raised to approximately 12,500, as is contemplated (with approximately 8,000 of these being "Pipeline"


278

personnel), the total number of individuals passing through this Base in the course of a year will then be approximately 28,000.

b. This station is separated by natural geographic features into two areas: The permanent party area which is north of Crow Creek, and the student area which is south of Crow Creek. The housing in the permanent party area is, for the most part, composed of permanent type brick structures, while that in the school area is entirely cantonment type in nature.

c. There is available in the Station Hospital area readily convertible space for the housing of any laboratory facilities which it may be desired to set up. This space, which is in a standard type W-1 ward, can be readily converted to laboratory needs with a minimum expenditure of money and labor. It is immediately adjacent to the present hospital laboratory.

d. Because of the presence at this station of such specialist schools as the carpenters' school, the electricians' school, the plumbing school and the sheet metal school, it will be possible to carry out such alterations and/or construction as may be required, either initially or later on, at a minimum cost and without delay.

e. A factor which is of prime importance to the successful accomplishment of the mission of such a group as is contemplated is the matter of cooperation and support of the Base Commander. Colonel Elliott, the Commanding Officer of this station, has long been personally interested in the matters of rheumatic fever and streptococcal infections and can be depended upon to give 100% moral and logistic support to any laboratory group which is sent to this station.

f. Another factor which would have a material effect on the work of any research group is the attitude of the medical officers at the station. The group of young medical officers now stationed here are far and away the best group of such young doctors I have had the pleasure of working with during my entire career in the army. Although young and relatively inexperienced, they are all enthusiastic, hardworking, cooperative and have plenty of initiative. This latter quality is illustrated by the proposed program of recording observations in cases of rheumatic fever which have been set up by the medical service in conjunction with Dr. Flett, the medical consultant.

2. Without having any personal knowledge of the situations at either Lowry Air Force Base or Camp Carson, I feel confident that the support which will be given to this research group, if it is established at Fort Warren, cannot be exceeded in any respect at either of the other two stations.

"A True Copy" John K. Cullen
Colonel, Medical Corps
Surgeon

F.M. Lunnie
Captain, MSC
Hospital Adjutant


279

1st Ind

CO/JCBE/mjm
7 Oct 1948

Headquarters Fort F.E. Warren and 3450th Technical Training Wing, Fort F.E. Warren, Wyoming

MEMORANDUM TO: Streptococcal Disease Commission

1. My attitude is that this problem of upper respiratory disease and rheumatic fever must be solved by preventive means - not run away from. There is much conflicting information on this subject, but it has not been proved to my satisfaction that the enlisted man who is susceptible to these infections will not still be so after one, two, or ten years of service if he enters a violent climate. If this is the case, it is better to eliminate this man early, before we have trained and shipped him to a theatre, only to lose his skill in a casualty. Our approach to this problem must be the same as that of malariato combat it preventively wherever it may be encountered with the simplest possible means. I also feel that any field problem must be solved by fact finding at that source, not by remote control suppositions. It is for this reason that I am so anxious to have the technicians work with us here.

2. We have here a climate subject to violent and deceptive changes. U.R.I.s starts when the heat is turned on in barracks and appear to follow in intensity the periods of daily maximum changes in temperature. Sixty-seven (67) percent of the time our weather is clear, and on a cold winter day when the wind is low in this dry climate, it is possible to be relatively comfortable. However, when the sun goes down, going out in the same clothing is a severe shock to the resistance of the body which is trying to pump a constant 98.6° temperature, and furthermore the altitude is no great assistance to the heart in this matter. This seems to be the crux of the matter. Of course our type barracks are fine incubators for the bugs who jump on the body of weakened resistance.

3. On the other hand our men must be trained to function efficiently in all climates and altitudes as we must be able to produce more with less men to survive the next conflict. Our engineering schools must be trained to function efficiently throughout the winter by use of proper clothing and clothing discipline if we are to meet this requirement. We work outside throughout the entire winter with some of our schools here, a more violent training requirement than will be found at either Lowry or Carson. Furthermore, we are probably the largest with the largest turnover. I think we are in the area where most can be learned and I am determined to solve this problem if it is humanly possible.

4. For the above reasons, I will throw every resource I can to the assistance of this unit if it will come in here and work with us. What Colonel Cullen says, goes for meI would like to have you define what you need before you leave here.

/s/ John C.B. Elliott
/t/ Colonel, USAF
Commanding


280

These documents are important for several reasons. They indicate the choice of Fort Warren as the Strep Lab site, recommend that the Lab be set up under the joint auspices of the Commission on Streptococcal Diseases and the CARD, and request a letter of authority, "originating on a high military level." (A copy of this letter has not been found and it is not known if such a letter ever existed.) They also indicate the strong endorsement of and support for the Lab at Fort Warren. These documents were dated from 5 October through 19 October 1948. Dr. Rammelkamp was named field director, as indicated in the AFEB Quarterly Report ending 31 December 1948.

The Strep Lab began to function officially on 24 January 1949. The following sections will describe more fully the construction of the Lab, its staffing, and the professional personnel participating in the studies. The accomplishments of the Lab will be described in a section on the clinical aspects of streptococcal infections and rheumatic fever and a section on the epidemiology of streptococcal infections. Brief mention will be made of specific laboratory observations, but laboratory studies will more often be described in conjunction with the clinical and epidemiology studies. Short sections will be devoted to the receipt of the Lasker Award by the Strep Lab, its closing in 1955, and a reunion held in Cheyenne in 1974. A complete list of publications generated from studies at the Strep Lab will complete the chapter.

The Laboratory

The decision was made to house the laboratory primarily in a W-1 one-story wooden hospital ward that was converted into adequate laboratory space. One such building formed the main laboratory; a few offices and space for some clinical studies were also available in an adjacent ward building. The laboratory was located at what was then Fort Francis E. Warren on the outskirts of Cheyenne, Wyoming. The surrounding country was extremely flat, almost desert-like in its lack of vegetation, and the laboratory overlooked nothing but this desolate plain. The small initial nucleus comprised of Drs. Rammelkamp, William Brink, Denny, and Wannamaker, at that time in the Department of Preventive Medicine at Western Reserve University School of Medicine in Cleveland, Ohio, designed the renovations to be made in the W-1 ward. Because Fort Francis E. Warren at that time was a technical training base and had a carpenters' school, students did the construction work. The results were entirely adequate, although not luxurious, but the Cleveland group in their naïveté had omitted the inclusion of any drawer space in the entire laboratory. As it turned out we learned very quickly that a very efficient laboratory could be run without drawers.

It is appropriate that the reader be introduced to the climate in southeastern Wyoming. The army base, Fort Francis E. Warren, subsequently changed to Warren Air Force Base, is located on the outskirts of Cheyenne, Wyoming, at an altitude of slightly over 6,000 feet. This dictated that the weather was never very warm and temperatures of -20°F were common, -25° occasional, and -35° witnessed at least on one occasion by the authors. The air was extremely dry, the wind at times during the winter was fierce, being recorded at above 90 mph on several occasions. The humidity was low.

Administration/Personnel

The technical staff of the laboratory was an interesting assortment of largely untrained individuals. Mary Riner, the daughter of a local supreme court judge and a college graduate in science, although not trained as a laboratory technician, was made the chief technician. This was an extremely fortunate choice because she was the mainstay of the technical staff for several years. Other local civilian and Air Force and Army individuals served as laboratory technicians; most of their training took place after joining the laboratory. The laboratory diener, John Datillo, a Chicago cab driver, was an interesting and colorful addition to the staff. The laboratory was furnished with an official car and a series of drivers. Master Sargent Marple joined the laboratory when it opened and remained the administrator and coordinator for the laboratory until its closure. His remarkable talents and dedication were indicated by


281

promotion to major and his nomination for a Legion of Merit Award during the last years of the laboratory.

The professional personnel of the Strep Lab during its years of existence are listed alphabetically in the table below; all were members of the Armed Forces, except Drs. Edward A. Custer and Willard C. Schmidt and the student research fellows from Western Reserve University. Special recognition should be given to Dr. Rammelkamp, who was its only director. He was a superb scientist who lead his staff throughout the many studies that will be described subsequently. One of his most notable characteristics was his generosity toward young associates. He was instrumental in the scientific and academic development of many of us who remember him with exceptional fondness. He was a workaholic in the true sense of the word and his consumption of Coca Cola and cigarettes was tremendous. He is remembered with great fondness by those of us whom he termed his ""birds."" For those whom he regarded with less affection he used the term "drut."

Because Dr. Rammelkamp did not relinquish his duties in the Departments of Preventive Medicine and Internal Medicine at the Western Reserve University School of Medicine, he appointed a series of assistant directors to help him administer the Strep Lab, as listed below:

Professional Staff

William R. Brink

1948-1949

Loring L. Brock

1951-1953

Frank J. Catanzaro, Sr. (Assistant Director 1953-1954)

1952-1954

Robert Chamovitz

1953-1954

Ernest J. Clark*

1951

Edward A. Custer

1949

Floyd W. Denny, Jr. (Assistant Director 1949-1951)

1948-1951

George C. Eckhardt

1950-1952

Edward O. Hahn

1949-1952

Harold B. Houser

1949-1952

Robert J. Kohen

1953

Richard M. Krause

1950-1951

Earl C. Marple§

1949-1955

Alton J. Morris

1953-1955

William D. Perry

1951-1953

Charles H. Rammelkamp, Jr., Director

1948-1955

Willard C. Schmidt

1954-1955

Alan C. Siegel

1952-1953

Chandler A. Stetson (Assistant Director 1952-1953)

1951-1953

Bertrand L. Stolzer

1951-1953

Daniel Stowens

1950-1951

Lewis W. Wannamaker (Assistant Director 1951-1952)

1948-1952

Richard D. Yoder

1949

*Member of hospital staff; assisted in rheumatic fever treatment studies.
Assisted in nephritis studies at Bainbridge Naval Training Station.
Medical student at Western Reserve University.
§Laboratory administrator.


282

MAJOR SCIENTIFIC ACCOMPLISHMENTS

Clinical Studies

Prevention of Acute Rheumatic Fever by Treating Acute Streptococcal Respiratory Infections

Clearly, the most outstanding accomplishment of the Strep Lab staff was the observation that the treatment of an acute streptococcal respiratory infection with an effective antimicrobial prevented the occurrence of rheumatic fever in the great majority of cases. This was reported first in the fall of 1950 before the Midwestern Section of the American Federation for Clinical Research. The report was received without great fanfare and it is of possible historical interest that the Central Society for Clinical Investigation had not accepted the article for presentation. In any event, these seminal observations appeared in the Journal of the American Medical Association in 1950 in an article entitled "The prevention of rheumatic fever by treatment of the preceding streptococcic [sic] infection." Because of its importance, this article is reproduced in its entirety in Appendix 6. In 1985 it was recognized as a "Landmark Article" by the Journal of the American Medical Association and was reproduced in the 26 July issue of that journal. It was accompanied by a commentary (Appendix 6) by Dr. Alan L. Bisno who emphasized its subsequent importance in reducing the occurrence of rheumatic heart disease.

These studies, the brainchild of Dr. Rammelkamp, were unusual in their simplicity and have been recognized as models for prospective, well-controlled clinical trials. Following the initial observation that the treatment of streptococcal infections with various doses of depot penicillin prevented the occurrence of acute rheumatic fever, Dr. Rammelkamp directed the Strep Lab staff in a series of studies to clarify the mechanism of prevention and the details of proper management of acute infections. The following sections describe in some detail these studies.

Effect of procaine penicillin G (suspended in peanut oil containing 2% aluminum monostearate). In this, the first study, airmen with exudative tonsillitis or pharyngitis were observed in the hospital between 24 January and 1 July 1949; 798 patients with even serial numbers received penicillin therapy and 804 with odd serial numbers served as controls. Penicillin was given as soon after admission as possible in two schedules: 278 patients received 300,000 units of penicillin on admission to the study and again in 72 hours; 520 patients received 300,000 units of penicillin on admission and again in 48 hours and 600,000 units 96 hours after the initial dose. Rheumatic fever developed in 2 treated patients and 17 untreated (P=.0006). Penicillin treatment greatly reduced the carriage of streptococci and the antistreptolysin O response was blunted. These preliminary studies set the stage for other studies that confirmed these results and clarified further the details of the treatment of patients with streptococcal pharyngitis and the prevention of rheumatic fever.

These early studies were extended and the final results published in the American Journal of Medicine in 1951. The basic format of the study was unchanged. The table at the top of page 283 shows the numbers of patients in the treated and untreated groups and the dosage schedules of penicillin.

Definite rheumatic fever developed within 45 days after the streptococcal infection in 28 untreated patients and 2 treated patients. As in the earlier studies, the carriage of streptococci was reduced and the antistreptolysin O titers blunted in the treated patients.

Effect of chlortetracycline. Between 23 February 1950 and 9 March 1951, 2,004 patients with exudative tonsillitis/pharyngitis were studied; 1,009 received 8 to 11 g chlortetracycline over a period of 4 to 6 days, and 1,035 served as controls. Within 35 days after the onset of infection, definite rheumatic fever occurred in 5 treated patients and 20 controls; within 45 days, there were 11 cases in the treated group and 24 in the untreated group. Thus, chlortetracycline, although effective in reducing the occurrence of


283

Study Format


Regimen


Treated


Untreated


Totals

I 300,000 units stat
300,000 units 48 hours
600,000 units 96 hours



634



582

1216

II 300,000 units stat
300,000 units 72 hours


254


288


542

III 600,000 units stat

290

292


582


Totals

1178

1162


2340

rheumatic fever, was not as effective as penicillin in the previous studies. This reduced effectiveness was mirrored in less effectiveness in eradication of the streptococcus from the throat and in reducing the antistreptolysin O response.

Effect of oxytetracycline. Between 10 March 1951 and 4 January 1953, 1,409 patients with exudative tonsillitis/pharyngitis were studied; 713 received 10 to 10.5 g oxytetracycline over a 5-day period and 696 served as untreated controls. Definite rheumatic fever occurred in 12 patients in the control group and in 5 in the treated group. As with chlorotetracycline, there was less reduction in the carriage of streptococci and antistreptolysin O in treated patients than was seen with penicillin treatment.

Effect of benzathine penicillin G (Bicillin). From 4 January to 9 July 1953, 257 patients with exudative pharyngitis were treated with 600,000 to 1,200,000 units of injectable benzathine penicillin at the time of hospital admission; 109 patients were untreated and acted as controls. The effect on the eradication of the carriage of streptococci was dramatic and the reduction of antistreptolysin O formation was marked. Rheumatic fever occurred in 2 control patients and in none of the treated.

Effect of sulfadiazine. Between April 1953 and February 1954, 291 patients received sulfadiazine (2 g initially, followed by 1 g every 6 hours for 5 days), and 264 patients served as untreated controls. Sulfadiazine did not eradicate the streptococcus, and rheumatic fever was not prevented in the treated group.

Factors responsible for the failure to prevent rheumatic fever in treated patients. Experience of treatment of 5,198 cases of group A streptococcus pharyngitis showed that rheumatic fever developed in 76. The primary cause of failure to prevent rheumatic fever was that the infecting organism was not eliminated by treatment. Other factors that may have accounted for some therapeutic failure were the acquisition of a new infection after therapy and, of less importance, a history of previous rheumatic fever or recent streptococcal infection.

Effect of delayed treatment on the occurrence of rheumatic fever. In studies on the role of the streptococcus in the pathogenesis of rheumatic fever, it was shown that rheumatic fever was prevented when penicillin therapy was delayed until 9 days after the onset of the streptococcal infection. Rheumatic fever occurred in 3 of 420 patients receiving delayed treatment and in 20 of 450 who were not treated or received sulfadiazine at the onset of illness. Delayed treatment resulted in elimination of the infecting streptococcus, but the development of antistreptolysin O was not significantly affected. In the sulfadiazine-treated patients, the streptococcus was not eradicated, but the antistreptolysin O response was blunted. In contrast, the control patients developed a full antistreptolysin O response and continued to carry the infecting streptococcus. These studies were interpreted to demonstrate that the persistence of the infecting streptococcus in the host's pharynx was more important in the pathogenesis of rheumatic fever than was the development of humoral antibody. A clear spinoff of these results, however, was the demonstration that the clinician caring for a patient with pharyngitis was not obligated to rush the administration of an antistreptococcal drug but could still prevent rheumatic fever by taking sufficient time to establish accurately the diagnosis of a streptococcal infection before treating.

Effect of the Duration of Antibiotic Therapy on the Eradication of the Infecting Streptococcus and on the Occurrence of Rheumatic Fever. The studies described above indicated that it was important to eradicate


284

the streptococcus from infected patients to effectively prevent rheumatic fever. These studies also indicated that the 5 to 7 days of treatment used in these studies were not always effective in eliminating the streptococcus. Studies were done using oxytetracycline, penicillin, erythromycin, and sulfisoxazole administered in regimens of 5, 8, and 10 days. The convalescent carrier rates were poorest in the 5-day regimens, better in the 8-day regimens, and best of all if penicillin was given for 10 days. The numbers of patients in these studies were too small to evaluate the effectiveness of these drugs in preventing rheumatic fever.

All of these studies provided the information for the modern management of the prevention of rheumatic fever by treating acute streptococcal infections. The various important points established by these studies are as follows.

• Penicillin G is the drug of choice for treating patients with streptococcal pharyngitis.
• Other antimicrobials tested were not as effective as penicillin, though they did prevent some cases of rheumatic fever.
• Sulfonamides were not effective in eradicating the streptococcus or preventing rheumatic fever.
• The effectiveness of an antibiotic in preventing rheumatic fever was related to its effectiveness in eradicating the streptococcus from the pharynx.
• Treatment for 10 days was more effective than shorter regimens in eradicating the streptococcus.
• Antibiotic therapy delayed as long as 9 days after onset of acute pharyngitis was effective in eradicating the streptococcus from the throat and in preventing rheumatic fever.

Effect of Antibiotic Treatment on Electrocardiographic Changes Associated with Acute Rheumatic Fever and Subsequent Valvular Disease

Shortly after the Journal of the American Medical Association publication of the rheumatic fever prevention article, Dr. Lewis Weinstein and colleagues, Boston University, published an uncontrolled penicillin treatment study of scarlet fever in children.20 Their conclusion that penicillin suppressed clinical symptoms of acute rheumatic fever (ARF) but did not prevent carditis gave Dr. Rammelkamp and the personnel of the Strep Lab great concern. The response of the Strep Lab personified one of Dr. Rammelkamp's scientific characteristicsdon't argue, but design a study to answer the question. The study designed was an ambitious one that resulted in the collection between November 1950 and March 1952 of approximately 8,000 electrocardiograms (ECGs) from 1,304 airman with treated (729) or untreated (575) streptococcal sore throat. Each man had six ECGs between day 3 and day 21 after onset of sore throat. Dr. Edward O. Hahn had the primary responsibility for carrying out the study, including the reading of the ECGs. Treatment was either with a tetracycline (196 men) or by one of three schedules of penicillin (533 men). There were no differences in the results among the various treatment schedules. Treatment significantly reduced the proportion with PR interval prolongation by 71% and with any abnormality by 56%. PR abnormality after onset of sore throat appeared on or before the 10th day in 65% to 70% of both the treated and the untreated groups. Definite ARF occurred in 8 (1.1%) and possible ARF in 2 (0.3%) of the treated group, whereas in the control group there were 25 (4.3%) with definite and 4 (0.7%) with possible ARF, a reduction in ARF of 73% by treatment.

These studies established that antibiotic treatment of streptococcal sore throat significantly reduced not only the occurrence of symptomatic ARF but also the frequency of ECG changes pathognomonic for ARF, and thus, presumably for valvulitis and subsequent valvular disease. The data are not inconsistent, however, with a possible suppression of clinical symptoms of ARF in a small proportion of patients. The story did not end here, however.

In 1955, Weinstein et al.21 published a follow-up of the patients and reported that 8 of 10 children with only ECG changes 7 years previously now had rheumatic valvular disease. This report convinced


285

Dr. Rammelkamp that a long-term follow-up of treated and untreated airmen was necessary to establish finally that treatment prevented not only ARF but also chronic valvular disease.

In 1967, Dr. Rammelkamp initiated a follow-up of 130 airmen from the ECG study who had either ECG changes only or clinical ARE This proved to be a frustrating undertaking despite the outstanding cooperation of the Veterans Administration. Some records had been destroyed by fire, some men could not be traced, and some men refused examination. Nevertheless, 90 subjects, 31 treated and 59 untreated, eventually were examined by Drs. Louis Rakita and Robert Bahler, colleagues of Dr. Rammelkamp at Metropolitan General Hospital. The follow-up, 19 to 20 years after the observed clinical state, revealed one person with rheumatic heart disease out of 31 treated and 5 with rheumatic heart disease out of 59 untreated. Although this difference was not statistically significant, the relative risk of 0.41 if treated was of the same order of magnitude as for ECG abnormalities, 0.44.

None of the studies described in this section was published in a peer-reviewed journal. Dr. Rammelkamp was saving them for something to do when he retired. He was working diligently on what was to be a series of five papers, at the time of his death in 1981. Sufficient analysis had been completed by that time so that he was secure in his knowledge that antibiotic treatment of streptococcal sore throat did indeed significantly reduce the occurrence of subsequent rheumatic heart disease.

20. Weinstein, L., Bachrach, L., and Boyer, N. H. Observation on the development of rheumatic fever and glomerulonephritis in cases of scarlet fever treated with penicillin. N. Engl. J. Med. 1950, 242, 1002-1010

21. Weinstein, L., Boyer, N. H., and Goldfield, M. Rheumatic heart disease in scarlet-fever patients treated with penicillin. N. Engl. J. Med. 1955, 253, 1-7.

The Effect of the Treatment on the Natural Course of Streptococcal Pharyngitis

Effect of chlortetracycline and penicillin. The effects of chlortetracycline and penicillin were evaluated in a controlled study of 495 patients with streptococcal tonsillitis and pharyngitis. Chlortetracycline was slightly more effective than penicillin in lowering the fever and causing rapid subsidence of symptoms. Both drugs exhibited slight action on abnormal physical signs. They were equally effective in inhibiting antibody formation. Penicillin usually eradicated the carrier state, whereas chlortetracycline failed to influence the incidence of convalescent carriers.

Effect of cortisone. Eighty-seven treated and 87 control patients were studied to determine the effect of cortisone on the clinical and immunological response to streptococcal respiratory infections. Cortisone exerted no effect on the symptoms or physical signs of patients. Patients who received cortisone exhibited fever for a longer period of time than the control patients. There was no significant effect on antistreptolysin O titers. The numbers of patients studied were too small to evaluate the occurrence of rheumatic fever.

It is of historical interest that these studies, showing clearly the effect of antibiotics on the course of streptococcal respiratory infections in well-controlled studies, were either ignored or interpreted incorrectly as showing no effect. Several studies done in the 1980s showing the same results were interpreted as demonstrating for the first time the beneficial clinical effects of treating patients with streptococcal tonsillitis and pharyngitis.

Relationship of Serological Type of Streptococcus to Acute Disease and Complications

As far as it can be ascertained, no systematic and comprehensive study of this phenomenon was made; certainly there were no published articles on the subject. In the annual report for 1949 and 1950, the following study was summarized:


286

Fifty-four patients with type 5 streptococcal infections, 49 with type 14 infections and 37 with type 24 infections, all untreated, were seen daily and their symptoms and signs recorded. Patients with type 24 infections were associated with a mild disease and recovery occurred more rapidly than observed in infections with types 5 and 14. In studies to be described in a later section on type-specific or anti-M protein antibodies it was shown that specific antibodies to types 5, 6, 14 and 24 differed markedly in the time of appearance while antistreptolysin O responses occurred at approximately the same time. Analysis of the occurrence of rheumatic fever following infections with various types of streptococci at Warren Air Force Base showed a rather constant attack rate of 2-3% in untreated patients. This was in marked contrast to the great propensity of type 12 streptococci to be associated with glomerulonephritis.

Susceptibility to Acute Respiratory Infections, Streptococcal Infections, and Rheumatic Fever

One of the original aims of setting up the Strep Lab was to study the reasons why respiratory infections, streptococcal infections, and rheumatic fever occurred so frequently in the mountain areas of the western part of the United States The first annual report from the Laboratory, 1949 to 1950, contains a short section on this subject as follows:

All men assigned to Francis E. Warren are interviewed to determine the effect, if any, that the state of residence, history of tonsillectomy, personal and family history of rheumatic fever have on the subsequent attack rates of various respiratory infections and rheumatic fever.

We can find no records, nor are there published articles, regarding any studies on the susceptibility to acute nonstreptococcal respiratory infections. A variety of studies was done to elucidate susceptibility to streptococcal infections and rheumatic fever. Factors important in the epidemiology of the spread of streptococci have been included in the section on epidemiology, as has the lack of effect of tonsillectomy and adenoidectomy. Aside from these observations, no further studies were done on susceptibility to the development of streptococcal infections. Observations on 122 airmen with a positive family history of rheumatic fever and 1,359 with a negative history showed similar attack rates for rheumatic fever. In contrast, airmen with a personal history of rheumatic fever, or who had rheumatic heart disease, had attack rates up to 10 times those recorded for airmen with a negative personal history. Extensive studies were done on the relationship of the formation of streptococcal antibodies to the development of rheumatic fever. In studies on patients with untreated streptococcal infections, 0.8% (7 of 856) with rises of 0 to 120 units of antistreptolysin O developed rheumatic fever, 3.6% (19 of 553) with rises of 121 to 250 units, and 5.5% (30 of 545) with rises over 250 units developed acute rheumatic fever. No relationship was found between initial levels of antistreptolysin O and subsequent attacks of rheumatic fever. Studies done in collaboration with Dr. Wilson measuring the response of patients with rheumatic fever to influenza and cholera antigens showed no differences when compared to normal controls.

Treatment of Rheumatic Fever

The staff of the Laboratory, in collaboration with the medical service of the Warren Air Force Base hospital, carried out the first controlled therapeutic trial of steroids in rheumatic fever in young adults. The Council on Rheumatic Fever and Congenital Heart Disease of the American Heart Association


287

began planning in early 1950 for a multicenter clinical trial of aspirin, cortisone, and adrenocorticotropin (ACTH) in treatment of acute rheumatic fever. Dr. Rammelkamp, a member of the Principal Investigators Subcommittee, actively involved the Laboratory in protocol and procedures development. The trial, one of the earliest multicenter clinical trials and the first multinational trial, involved 12 clinical centers in the United States, Canada, and Great Britain. The only center treating adults was the Warren Air Force Base center.

Acquisition of patients began in January 1951 and continued to June 1952. The studies at Warren Air Force Base included the drug 3-hydroxy-2-phenylcinchoninic acid (HPC) as well as aspirin, cortisone, and ACTH. Dr. James G. Hirsch, Chief of the Medical Service at Warren Air Force Base, and Dr. D. M. Flett, civilian consultant, had begun evaluation of HPC when the planning for the multicenter study began. A quid quo pro for agreement of the medical service to participate in the multicenter study was inclusion of HPC as one of the therapeutic agents to be evaluated. The steering committee of the trial agreed to this and the trial at Warren began with one third of the patients assigned to the HPC treatment, one third to aspirin, and one sixth each to cortisone and ACTH. The HPC arm was discontinued in June 1951 after which there was equal allocation to the remaining three groups. One hundred eighty-six men entered the study. This contrasts with the total of 505 children enrolled at the other 12 clinical centers.

The study at Warren Air Force Base, while following the basic protocol, increased the frequency of clinical, ECG, and laboratory observations. The protocol required clinical observations daily during the first week of treatment, once a week for the remaining 5 weeks of treatment, daily for the first 2 weeks posttreatment, and once during the 3rd week posttreatment. Dr. Rammelkamp and the associate investigators, Dr. Houser of the Strep Lab and Captain Ernest J. Clark of the hospital medical service, decided to make daily observations on all patients for the full 9 weeks. It was also decided that each patient would have the same observer through the observation period. Thus, for 18 months, a day off was a rarity for the observer and leave time was not even a subject for discussion. Dr. Bertrand L. Stolzer joined the Strep Lab in 1952 and participated in the later stage of the study. Dr. Walter Pritchard, Western Reserve University, examined 87% of the patients between the 10th and 16th months after start of therapy.

The course of illness by treatment group in the young adult patients (average age was 20 years) was similar to that observed in the children in the study at the other clinical centers. No one drug exhibited any advantage over the others either during the acute illness or in residual valvular disease at 14-month follow-up. A statement is made in the publication describing the 14-month follow-up that longer term follow-up was to be carried out. None of the available records indicates that such a follow-up did occur.

Additional patients were treated with aspirin or cortisone over the next 2 years. In the annual report for years 1955 and 1956, an analysis of 96 aspirin-treated patients and 72 cortisone-treated patients showed a significant difference in murmurs 8 months after the beginning of therapy. Forty-nine (51%) of aspirin-treated patients had clinically significant murmurs in contrast to 20 (26.3%) in the cortisone group. Most of the difference was attributable to the absence of aortic diastolic murmurs in all but one patient in the cortisone group. It was speculated that the failure of the studies in children to show a similar advantage of cortisone over aspirin was due to the earlier treatment in the airmen. Fifty percent of the young adults began treatment during their 1st week of illness in contrast to a median time of 2 weeks in the children. There is no record that these results were published.

The decision to increase the frequency of ECG and laboratory observations over protocol requirements resulted in information about the course of illness of acute rheumatic fever not previously or subsequently observed in a large cohort of acute rheumatic fever patients. Twenty-five percent of patients had prolonged A-V conduction time at the time of diagnosis; however, the daily or every other day frequency of ECG s showed that 50% of patients exhibited prolonged conduction at some time during the 9 weeks after onset. The frequent antistreptolysin O and erythrocyte sedimentation determinations resulted in analyses unique to the Warren studies.


288

Shortly before the closing of the Strep Lab, a study of the effect on valvular disease of treatment with large doses of penicillin during acute rheumatic fever was initiated. The small number of cases at Warren and in Cleveland, where a similar study was started, resulted in the shifting of these studies to Chile, where they were carried out by Dr. Rammelkamp after the closure of the Strep Lab.

Epidemiological Studies

Occurrence of Respiratory Infections and Rheumatic Fever at Warren Air Force Base

From the opening of the Strep Lab in January 1949 until its closure in September 1955, hospital admissions for acute respiratory infections and rheumatic fever were monitored. The following table shows these results; unfortunately the results after March 1954 cannot be found.

Hospital admissions for respiratory disease and rheumatic fever at Warren Air Force Base, 1949 to 1954

Year

Respiratory Admissions

 

Rheumatic
Fever
Admission

Total

Non-Strep

Strep

Streptococcal Type

Predominant

Common

1949

3,846

1,640

2,206

14

24,5

117

1950

3,164

1,311

1,853

14

5

54

1951

5,646

2,060

3,586

14

5,1,6

144

1952

4,843

2,008

2,835

30

14,3,18

125

1953

3,459

1,255

2,204

30

19,3,14

136

1954*

157

101

56

---

5,14,19

1

*1 January to 1 March

During the period for which records are available, 12,740 cases of streptococcal tonsillitis/pharyngitis and 577 cases of rheumatic fever were studied. During the 5-year period, two influenza outbreaks occurred, one in January 1950 and another in January 1953; the attack rates for hospitalized patients were 32 and 46/1,000/week, respectively. The table also shows the types of group A streptococci that predominated and those that were common during that time. The rates for hospitalization for airmen with streptococcal disease were low during the warmer months of the year but rose to high levels during the winter and spring months. Rates of 12 to 15/1,000/week, were not unusual and a rate as high as 24/1,000/week was recorded in February 1951. Surveys for the pharyngeal carriage of streptococci were done in several population groups. For airmen already in place on the base, carrier rates were shown to be from 30% to 38%. At the time, the rate was 30% in airmen and the rate in Cheyenne high school students was 11%; the distribution of streptococcal types in the two groups was similar. In contrast, culture surveys of new arrivals on the base showed rates of 5% to 22%, and the distribution of types was different from those prevalent on the base at that time. The clinical studies that were performed on these patients with streptococcal pharyngitis have been described above. In addition to the studies done on hospitalized patients, a variety of studies was performed on individuals who were not admitted to hospital as a necessary part of the study.


289

The Effect of Environmental, Host, and Bacterial Factors on the Spread of Group A Streptococci

Extensive studies were performed during the entire period of operation of the Strep Lab to elucidate the factors responsible for the spread of group A streptococci from person to person. The effect of climate on recovery from streptococcal infections was evaluated in a special study in which infected airmen were moved to Tyndall Air Force Base, Florida, and compared to a group remaining at Warren Air Force Base. The effect of tonsillectomy and adenoidectomy was studied as a part of the routine investigation of respiratory infections of airmen at Warren Air Force Base. These studies will be outlined in a subsequent section. The remainder of the studies outlined below was done under carefully controlled conditions in special barracks where the spread of streptococci from infected to uninfected airmen was documented.

The role of the organism. The prevalent or "epidemic" types of streptococci spread more readily than did nonprevalent or "nonepidemic" types, but it was not possible to rule out the role of infection outside of the barracks. Also, the presence of viable streptococci in dry dust did not increase the spread of streptococci. This observation was confirmed by volunteer studies that showed that streptococci in dust dried 4 to 8 hours and inoculated into the pharynx in volunteers did not cause infections, whereas "wet" streptococci did.

The role of the host. The presence of type-specific antibody (anti-M-protein) provided protection to infection with homologous-types of streptococci but not to heterologous types. No evidence was found that tonsillectomy and adenoidectomy reduced the risk to acquiring a streptococcal infection or developing acute rheumatic fever. The severity of the course of streptococcal infections was also not altered by tonsillectomy and adenoidectomy.

The role of human reservoirs. These studies, possibly related to the host, showed that the duration of carriage of streptococci following acute infection was related inversely to the infectivity of the organism for contacts. The likelihood of infection in contacts was directly related to the quantity of streptococci in cultures of the infectious "spreader" and also to the number of streptococcus carriers in the barracks. The increased infectiveness of the nasal carriers was also demonstrated, confirming earlier studies by Dr. Hamburger.

Modes of spread. Studies on this facet of the epidemiology of streptococci were done in an attempt to clarify the importance of the airborne route (by droplet nuclei and dust), compared with more direct contact, which includes spread by large droplets. It was found that the spread of infection was indirectly related to the distance of the carrier from the uninfected airman. These studies, and the failure of dry dust containing viable streptococci placed in barracks to cause infection, indicated that the major mode of spread of streptococci is by close contact and large droplets, thus emphasizing the importance of crowding in the epidemiology of streptococcal infections.

Effect of the environment. Already mentioned was the failure of dust containing streptococci to cause infection. Further confirmation of the lesser importance of dry streptococci in the environment was demonstrated by the failure of blankets containing larger numbers of streptococci, and used by airmen, to cause infection. The role of climate was more difficult to evaluate in that it could not be controlled easily. A solution to this problem was sought by moving a group of airmen just recovering from an untreated streptococcal infection to Tyndall Air Force Base, Florida, and comparing the rate of disappearance of the carrier state to a similar group left in Wyoming. Almost all patients continued to harbor group A streptococci for 16 to 19 weeks, at which time the study was terminated. There was no evidence that the change in climate had any effect on the length of the carrier state or the number of organisms isolated from the pharynx, although nontypable variants appeared slightly earlier and streptococci disappeared from the anterior nares sooner in the group transferred to a warmer climate.

Dr. Krause demonstrated that these nontypable variants were less infectious for monkeys than were the typable strains. Furthermore, the monkeys that were infected subsequently shed streptococci of the same M type as the original infecting strains.


290

These studies, performed primarily by Drs. Rammelkamp and Wannamaker, demonstrated the role of type-specific immunity in streptococcal infections and showed the importance of the acutely infected host in spreading infection by direct contact or large droplets to susceptible hosts. They also showed the lack of importance of streptococci in the environment and helped explain past failures to control the spread of streptococci by aerosols and ultraviolet light.

Studies on Penicillin Prophylaxis

When it was demonstrated that penicillin, in contrast to sulfadiazine, eradicates the streptococcus from the throat of carriers, is relatively nontoxic to the patient, and does not cause the development of resistant streptococcal strains, a series of studies was undertaken to clarify its role in preventing streptococcal infection and rheumatic fever in armed forces personnel. Initial investigations were divided into two parts: (1) studies comparing the effect of several penicillin regimens on the carrier state, and (2) a study evaluating the effect of oral penicillin on streptococcal carrier and disease rates in large groups of airmen.

For studies on the effect on the carrier state, only confirmed, chronic carriers were included. Oral penicillin, procaine penicillin in oil, and intramuscular benzathine penicillin (Bicillin) in various dosage schedules were compared. Oral penicillin in twice daily doses of 500,000 units or 1,000,000 units for 10 days was effective in total eradication of streptococci. If 1,000,000 units was given twice daily for 5 days, the carrier state was reduced effectively while the drug was being administered, but the organism promptly reappeared in the majority of cases. A regimen of 250,000 units once daily for 10 days was only 75% effective in reducing the carrier state, but most eradications persisted for 3 weeks. Penicillin in oil, 600,000 units every other day for 4 doses (8 to 10 days coverage), eradicated streptococci permanently from all carriers, whereas a single injection of 600,000 units (2 to 3 days coverage) rendered carriers culture negative for 48 hours, after which streptococci promptly reappeared. Intramuscular benzathine penicillin given in a single injection of 600,000 units or two simultaneous injections of 900,000 units each (total 1,800,000 units) was effective in eradicating the streptococcus; the larger dose was probably slightly more effective.

These studies showed that two factors were necessary if the group A streptococcus was to be eradicated from carriers: (1) the dose must be adequate, and (2) penicillin should be administered for a relatively long period of time, 10 days being sufficient in these studies.

In the second part of these studies, 1,000,000 units of oral penicillin G was administered twice daily for either 5 or 10 days to entire squadrons of men; approximately 1,300 men were included in each schedule. The longer dosage schedule was more effective in eradication of the streptococcus and in reducing the incidence of streptococcal infections. Following discontinuation of the drug, there was a gradual loss of effect, and after the 4th week, rates again reached control levels.

After the initial studies had shown the effectiveness of penicillin prophylaxis, three subsequent large-scale trials were done to establish appropriate drug regimens, including duration of protection, and occurrence of drug reactions. In the first study, benzathine penicillin was administered as a single intramuscular injection in doses of 1,200,000 and 600,000 units to 960 and 950 young men. Oral penicillin, in doses of 250,000 units twice daily, was given to 845 men for 10 days. These regimens resulted in sensitivity reactions of 5.21, 2.10, and 1.07%, respectively; reactions were mild and consisted of urticarial skin rashes. All three regimens were effective in eliminating the carrier state, but the larger dose of benzathine penicillin was most effective.

In the second study, a single intramuscular injection of benzathine penicillin was given to 2,214 airmen exposed to epidemic streptococcal infections. There was prompt reduction in streptococcal infections in the group receiving prophylaxis compared with an untreated control group. In the third study, benzathine penicillin G was administered as a single intramuscular injection in doses of 1,200,000, 600,000, and 300,000 units to 246, 255, and 240 men, respectively, during an epidemic of streptococcal pharyngitis. The duration of protection provided by each dose as determined by the development of exudative pharyngitis due to group A streptococcus was 6 to 7 weeks, 4 to 5 weeks, and 1 to 2 weeks,


291

respectively. All three regimens were equally effective in eradicating streptococci from carriers. These studies confirmed the data obtained in the earlier studies and provided the necessary information to recommend to the Armed Services, appropriate prophylactic regimens in military populations.

Studies on Glomerulonephritis

Although the Strep Lab was developed to investigate the relationship between streptococcal respiratory infections and rheumatic fever, one of the notable observations made was the relationship of infections due to specific types of group A streptococci to acute glomerulonephritis. The first mention of this appeared in the annual report of the Laboratory for 1952 and 1953. The section of that report describing the outbreak of nephritis following type 12 streptococci covers completely the initial observations. We believe this section was written by Dr. Rammelkamp. The nephritogenicity of specific types of streptococci was his "brainchild" and this study was "vintage Rammelkamp." The section follows:

Studies on post-streptococcal glomerulonephritis at the
U.S. Naval Training Center, Bainbridge, Maryland.

During the years 1949-1952, only 2 cases of acute glomerulonephritis were observed at Warren Air Force Base Hospital, although the streptococcal and rheumatic disease rates were high during this period. This fact suggests that the nephritogenic capacity of the streptococcal strains prevalent in this area during these years was low. In contrast to this situation, acute glomerulonephritis was frequently observed during the winter of 1951-1952 at the Bainbridge Naval Training Center, cases of this disease outnumbering those of rheumatic fever in a ratio of 2 to 1. It was found that nearly half of the cases of exudative pharyngitis at Bainbridge were due to group A type 12 streptococci, and that there was a close association between infections due to this type of streptococcus and the subsequent development of acute nephritis. During a controlled study involving approximately 400 patients, 15 cases of acute nephritis occurred following type 12 streptococcal infections, while no cases were observed after infections with types 3, 6, or 19 streptococci.

Penicillin therapy of acute type 12 streptococcal pharyngitis in 50 cases appeared to be effective in preventing acute nephritis, while large doses of gamma globulin administered early in the course of the acute pharyngitis in 32 patients did not prevent this complication and may indeed have increased the attack rate.

Addis counts performed each day on each patient indicated that there is frequently a mild transient hematuria during the first few days of acute streptococcal infections; type 12 infections did not differ significantly in this respect from infections due to other types studied at Bainbridge and Warren Air Force Base. After the subsidence of this initial microscopic hematuria, fifteen patients with type 12 infections developed albuminuria, cylindruria and hematuria of marked degree, and were considered to have acute glomerulonephritis. The majority of these patients showed a significant elevation in blood pressure, approximately half had headache, nausea, vomiting or other symptoms commonly associated with this disease, while only 3 had edema. The average interval between the onset of streptococcal pharyngitis and the onset of acute nephritis was 10.5 days in these patients. Twenty-four other patients with type 12 infections showed urinary abnormalities (usually consisting only of microscopic hematuria) and may be classified as possible or mild cases of acute nephritis.

Immunologic studies have revealed no striking difference in antibody response to those patients developing acute nephritis as compared to those with uncomplicated streptococcal pharyngitis. The gamma globulin levels in the patients with nephritis appear to show a greater average rise, and may be a reflection of the rather high incidence of suppurative complications in this group.

Several publications by Dr. Rammelkamp and his coworkers appeared before the appearance of the observations made at the Bainbridge Naval Training Center. These summarize other data that suggest that acute glomerulonephritis tends to follow infection with a limited number of streptococcal


292

types. In addition to these studies, an outbreak of streptococcal infections associated with type 12 streptococci in a kindergarten in Cheyenne was also described. The attack rate for nephritis of children with type 12 streptococci was unusually high, whereas nephritis did not follow infections due to other types. This prospective study allowed the delineation of the clinical spectrum of nephritis following infection with a nephritogenic strain of streptococcus.

Laboratory Studies

The princiale focus of the Strep Lab was on clinical and epidemiological studies, with the laboratory furnishing supporting data for these investigations. The magnitude of this support is shown by figures given in the first annual report for 1949 and 1950. In the first year, approximately 20,000 throat cultures were processed and 6,000 strains of streptococci identified! Many representative strains were lyophilized for future study.

Acute and convalescent bloods by the hundreds were collected, processed, and the sera frozen at -20°C. No records exist of the total numbers of routine laboratory tests performed, but the above figures give some idea of the magnitude of this part of the operation. Although specific laboratory studies were not a major effort of the Strep Lab, several deserve mention.

Use of Maxted's Method for Group Classification of Hemolytic Streptococci

W. R. Maxted's method, using an enzyme produced by a strain of Streptomyces albus was compared with conventional methods using 1,010 consecutively isolated strains of hemolytic streptococci. Classification by this method was successful in 998 strains; its accuracy was comparable to other methods, and it was easier to perform.

Type-Specific Streptococcal Antibody

A modification of the bacteriostatic assay for demonstration of type-specific streptococcal antibodies described by Dr. Sidney Rothbard was developed. This consisted of the ability of constant dilutions of test serum in the presence of leucocytes to inhibit varying dilutions of specific types of group A streptococci as demonstrated by the presence (no antibody) or absence (antibody present) of hemolysis after adequate incubation. Type-specific antibody developed in the majority of patients following streptococcal infections. In contrast to antistreptolysin O, this antibody developed slowly and showed marked variation in the time of development according to the infecting type of streptococcus. Treatment with penicillin and chlortetracycline inhibited formation of this antibody, with penicillin causing the greater degree of inhibition. The degree of inhibition appeared to be related to the successful elimination of the organism by therapy. This method of demonstrating type-specific antibody was used in the epidemiological studies described previously.

Studies on M Protein

Several questions regarding M protein were addressed during the life of the Strep Lab. The studies on type-specific bacteriostatic antibodies are described in the section above and the role of these antibodies in host protection has been described in a previous section. In the studies on the effect of climate on clinical streptococcal infections, it was shown that the carriage of streptococci persisted for several


293

months but that the isolated organisms frequently had lost their M protein and thus were nontypable. Efforts were made to quantitate the M protein of specific isolates so that this phenomenon could be investigated further. These studies are described in an earlier section.

Studies were also done on the determination of type 19 M antibody in sera using the quantitative precipitin test, and with the stimulation of type 19 antibody formation in humans following the subcutaneous injection of purified type 19 M protein. The details of the reaction using rabbit antisera were explored and published. Efforts to immunize volunteers were thwarted by the toxicity of the M protein preparation in some individuals and the insensitivity of the method. In the results recorded in the annual reports, only the occasional patient responded with significant antibody formation.

Miscellaneous Studies

Stool Culture Survey

Stool cultures were taken from approximately 400 airmen with streptococcal pharyngitis, 300 of whom were untreated. A total of 63 patients, or 15.8%, had one or more cultures positive for the same type of streptococcus isolated from the throat culture. There was no correlation between the presence of streptococci in the stool and the gastrointestinal manifestations seen in patients with streptococcal pharyngitis. The two cases of rheumatic fever in the observed patients had negative stool cultures.

This study recalls to the authors certain events surrounding its inception and follow-up. The study was arranged by Dr. Rammelkamp because of a conversation he had had with Dr. Maxwell Finland, who had told Dr. Rammelkamp of the importance of the stool carriage in some of his patients with streptococcal disease. At the completion of the study described above it was presented to Dr. Finland at an annual meeting. His response was: "But Rammel, I said staphylococci, not streptococci!"

Blood Culture Survey

In an effort to study the possible role of streptococcal sepsis in streptococcal pharyngitis and rheumatic fever, 2,164 blood cultures were obtained from 364 patients, four of whom developed rheumatic fever. No streptococci were isolated from the blood of these four patients. Of the remaining 360 patients, 4 had single isolates of group A streptococci but these were different types from those isolated from the throats. In addition, 10 to 15 blood cultures were obtained from each of 24 patients with rheumatic fever, 12 treated with cortisone and 12 with aspirin; no streptococci were isolated. None of these observations supported the thesis that streptococcal bacteremia is associated with the development of rheumatic fever.

Steroid Excretion

Extensive efforts were made to study the steroid excretion in patients with streptococcal pharyngitis who did and did not develop rheumatic fever. Twenty-four-hour collections of urine were obtained from 200 patients during the acute phase of illness and 3 to 4 weeks later in control patients and in those developing rheumatic fever. All urine specimens were transported by air to Cleveland for analysis. Technical, logistical, and administrative problems plagued these studies, and no meaningful results were obtained.


294

Studies by Outside Scientists

Because of the nature of the clinical and epidemiological studies being carried out at the Strep Lab, it provided the opportunity for and the site of a variety of studies by scientists not directly associated with the Lab.

Studies on Influenza

As noted earlier, two epidemics of influenza occurred during the early years. Acute and convalescent sera were collected on several hundred airmen, and respiratory secretions were obtained on selected cases for isolation of viruses. These studies were done in the Department of Preventive Medicine at Western Reserve University or at the WRAIR. In addition, the airforce personnel at Warren Air Force Base were utilized in a field trial of immunization against influenza in cooperation with Dr. Thomas Francis. The final results of these studies have been lost to the authors.

Chlortetracycline Treatment of Atypical Pneumonia

In cooperation with Captain Hirsch and Colonel Cullen at Warren Air Force Base, the effect of chlortetracycline in primary atypical pneumonia was evaluated. All patients had roentgenologic evidence of pneumonia. Although the numbers of patients were rather small, there was no evidence that treated patients cleared their pneumonia more quickly than occurred in control patients.

Studies by visiting scientists

Between 1949 and 1950, visiting scientists spent several weeks in the Strep Lab working on problems of their own interest. Dr. Wilson studied the inhibition of streptococci by substances present in milk, Dr. Stollerman worked on antistreptolysin S responses in rheumatic and nonrheumatic subjects, Dr. Robert Thompson investigated antihyaluronidase responses, and Dr. William Jeffries collaborated on steroid responses in infected airmen.

VISITORS TO THE LABORATORY

The visiting scientists who spent several weeks working in the Laboratory are listed above. In addition, the Commission on Streptococcal Diseases held a meeting at Warren Air Force Base in November 1950. The annual reports record that the following people were visitors to the Laboratory in some capacity:

Dr. George Badger
Dr. Robert Cruickshank
Dr. John Dingle
Colonel Fratis Duff
General Eubanks
Dr. T. Duckett Jones
Colonel F. J. Knoblauch
Dr. Clayton Loosli
Dr. Gordon Meiklejohn
Colonel Donald Preston
Dr. Walter Pritchard
Colonel Hartwin Schilze


295

CLOSING OF THE LABORATORY

The Laboratory was closed in September 1955. Because of the significance of this event, the paragraph by Dr. Rammelkamp outlining this event is reproduced below in its entirety.

The studies conducted since 1 January 1949 at Warren Air Force Base under the joint auspices of the Commissions on Acute Respiratory Diseases and Streptococcal Diseases were terminated on 15 September 1955 and the Laboratory closed. The staff included Captain Alton J. Morris and Dr. Williard C. Schmidt. Captain Morris resigned June 1955 and Dr. Schmidt transferred to Cleveland in September 1955. All of the records, serum specimens and cultures were transferred to Cleveland. Captain Earl C. Marple, USAF, who served as administrator of the unit since 1949, was responsible for the transfer of the records, sera, etc. Because of his contributions to the laboratory, epidemiological studies, and volunteer inoculation, he was recommended for a Legion of Merit Award.

The greatest recognition of the accomplishments of the Laboratory came with the receipt of the Lasker Award in 1954. Because of its significance, the Award is presented in its entirety.

American Public Health Association's
Albert Lasker Group Award

1954

to the

Streptococcal Disease Laboratory
Armed Forces Epidemiological Board
Francis E. Warren Air Force Base
Cheyenne, Wyoming

The Streptococcal Disease Laboratory at Francis E. Warren Air Force Base was established in 1949 under the joint auspices of the Commissions on Streptococcal Diseases and Acute Respiratory Diseases of the Armed Forces Epidemiological Board. From its beginning the Laboratory has been directed by Dr. Charles H. Rammelkamp, Jr. The success achieved is due in great measure to his deep originality, brilliant leadership of a group of young medical corps officers and civilian physicians, and keen awareness of the advantages afforded by military populations in epidemiological analyses. The collaboration of the medical departments of all three military services in the work of the Laboratory, with minor exceptions, has been exemplary.

The Laboratory's contributions to knowledge of streptococcal diseases are in the forefront of advances in preventive medicine in this generation and include: significant information on direct spread of streptococci from man to man with deemphasis of the airborne route lately in fashion; the role of specific antibodies in active immunity of man; the efficacy of antibiotics in preventing rheumatic fever when used to treat the antecedent streptococcal infection; controlled studies of therapy of rheumatic fever, rational chemoprophylaxis of streptococcal infections; and the brilliant addition to our knowledge of acute kidney infections through discovery of strains of streptococci which cause kidney lesions.

Lowell J. Reed, Chairman
The Lasker Awards Committee of the American Public Heath Association

Hugh R. Leavell, President
The American Public Health Association


296-302

TWENTY-FIFTH REUNION OF THE STREPTOCOCCAL DISEASE LABORATORY IN 1974

To celebrate the 25th anniversary of the opening of the Strep Lab, a reunion of staff and military dignitaries was held at Warren Air Force Base on 3 October 1974. The program of events is reproduced below.

Program of Events at 25th Anniversary of Strep Lab

Twenty-fifth Anniversary Symposium in
Commemoration of the Streptococcal Disease
Laboratory, Warren AFB, Wyoming

A Festschrift for
Charles H. Rammelkamp, M.D.
Mentor, Colleague, Critic

October 3, 1974

Francis E. Warren Air Force Base, Wyoming

H.B. Houser, M.D. Chairman

9:45 am

Welcoming Remarks

Col. Christopher S. Adams, Jr.
Commander, 90th Strategic Missile Wing

Colonel (Dr.) G. Douglas Adamson,
Commander, USAF Hospital,
Francis E. Warren Air Force Base
Leroy R. Maki, Ph.D., President,
Wyoming Heart Association

9:00 -10:25

Richard M. Krause, M.D., Presiding

9:00 - 9:20

Lewis W. Wannamaker, M.D.
A Search for Better Antibody Tests for Group A and Group B Streptococcal Infections

9:25 - 9:55

W.R. Maxted, Honorary Ph.D.
The Evolution of the Typing System for Group A Streptococci

10:00 -10:20

R.M. Krause, M.D.

On the Ways Antibodies to Streptococcal Carbohydrates Can Substitute for Myeloma Proteins

10:25 -10:45

Break

10:45 -12:00

Chandler A. Stetson, M.D., Presiding

10:45 - 11:05

Melvin H. Kaplan, M.D.
Immunopathologic Studies of Rheumatic Heart Valves

11:10 -11:30 Paul P. Cleary, Ph.D.

The Genetic Instability of Serum Opacity and Resistance to Phagocytosis of Group A Streptococci

11:35 -11:55 Jiri Rotta, Ph.D.

Biological Reactions to Peptidoglycan of Group A Streptococcus and Other Bacteria

12:00 -1:30 Lunch, Officers Open Mess

1:30 - 3:30 Floyd W. Denny, Jr., M.D., Presiding

1:30 - 2:00 Hugh C. Dillon, M.D.

Post-Streptococcal Glomerulonephritis: The Pyoderma Era

2:05 - 2:25 Harold B. Houser, M.D.

Observations on the Epidemiology of Rheumatic Fever

2:30 - 2:50 Gene H. Stollerman, M.D.

The Relative Rheumatogenicity of Group A Streptococcal Strains

2:55 - 3:25 Aziz El Kholy, M.D.

The Pattern of Acquisition and Spread of Group A Streptococci in Families

3:30 - 4:00 Break

4:00 - 5:10 Harold B. Houser, M.D., Presiding

4:00 - 4:20 Loring Brock; M.D.

Recreational and Vocational Evaluation and Planning for the Young Cardiac Patient

4:25 - 4:45 Floyd W. Denny, Jr., M.D.

Mycoplasma pneumoniae Disease: An Immune Paradox

4:50 - 5:10 Chandler A. Stetson, M.D.

Crystal Gazing

6:00 - 7:30 Reception, Officers Open Mess

7:30 p.m. Dinner, Officers Open Mess

Lewis W. Wannamaker, M.D., Presiding
Edward A. Mortimer, M.D.
Frederick C. Robbins, M.D.
Maclyn McCarty, M.D.

Program Participants

Loring Brock, M.D., Director, Spalding Rehabilitation Center, Denver, Colorado

Paul P. Cleary, Ph.D., Assistant Professor of Pediatrics, University of Minnesota, Minneapolis, Minnesota

Floyd W. Denny, Jr., M.D., Professor and Chairman, Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina

Hugh C. Dillon, M.D., Professor of Pediatrics, University of Alabama, Birmingham, Alabama

Aziz El Kholy, M.D., Director, Rheumatic Fever Project, Cairo, Egypt

Harold B. Houser, M.D., Professor of Epidemiology, Case Western Reserve University, Cleveland, Ohio

Melvin H. Kaplan, M.D., Professor of Medicine, Case Western Reserve University, Cleveland, Ohio

Richard M. Krause, M.D., Professor, The Rockefeller University, New York, New York

W.R. Maxted, Honorary Ph.D., Central Public Health Laboratory, Colindale, England

Maclyn McCarty; M.D., The Rockefeller University, New York, New York

Edward A. Mortimer, Jr., M.D., Professor and Chairman, Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico

Frederick C. Robbins, M.D., Professor of Pediatrics and Dean, School of Medicine, Case Western Reserve University, Cleveland, Ohio

Jiri Rotta, Ph.D., Director, WHO International Streptococcal Center, Prague, Czechoslovakia

Chandler A. Stetson, M.D., Dean, School of Medicine, University of Florida, Gainesville, Florida

Gene H. Stollerman, M.D., Professor and Chairman, Department of Medicine, University of Tennessee, Memphis, Tennessee

Lewis W. Wannamaker, M.D., Professor of Pediatrics, University of Minnesota, Minneapolis, Minnesota

Acknowledgements

The Organizing Committee thanks Dr. Edwin H. Lennette, President; Lt. Col. Duane G. Erickson, Executive Secretary; and Miss Elizabeth Gilbert, Executive Assistant, of the Armed Forces Epidemiological Board for their support and assistance which made this symposium possible.

The following organizations have generously contributed financial support for the symposium:

Abbott Laboratories, North Chicago, Illinois
Eli Lilly and Company, Indianapolis, Indiana
The Upjohn Company, Kalamazoo, Michigan
Wyeth Laboratories, Philadelphia, Pennsylvania

The Committee acknowledges with thanks the efforts of Colonel Christopher S. Adams, Jr., Colonel Godfrey D. Adamson, Colonel John Brashear and the personnel of Francis E. Warren Air Force Base.

The Committee
H.B. Houser, Chairman
R.M. Krause, Co-Chairman
F. W. Denny
L.W. Wannamaker

Publications

1950

Denny, F.W., Wannamaker, L.W, Brink, WR., Rammelkamp, C.H., Jr., and Custer, E.A. Prevention of rheumatic fever by treatment of the preceding streptococcic infection. J. Am. Med. Assoc. 1950, 143, 151-153.

Stollerman, G.H., and Bernheimer, A.W. Inhibition of streptolysin S by the serum of patients with rheumatic fever and acute streptococcal pharyngitis. J. Clin. Invest. 1950, 29, 1147-1155.

Wannamaker, L.W., Denny, F.W., Rammelkamp, C.H., Jr., and Brink, W.R. Use of Maxted's method for group classification of hemolytic streptococci. Proc. Soc. Exp. Biol. Med. 1950, 73, 467-469.

1951

Brink, W.R., Rammelkamp, C.H., Jr., Denny, F.W., and Wannamaker, L.W. Effect of penicillin and aureomycin on the natural course of streptococcal tonsillitis and pharyngitis. Am. J. Med. 1951, 10, 300-308.

Hahn, E.O., Houser, H.B., Rammelkamp, C.H., Jr., Denny, F.W., and Wannamaker, L.W. Effect of cortisone on acute streptococcal infections and post-streptococcal complications. J. Clin. Invest. 1951, 30, 274-281.

Streptococcal Disease Laboratory, Francis E. Warren Air Force Base; Commission on Acute Respiratory Diseases Armed Forces Epidemiological Board and Department of Preventive Medicine, School of Medicine, Western Reserve University. Prevention of rheumatic fever. U. S. Armed Forces Med. J. 1951, 2, 607-613.

Wannamaker, L.W., Rammelkamp, C.H., Jr., Denny, F.W, Brink, W.R., Houser, H.B., Hahn, E.O., and Dingle, J.H. Prophlaxis of acute rheumatic fever by treatment of the preceding streptococcal infection with various amounts of depot penicillin. Am. J. Med. 1951, 10, 673-695.

1952

Houser, H.B., and Eckhardt, G.C. Recent developments in the prevention of rheumatic fever. Ann. Intern. Med. 1952, 37,1035-1043.

Rammelkamp, C.H., Jr. Prevention of rheumatic fever. Bull. Rheum. Dis. 1952, 2, 13-14.

Rammelkamp, C.H., Jr., Wannamaker, L.W, and Denny, F.W. The epidemiology and prevention of rheumatic fever. Bull. N. Y. Acad. Med. 1952, 28, 321-334.

Rammelkamp, C.H., Jr., Denny, F.W, and Wannamaker, L.W. Studies on the epidemiology of rheumatic fever in the armed services. In: Thomas, L., editor. Rheumatic Fever, A Symposium. Minneapolis, Minn.: University of Minnesota Press, 1952, pp. 72-89.

Rammelkamp, C.H., Jr., Weaver, R.S., and Dingle, J.H. Significance of the epidemiological differences between acute nephritis and acute rheumatic fever. Trans. Assoc. Am. Physicians 1952, 64,168-175.

Rammelkamp, C.H., Jr., Houser, H.B., Hahn, E.O., Wannamaker, L.W., Denny, F.W., and Eckhardt, G.C. The prevention of rheumatic fever. In: Thomas, L., editor. Rheumatic Fever, A Symposium Minneapolis, MN: University of Minnesota Press, 1952, pp. 304-315.

Rammelkamp, C.H., Jr., and Denny, F.W. Prevention of rheumatic fever. In: Bean, W .B., editor. Monographs in Medicine Baltimore, MD: Williams & Wilkins, 1952, pp. 295-314.

1953

Brock, L.L., and Siegel, A.C. Studies on the prevention of rheumatic fever: the effect of time of initiation of treatment of streptococcal infections on the immune response of the host. J. Clin. Invest. 1953, 32, 630-632.

Chamovitz, R., and Catanzaro, F.J. Evaluation of dibenzylethylenediamine penicillin G in the prevention
of rheumatic fever by treatment of the preceding streptococcal illness. Antibiotics Annual, 1953-54. New York, NY: Medical Encyclopedia, Inc., 1953, p. 113.

Clark, E.J., and Houser, H.B. Comparative effects of 3-hydroxy-2-phenylcinchoninic acid (HPC) and aspirin on the acute course of rheumatic fever and the occurrence of rheumatic valvular disease. Am. Heart J. 1953, 45, 576-588.

Denny, F.W., Wannamaker, L.W, and Hahn, E.O. Comparative effects of penicillin, aureomycin and terramycin on streptococcal tonsillitis and pharyngitis. Pediatrics 1953, 11, 7-14.

Dingle, J.H., Rammelkamp, C.H., Jr., and Wannamaker, L.W. Epidemiology of streptococcal infections and their non-suppurative complications. Lancet 1953, 1, 736-738.

Houser, H.B., Eckhardt, G.C., Hahn, E.O., Denny, F.W., Wannamaker, L.W., and Rammelkamp, C.H., Jr. Effect of aureomycin treatment of streptococcal sore throat on the streptococcal carrier state, the immunologic response of the host and the incidence of acute rheumatic fever. Pediatrics 1953, 12, 593-606.

Rammelkamp, C.H., Jr., and Weaver, R.S. Acute glomerulonephritis. The significance of variations in the incidence of the disease. J. Clin. Invest. 1953, 32, 345-358.

Rammelkamp, C.H., Jr. Glomerulonephritis. Proc. Inst. Med. Chic. 1953, 19, 371-384.

Wannamaker, L.W., Denny, F.W., Perry, W.D., Rammelkamp, C.H., Jr., Eckhardt, G.C., Houser, H.B., and Hahn, E.O. The effect of penicillin prophylaxis on streptococcal disease rates and the carrier state. N. Engl. J. Med. 1953, 249, 1-7.

1954

Catanzaro, F.J., Stetson, C.A., Morris, A.J., Chamovitz, R., Rammelkamp, C.H., Jr., Stolzer, B.L., and Perry, W.D. The role of the streptococcus in the pathogenesis of rheumatic fever. Am. J. Med. 1954, 17, 748-756.

Chamovitz, R., Catanzaro, F.J., Stetson, C.A., and Rammelkamp, C.H., Jr. Prevention of rheumatic fever by treatment of previous streptococcal infections. I. Evaluation of benzathine penicillin G. N. Engl. J. Med. 1954, 251, 466-471.

Denny, F.W., Jr. The prophylaxis of streptococcal infections. In: McCarty, M., editor. Streptococcal Infections. New York, NY: Columbia University Press, 1954, p. 176.

Dingle, J.H. The clinical pattern of streptococcal infection in man. In: McCarty, M., editor. Streptococcal Infections. New York, NY: Columbia University Press, 1954, p. 120.

Houser, H.B., Clark, E.J., and Stolzer, B.L. Comparative effects of aspirin, ACTH and cortisone on the acute course of rheumatic fever in young adult males. Am. J. Med. 1954, 16, 168-180.

Rammelkamp, C.H., Jr., Stetson, C.A., Krause, R.M., Perry, WD., and Kohen, R.J. Epidemic nephritis. Trans. Assoc. Am. Physicians 1954, 67, 276-282.

Rammelkamp, C.H., Jr., and Stolzer, B.L. The treatment and prevention of rheumatic fever. In Pediatric Clinics of North America. Cardiovascular Diseases, February 1954, pp. 265-274.

Rammelkamp, C.H., Jr. Acute hemorrhagic glomerulonephritis. In: McCarty, M., editor. Streptococcal Infections. New York, NY: Columbia University Press, 1954, p. 197.

Stetson, C.A., Jr. The relation of antibody response to rheumatic fever. In: McCarty, M., editor. Streptococcal Infections. New York, NY: Columbia University Press, 1954, p. 208.

Stolzer, B.L., Houser, H.B., and Clark, E.J. Comparative effects of aspirin, ACTH, and cortisone on the antistreptolysin O titer and gamma globulin concentration in rheumatic fever. J. Lab. Clin. Med. 1954, 44, 229-234.

Wannamaker, L.W. The epidemiology of streptococcal infections. In: McCarty, M., editor. Streptococcal Infections. New York, NY: Columbia University Press, 1954, p. 157.

1955

Catanzaro, F.J., Brock, L., Chamovitz, R., Perry, W.D., Siegel, A.C., Stetson, C.A., Rammelkamp, C.H., Jr., Houser, H.B., Stolzer, B.L., Wannamaker, L.W., and Hahn, E.O. Effect of oxytetracycline therapy of streptococcal sore throat on the incidence of acute rheumatic fever. Ann. Intern. Med. 1955, 42, 345-357.

Chancey, R.L., Morris, A.J., Conner, R.H., Catanzaro, F.J., Chamovitz, R., and Rammelkamp, C.H., Jr. Studies of streptococcal prophylaxis: Comparison of oral penicillin and benzathine penicillin. Am. J. Med. Sci. 1955, 229, 165-171.

Rammelkamp, C.H., Jr. Prevention of acute nephritis. Ann. Intern. Med. 1955, 43, 511-517.

Rammelkamp, C.H., Jr. The natural history of streptococcal infections. Bull. N.Y. Acad. Med. 1955, 31,103-112.

Rammelkamp, C.H., Jr. Epidemiology of Streptococcal Infections. Harvey Lectures. Ser. 51 New York, NY: Academic Press, 1955-56, pp. 113-142.

Siegel, A.C., Rammelkamp, C.H., Jr., and Griffeath, H.I. Epidemic nephritis in a school population. The relation of hematuria to group A streptococci. Pediatrics 1955, 15, 33-44.

Stetson, C.A., Rammelkamp, C.H., Jr., Krause, R.M., Kohen, R.J., and Perry, W .D. Epidemic acute nephritis. Studies on etiology, natural history and prevention. Medicine 1955, 34, 431-450.

Stolzer, B.L., Houser, H.B., and Clark, E.J. Therapeutic agents in rheumatic carditis. AMA Arch. Intern. Med. 1955, 95, 677-688.

1956

Morris, A., Chamovitz, R., Catanzaro, F.J., and Rammelkamp, C.H., Jr. Prevention of rheumatic fever by treatment of previous streptococcal infection. Effect of sulfadiazine. J. Am. Med. Assoc. 1956, 160, 114-116.

Mortimer, E.A., Jr., and Rammelkamp, C.H., Jr. Prophylaxis of rheumatic fever. Circulation 1956, 14, 1144-1152.

Rammelkamp, C.H., Jr. Streptococcal infections in relation to rheumatic fever and nephritis. Trans. Studies Coll. Physicians Phila. 1956, 23, 115-121.

1957

Davis, J., and Schmidt, W.C. Benzathine penicillin G. Its effectiveness in the prevention of streptococcal infections in a heavily exposed population. N. Engl. J. Med. 1957, 256, 339-342.

Denny, F.W., Jr. Sore throat, hemolytic streptococcal. In Current Therapy. Philadelphia, PA: W.B. Saunders Co, 1957, p. 100.

Denny, F.W, Perry, W.D., and Wannamaker, L.W. Type-specific streptococcal antibody. J. Clin. Invest. 1957, 36, 1092-1100.

Morris, A.J., and Rammelkamp, C.H., Jr. Benzathine penicillin G in the prevention of streptococcic infections. J. Am. Med. Assoc. 1957, 164, 664-667.

Perry, W.D., Siegel, A.C., and Rammelkamp, C.H., Jr., Wannamaker, L. W., Maple, E. C. Transmission of group A streptococci. I. The role of contaminated bedding. Am. J. Hyg. 1957, 66, 85-95.

Perry, WD., Siegel, A.C., and Rammelkamp, C.H., Jr. Transmission of group A streptococci. II. The role of contaminated dust. Am. J. Hyg. 1957, 66, 96-101.

Rammelkamp, C.H., Jr. Microbiologic aspects of glomerulonephritis. J. Chron. Dis. 1957, 5, 28-33.

Schmidt, W.C. Bacterial infections of the nasoparynx. In Pediatric Clinics of North America. Philadelphia, PA: W.B. Saunders Co., 1957, pp. 139-154.

Schmidt, W.C. The quantitative precipitin reaction of type 19 M protein antigen of group A streptococci and antistreptococcal rabbit sera. J. Immunol. 1957, 78, 178-184.

Sherwood, R.W., Gronbeck, C., and Denny, F.W., Jr. Reactions from multiple injections of benzathine penicillin G. J. Am. Med. Assoc. 1957, 165, 667-670.

1958

Catanzaro, F.J., Rammelkamp, C.H., Jr., and Chamovitz, R. Prevention of rheumatic fever by treatment of streptococcal infections. II. Factors responsible for failures. N. Engl. J. Med. 1958, 259, 51-57.

Rammelkamp, C.H., Morris, A., Catanzaro, F.J., Wannamaker, L.W., Chamovitz, R., and Marple, E.C. Transmission of group A streptococci. III. The effect of drying on the infectivity of the organism for man. J. Hyg. 1958, 56, 280-287.

Schmidt, W.C., and Rammelkamp, C.H., Jr. Etiology and pathogenesis of glomerulonephritis. Adv. Intern. Med. 1958, 9, 181-205.

1960

Chamovitz, R., Rammelkamp, C.H., Jr., Wannamaker, L.W., and Denny, F.W., Jr. The effect of tonsillectomy on the incidence of streptococcal respiratory disease and its complications. Pediatrics 1960, 26, 355-367.

1961

Rammelkamp, C.H., Jr., and Stolzer, B.L. The latent period before the onset of acute rheumatic fever. Yale J. Biol. Med. 1961-62, 34, 386-398.

1962

Krause, R.M., Rammelkamp, C.H., Jr., Denny, F.W., Jr., and Wannamaker, L.W. Studies on the carrier state following infection with group A streptococci. I. Effect of climate. J. Clin. Invest. 1962, 41, 568-574.

Krause, R.M., and Rammelkamp, C.H., Jr. Studies on the carrier state following infection with group A streptococci. II. Infectivity of streptococci isolated during acute pharyngitis and during the carrier state. J. Clin. Invest. 1962, 41, 575-578.

 

EFFORTS OF THE CSSD TO CONTROL STREPTOCOCCAL INFECTIONS AND RHEUMATIC FEVER IN THE ARMED FORCES

Treatment of acute streptococcal infections with penicillin, as demonstrated by the Streptococcal Disease Laboratory, prevented rheumatic fever in treated persons; however, this method by itself did not control epidemic rheumatic fever. The majority of military personnel presenting with rheumatic fever had no antecedent clinical infection or did not present to sick call for diagnosis and treatment. The mass penicillin prophylaxis studies initiated in 1951 at the Streptococcal Disease Laboratory and at the Great Lakes Naval Training Station demonstrated conclusively the ability to control epidemic streptococcal disease and rheumatic fever in recruit and trainee populations. These studies led to recommendations from the CSSD for control of rheumatic fever and streptococcal disease. The recommendations were for appropriate laboratory identification of P-hemolytic streptococci, treatment of streptococcal infections, and epidemiological surveillance with guidelines for initiation of targeted mass prophylaxis.

The ad hoc committee organized in 1953 was formalized in 1955 as the Committee on Prophylaxis of Streptococcal Infections in the Armed Forces. The Committee annually reviewed current developments in studies of prophylaxis and transmitted recommendations to the preventive medicine officers of the three services. An initial recommendation for oral penicillin as the first choice for prophylaxis


303

THE LASKER AWARD


304

was eventually superseded by a recommendation of intramuscular benzathine penicillin as the drug of choice for prophylaxis. The latter recommendation came only after allaying the concern of the military services that there would be an unacceptable level of sensitivity reaction to the injectable penicillin. The issue of sensitivity reactions was debated at the AFEB Board meeting of May, 1957, as the following excerpt from the minutes indicates:

Dr. Rammelkamp expressed concern over the effect that a TB Med on the importance of the problem of sensitization to penicillin might have on the use of this drug in the prophylaxis and prevention of streptococcal infections. Dr. Rammelkamp stated his belief that prophylactic use would be stopped but that therapeutic use would not be decreased. Dr. Feller agreed and expressed the opinion that streptococcal infections were not being adequately treated at the present time. Dr. Shepard pointed out that the benefits from penicillin outweighed the chances of difficulty at the present time. Dr. Kern suggested the oral administration of penicillin which he believed to be a safer product. Dr. Wood emphasized that the administration of any drug depended on judgment and that a TB Med could not give that. Dr. Eisen stated that Dr. Pillsbury did not have in mind a directive that would jeopardize therapeutic and prophylactic administration of penicillin. Dr. Dingle asked that Dr. Eisen convey to Dr. Pillsbury the sense of the discussion and requested that the Commission on Cutaneous Diseases outline a proposed circular letter or TB Med.

This issue was not settled so far as the military was concerned until the AFEB held a special meeting in early 1959 directed specifically to the question of penicillin reactions and their relation to prophylaxis and treatment of streptococcal infections. The consensus from the meeting was that the risk of anaphylaxis with intramuscular penicillin in a population screened for sensitivity was negligible and that the slightly increased occurrence of other sensitivity reactions did not outweigh the marked advantage of injectable benzathine penicillin over oral penicillin in control of epidemic disease.

The Committee, initially advisory to the preventive medicine offices of the three services, assumed a more active role in 1957. Epidemic streptococcal disease and rheumatic fever continued to occur at recruit and other military bases, and it was apparent that the recommendations for control were not being implemented. At the May 1957 meeting of the Board, Dr. Rammelkamp proposed that an annual seminar be presented for orientation of personnel at the military base level. Dr. Rammelkamp's preamble statements and recommendation follow:

A) The Commission was concerned with reports of epidemics of streptococcal infection and rheumatic fever at several military establishments. It should again be emphasized that the occurrence of multiple cases of rheumatic fever at a single military base indicates failure to apply presently available preventive measures. Every effort should be made to assure adequate reporting, so that immediate control measures can be established without delay.

B) The Commission would like to call to the attention of the Military Services the fact that approximately four percent of men entering the services give a personal history of a previous attack of rheumatic fever. Since the risk of recurrent rheumatic fever following a streptococcal infection in these men is 20 percent, some consideration as to the desirability of prophylaxis should be entertained. Certainly, good preventive medical practices would include prophylaxis for those men assigned to areas where the risk of streptococcal infection is high.

C) In view of the fact that streptococcal infections, nephritis, and initial and recurrent attacks of rheumatic fever may be prevented by prophylactic measures, a vigorous effort should be made to protect military personnel from these diseases. It is therefore recommended that the Surgeons General establish an an nual joint orientation seminar for selected medical personnel from those bases where these diseases have been a recurrent problem for the purpose of establishing adequate control measures. The Commission on Streptococcal Diseases would welcome the opportunity to participate in such a program.

The recommendation was accepted and the Committee on Prophylaxis of Streptococcal Infections was charged with the responsibility to organize and conduct the annual seminars. The first seminar was held at Fort Carson in the fall of 1957. Annual seminars continued, with the last at Lowry Air Force Base in 1970.


305

The seminars were held on military bases selected by one of the three services on a rotating basis. Attendees were primarily preventive medicine and laboratory officers from Army, Navy, and Air Force bases. The average military attendance per year for the 14 seminars was 42.5 persons with 22.7, 6.9, and 12.9 persons, respectively, from the Army, Navy, and Air Force.

The seminars were usually 1 day in length and consisted of a series of presentations by Committee members and reports from military bases selected by the committee from responses to questionnaires sent to the bases after the prior respiratory disease season. The following program for the seminar at Lackland Air Force Base on 10 October 1961 is illustrative of the content and format of the seminars.

Program for Seminar at Lackland Air Force Base, 10 October 1961

Conference on Prophylaxis of Streptococcal Infections
Lackland Air Force Base, Texas
10 October 1961

0900-0910

Introduction


0910-0920


Streptococcal Infections and the Armed Forces

Dr. C. H. Rammelkamp

0920-0945

Epidemiology of streptococcal infections in military populations

Dr. H. B. Houser

0945-1005

The clinical diagnosis of streptococcal infection and rheumatic fever

Dr. R. H. Krause

1005-1030

The laboratory diagnosis of streptococcal infection

Mr. P. F. Frank

1030-1100

Theoretical and practical aspects of treatment of streptococcal infection

Dr. E. A. Mortimer, Jr

1115-1130

Methods of prophylaxis of streptococcal infection

Dr. H. F. Wood

1130-1200

Discussion

1200-1330

Lunch

1330-1400

The development of streptococcal prophylaxis programs at Great Lakes Naval Training Center

Capt. L. F. Miller

1400-1430

Discussion

1430-1500

Epidemic streptococcal disease, 1960-61, at Lowry Air Force Base, Colorado

Dr. S. S. Shkolnik
Dr. R. B. McFarland


1500-1530

Epidemic streptococcal disease 1960-61, Camp Pendleton and San Diego, California

Capt. R. A. Mount

1530-1700

Discussion

In subsequent years, the seminars were occasionally 1.5 days in length because other Commissions found the seminars useful for education related to a current problem in the military. For example, the 12th annual seminar at Great Lakes Naval Training Station had formal presentations by Theodore Eickhoff, Committee on Meningococcal Infection, CARD, and Fred Davenport, Director, Commission on Influenza.

The seminars had immediate impact on the control of epidemic rheumatic fever. Lowry Air Force Base, averaging 30 cases of rheumatic fever per year for the 4 years preceding the 1957 seminar, initiated a surveillance and mass prophylaxis program following the 1957 seminar and had only five cases of rheumatic fever in the 1957 and 1958 season. No further cases were identified at Lowry until 1967 and 1968, when a nonhemolytic group A streptococcus became epidemic and seven cases of rheumatic fever occurred before the laboratory at Lowry became alerted to its presence. Amarillo Air Force Base, Texas, also experienced a high rheumatic fever rate, 7/1,000/year, in the 1967 and 1968 season, prob-


306

ably attributable to the nonhemolytic strain. Recruits from Amarillo sent to Lowry for training are likely to have introduced the strain to Lowry.

Lackland Air Force Base, Texas, also instituted a streptococcal program following the 1957 seminar and, after averaging 33 cases of rheumatic fever for the previous 3 years, reported only three cases in 1957 and 1958. Other Army Air Force and Navy bases with traditionally high rates of rheumatic fever reported small numbers of cases as the surveillance and treatment programs were put in place.

The only installations with continuing problems in the early 1960s were the San Diego Naval Training Center and Marine Corp Recruit Depot and Great Lakes. San Diego averaged 13.8 cases per year between 1961 and 1965, and Great Lakes had 45 cases in the two seasons 1961 to 1962 and 1962 to 63. Although these numbers were nowhere near the hundreds of cases occurring in the late 1940s and early 1950s, the Navy felt it was not achieving the desired results from surveillance and intervention when indicated. Ft. Leonard Wood had initiated routine administration of benzathine penicillin to all incoming recruits rather than relying on the recommended surveillance program. The Navy instituted similar routine prophylaxis programs at Great Lakes and Parris Island in the early 1960s and at San Diego following the 1965 seminar at San Diego. No cases of rheumatic fever were reported by Great Lakes and San Diego in 1966 to 1967 or 1967 to 1968.

Whether the decline in rheumatic fever over the years of the seminars was the result of the control programs rather than a secular change in risk for rheumatic fever was a topic of discussion at each seminar during the mid to late 1960s. A rapidly decreasing incidence of rheumatic fever was also occurring in the civilian population at the same time. The Committee was concerned with the routine administration of benzathine penicillin to incoming recruits with its attendant sensitivity reactions, particularly if there no longer were indications for its use. At the behest of the Committee, Ft. Leonard Wood did abandon its routine prophylaxis program in 1967 to 1968 and 1968 to 1969 and followed the surveillance guidelines. Although there was no evidence that the surveillance program was less effective, the increased amount of time required by the preventive medicine officer and his staff for surveillance prompted the base to return to the routine prophylaxis program. Routine prophylaxis for new recruits became firmly entrenched as a procedure by the Navy and persisted into the 1980s.

After the 1970 seminar at Lowry Air Force Base, the Committee raised the question of continuation of the seminar with the military medical officers in attendance at Lowry. Their consensus was that the annual review of streptococcal disease and its sequelae served a useful purpose for continuing education of military medical officers in the recognition and control of streptococcal diseases. Accordingly, the recommendation of the Committee was to hold the seminar in 1971. The Navy extended an invitation for the meeting to be held at Orlando Naval Training Center, Florida, in the fall of 1971. This announcement at the spring meeting of the CSSD,11 March 1971, brought a response from the preventive medicine offices of the three services that, before concurring in plans for a 1971 seminar, they planned to examine the need for another seminar.

At the Executive Meeting of the AFEB on 19 May 1971, Lieutenant General H. B. Jennings, Jr., Surgeon General, United States Army, requested that "the symposium (seminar)...be modified this year by making it a two-sided re-evaluation, ad hoc committee or study group....and to totally reevaluate the streptococcal disease problem, establish its relative priority and plan future requirements."

The Committee accepted this recommendation, cancelled plans for the seminar, and scheduled a meeting for reevaluation on 29 November 1971 at WRAIR.

A planning meeting was held in Washington, DC on 14 July 1971. In attendance at this meeting were Dr. Gustave Dammin, President, AFEB; Dr. Wannamaker, Director, Commission on Streptococcal and Staphylococcal Diseases; Colonel Bradley W. Prior, Executive Secretary, AFEB; Committee members, Dr. Houser, Chairman, and Drs. Dillon, Edward A. Mortimer, Jr., and Krause. Colonel P Nugent, Captain C. H. Miller, and Colonel J. H. Greenberg represented the Preventive Medicine Offices of the Air Force, Navy, and Army, respectively. Lieutenant Colonel R. E. Winter, and Major C. T. Kaelber accompanied Colonel Greenberg. Colonel D. W. Sample and Major M. A. Moussa represented Headquarters, United States Army Medical Research and Development Command.


307

The meeting resulted in a memorandum from the AFEB to the three Surgeons General requesting information about streptococcal problems and programs during 1970 and 1971 for discussion at the 19 November meeting. The memorandum also concisely described the purposes of the annual seminar format as follows: Memorandum dated 26 July 1971 from Bradley W. Prior, Colonel USAF, MC, Executive Secretary, AFEB to the Surgeons General of the Army, Navy, and Air Force.

These include continuing education of the military personnel responsible for control and management of streptococcal disease and its sequelae in populations of recruits or others, translation of research and development activities into application in the field, and exhibition and discussion of field problems with the members of the committee. The last has been an extremely important aspect of the seminars since it has provided an opportunity for annual monitoring of streptococcal experience at the individual military base level.

Military representatives in their presentations emphasized the decreasing and low rates of acute rheumatic fever in the services. The incidence rates per 100,000 military personnel per year for acute rheumatic fever in 1970 were 9, 8, and 3.8 respectively, for the Army, Navy, and Air Force. The Army reported 125 cases in dependents in 1970 and the Air Force in the same period had 44 dependent cases. All three services agreed that continued surveillance of streptococcal infections was indicated but that the seminar was not an effective or efficient way to disseminate information to those people intimately concerned with surveillance. The discussion then centered on alternatives to the seminar that would continue the input of the members of the CSSD and would also permit the CSSD to remain abreast of current problems in the military.

Each preventive medicine officer was requested to submit a specific plan for continuation of the education and information program of the seminar relative to his or her own service. At the executive meeting of the CSSD the next day, the Navy, through Commander Comer, affirmed its stand that the seminar was not necessary and that it did not plan to propose any formal mechanism to replace it. Colonel Nugent stated that the Air Force adopted the Navy position. Colonels Greenberg and Ward stated that the Army planned to submit a specific proposal that would include the appointment of consultants to the preventive medicine officers of eight basic recruit training bases plus two others. The Army followed through on its proposal, and several members of the Committee and CSSD visited selected bases as consultants to The Army Surgeon General for the next 2 to 3 years.

The activities of the Committee on Prophylaxis of Streptococcal Infections resulted in the CSSD having the closest contact with preventive medicine officers in the field of any of the AFEB Commissions. Implementation of streptococcal control programs was hastened by this contact with a resultant savings in morbidity for all the Armed Forces during the late 1950s and early 1960s.

The members of the Committee on Prophylaxis of Streptococcal Infections in the Armed Forces follow:

F. Stephen Chapman, Ph.D.
Floyd W. Denny, M.D., Chairman, 1955 to 1961
Hugh C. Dillon, M.D.
Paul F. Frank, M.S.
Harold B. Houser, M.D., Chairman, 1961 to 1971
Richard M. Krause, M.D.
Robert B. McFarland, M.D.
Edward A. Mortimer, Jr., M.D.
Willard C. Schmidt, M.D.
Gene H. Stollerman, M.D.
Harrison F. Wood, M.D.


308

MAJOR SCIENTIFIC ACCOMPLISHMENTS OF WORK SUPPORTED BY CONTRACTS OF THE CSSD

The Streptococcus

Epidemiology

The epidemiology of streptococcal throat and skin infections and their relationship to pharyngitis and acute glomerulonephritis. Major observations were made on this subject in the laboratories of Drs. Wannamaker and Dillon. The Wannamaker studies were performed in Minneapolis, with the field observations being made at the Red Lake Indian Reservation in northern Minnesota; Dr. Dillon's observations were made in Birmingham, Alabama. Because the overall results from both sites were quite similar, they will be reported together. Extensive studies at both sites indicated that the epidemiology and bacteriology of throat and skin infections were different and, in general, the two clinical entities were not related. It was shown that group A streptococci were carried on normal skin before onset of pyoderma and that this was not related to throat carriage. The types of group A streptococci isolated from the two sites were different and special, such as the 8 / 23 / Imp. 19 and 3 / 13 / B complexes, and were found frequently in pyoderma. Superimposed staphylococcal infection occurred frequently in the pyoderma patients but not in pharyngitis patients. Pyoderma occurred in late summer and early fall, frequently in very young children, whereas pharyngitis occurred more frequently in older children in the winter and early spring. Acute glomerulonephritis followed infection of the skin with special "nephritogenic types" that were different from pharyngitis "nephritogenic types"; rheumatic fever did not occur following streptococcal pyoderma. The latent period of nephritis following pyoderma was much longer, 21 days, than the latent period following pharyngitis, 10 days. Dr. Dillon and his group demonstrated that reduced serum complement was an especially good diagnostic test in poststreptococcal glomerulonephritis. Studies by both groups delineated effective treatment regimens. Following the demonstration by Dr. Wannamaker that anti-deoxyribonuclease (DNase) B was a useful diagnostic test in streptococcal infection, both groups confirmed this usefulness in diagnosing the presence of a previous streptococcal infection in patients with acute glomerulonephritis. This was an especially helpful observation when it was demonstrated that antistreptolysin O responses were poor following pyoderma, probably because of lipids in the skin. These seminal observations, made by investigators working under contracts with the CSSD, provided much of the information regarding streptococcal skin infections that remains valid at this time.

Food-borne epidemic of streptococcal pharyngitis at the Air Force Academy. One of the largest food-borne epidemics of streptococcal infection on record occurred among cadets of the U. S. Air Force Academy in the spring of 1968. Over 1,200 cadets (38.4% of the population) developed symptoms of streptococcal pharyngitis. Drs. Wannamaker and Dillon and their coworkers did an extensive surveillance of 214 convalescent cadets. Most developed antibodies to antistreptolysin O and deoxyribonuclease B. Intramuscular benzathine penicillin was more effective than oral erythromycin in eradicating streptococci; there were 1.5% failures with the penicillin compared with 15% with erythromycin. The infecting streptococcus was a type 12 by T-agglutination but no nephritis occurred, suggesting that the strain was not nephritogenic. No rheumatic fever occurred, suggesting that the antibiotic treatment of all infected personnel was effective prevention.

Streptococcal infections at Loring Air Force Base, Maine. Studies were done at this base by Dr. Krause because of the prevalence of streptococcal infections at an installation that was not a training commandthat is, there were few recruits and the personnel resembled civilian populations. It was found that the family was the site of spread of many streptococcal infections; the attack rates of positive cultures in families from a positive index case were five times greater than in families of a negative index case. These studies emphasized the importance of the family in the spread of infections in the military.


309

Streptococcal infections in Cleveland school children. Studies done by Rammelkamp and his group in conjunction with an extensive rheumatic fever prevention program in northeast Ohio clearly showed the importance of the school as a site of spread of group A streptococci. These studies confirmed the studies at Loring described above and those done in Nashville, Tennessee, and Casper, Wyoming.

Basic Laboratory Observations

Studies on the bacteriolytic properties of streptomyces albus and its action on hemolytic streptococci. These studies reported in a preliminary way in the annual report of 1949 and 1950 are cited only because they are done by Dr. Avery working with Bertram E. Sprofkin at Vanderbilt University after Dr. Avery had retired from the Rockefeller Institute. One of the authors (F. D.), also at Vanderbilt during the 1950s, had many delightful visits with Dr. Avery before his death.

Group A streptococcal M protein. Considerable interest was placed on M protein, and the antibodies formed in response to it following streptococcal infection, because these antibodies protect against subsequent infection due to the same type of streptococcus. Dr. Lancefield showed years before that rabbits and mice injected with whole streptococcal cells developed type-specific, or anti-M-protein antibodies. Studies performed at the Strep Lab showing the protective effects of these antibodies have been described in a previous section. Unfortunately, attempts to develop a vaccine that was suitable for human use were largely unsuccessful. Dr. Krampitz from Western Reserve University had a contract for several years in an effort to purify M protein so that the events leading to its synthesis could be elucidated. Great difficulty was encountered in trying to purify the protein without losing serological activity. It was learned that group A streptococci stripped of their M protein by enzymes were still viable and capable of making new M protein without subsequently dividing.

Dr. Barkulis, University of Illinois, used a cell-wall preparation of group A streptococci in an attempt to develop an effective vaccine. His preparation was effective in rabbits, but when given to volunteers, only 4 of 24 vaccinated subjects developed type-specific antibodies.

Studies by Willard Schmidt of Western Reserve University using an M protein preparation from type 19 streptococci were begun at the Streptococcal Disease Laboratory and have already been described. These were continued in Cleveland after the Strep Lab closed, but were discontinued after only 2 of 22 children developed bactericidal antibodies after vaccination.

Dr. Stollerman, then at Northwestern University, appeared to have more success than others at developing a satisfactory M protein preparation for use in humans. Using type 12 cell-wall vaccines prepared by the method of Dr. Barkulis, he showed that rabbits, and subsequently humans, developed recall responses when vaccinated at a time when antibodies following previous natural infection had fallen to low or undetectable levels. Subsequent use of the vaccine in subjects who failed to develop type-specific antibody following type 12 infection showed antibody conversion in 4 of 5 children. Similar results were shown in children using a type 5 vaccine. Further studies, however, showed very poor responses in individuals who had not been previously infected with the homologous type of streptococcus, even when water-in-oil emulsions were used in the vaccines.

It is of interest that efforts are still being made currently to produce vaccines to group A streptococci, but none have been successful.

The type-specific long-chain formation by group A streptococci. In his studies on M protein and vaccines, Dr. Stollerman made the interesting observation that the most virulent strains of streptococci produced the shortest chains and that these strains, in the presence of type-specific antibodies, produced long chains. He subsequently developed this observation into a test for type-specific antibodies that gave results comparable to those using the bactericidal test.

The relationship of biological to epidemiological characteristics of group A streptococci. This is the title of a long-term contract held by Dr. Wannamaker at the University of Minnesota. Dr. Wannamaker's bril-


310

liant observations on the epidemiology of streptococcal respiratory infection in airmen at Warren Air Force Base, and the epidemiology of skin and throat infections in Native Americans on the Red Lake Reservation, have already been described. In addition, his laboratory was the center for important observations on the biology of group A streptococci and the relationships of these streptococcal biological products to streptococcal respiratory and skin infections, rheumatic fever, and acute glomerulonephritis.

Possibly the most noteworthy observations concerned the deoxyribonucleases produced by group A streptococci. Dr. Wannamaker and his coworkers described four such enzymes termed A, B, C, and D. All were thoroughly investigated, but DNase B and the antibodies produced to it proved the most useful in the clinical setting. It was shown that anti-DNase antibodies developed as frequently as did antistreptolysin responses in patients with streptococcal pharyngitis. In contrast, patients with streptococcal pyoderma developed anti-DNase antibodies much more frequently than antistreptolysin O. Further studies on streptococcal antibodies compared the responses in patients with uncomplicated pharyngitis to those responses of patients with rheumatic fever and nephritis. The decline of antibodies in these groups was carefully delineated.

In addition to the studies on the deoxyribonucleases, Dr. Wannamaker's group also made observations on diphosphopyridine nuclease (DPNase), the streptokinases, the lipoproteinases, the serum opacity factor, nicotinamide adenine dinucleotidase (NADase), and on the RNA and protein content of cell walls.

This group made some of the first observations on the use of fluorescent antibody to identify group A streptococci in laboratory cultures and in specimens from infected patients. Extensive studies were done on patients in an attempt to identify reliable methods for differentiating patients with an acute streptococcal infection from those with the streptococcal carrier state.

It is appropriate to note here that the Wannamaker laboratory was the site of many more important observations than those cited here and was a haven for the development of a whole new generation of young scientists who now maintain prominent positions throughout the world.

Streptococcal L forms. The possible role of streptococcal cells without walls in the pathogenesis of the complications of streptococcal infections interested several investigators, and the CSSD supported contracts to investigate this phenomenon in several laboratories. In general, these investigations proved fruitless and eventually were discontinued. Dr. Harry Gooder at the University of North Carolina chose the group D streptococcus as a model and did extensive studies on the optimal conditions for the induction, stabilization, and growth of L forms in this group of streptococcus. Dr. Mortimer at the University of New Mexico chose mouse and hamster models for the study of group A L forms and concentrated particularly on hamster skin infections. Preliminary studies on group A L forms were also described from the laboratories of Drs. Dillon and Wannamaker. As with the other studies, these trials provided no new insights into streptococcal infections and their complications.

Streptococcal proteinase. This contract, under the direction of Stanford Moore of the Rockefeller Institute, was of interest to the CSSD because Stuart Elliott had earlier described this enzyme that had the ability to destroy the serologic activity of the type-specific antigen, M protein, of group A streptococci. Dr. Elliott had determined that it could be prepared in gram quantities; it was ideal for studies of the mechanism of its action on streptococcal cells and of the comparative biochemistry of proteins. Over a period of several years, these workers determined the chemical nature of the enzyme, including its amino acid composition, and the portion of the molecule that is the site of immunological specificity.

Streptococcal group carbohydrate. Several investigators explored the chemical nature and immunological response to the group-specific carbohydrates of streptococci. Dr. Krause, working at the Rockefeller Institute, studied the chemical composition of streptococcal cell walls and showed that groups A, B, C, D, and G were similar. He also demonstrated that mice immunized with cell-wall vaccines were protected on challenge. In continuation of these studies, he was able to show that humans developed antibody to group A carbohydrates. He also found that certain rabbits immunized with streptococcal vaccines developed large amounts of electrophoretically uniform gammaglobulin with specificity to the group carbohydrate. Dr. Krause was able to selectively breed rabbits that were exceptionally good antibody producers. Dr. Schmidt, working with Dr. Rammelkamp, studied differ-


311

ent methods of preparing cell walls and, determining their fate in mice, he was able to detect soluble, serologically active group A carbohydrate in tissue extracts and in urine.

Penicillin Treatment of Acute Rheumatic Fever

Studies to evaluate the effect on acute rheumatic fever of prolonged treatment with large doses of penicillin were carried out in Chile by Dr. Rammelkamp and coworkers Mortimer, Rakita, and Krause. The rationale for these studies was based on indirect evidencefailure to prevent rheumatic fever if the infecting organism is not eradicated by treatment and reduction in risk of rheumatic fever even after delay of streptococcal treatment for 9 days, and on theorypersistence of living streptococci in heart tissues is related to the pathogenesis of valvular disease.

Three studies were conducted in Santiago, Chile, in 1956,1958, and 1961. Patients admitted to three Santiago hospitals with acute rheumatic fever were randomly assigned to penicillin treatment or no penicillin treatment. All patients were treated with aspirin. Intramuscular aqueous sodium penicillin G, 500,000 units every 4 hours, was administered for 1 week, followed by aqueous procaine penicillin G, 600,000 units every 12 hours, for 2 weeks, and 1,200,000 units of benzathine penicillin G on the 22nd day. Benzathine penicillin prophylaxis was given to all patients on the 43rd day and continued until the time of the 1-year follow-up.

The results of the first study of 66 patients, while not showing significant difference overall in valvular disease atl,1 year, did show a favorable effect of penicillin on valvular disease in subjects with "nonfixed" valvular disease at the time of admission. The latter finding led to a rather optimistic reporting of the effectiveness of penicillin treatment. It was decided that the study should be replicated, so an additional 63 patients were studied in Santiago in 1958. No protective effect of penicillin treatment was observed. A third study of an additional 97 patients was carried out in 1961. The results were similar to those of the second study. When all studies were combined, the 122 penicillin-treated patients with 1-year follow-up had no significant difference in valvular disease from the 120 control patients.

Although these studies produced negative results, they further illustrated the methodical approach of Dr. Rammelkamp to defining the role of the streptococcus in the pathogenesis of rheumatic fever.

Nephritis

The studies of Dr. Rammelkamp leading to the definition of nephritogenic types of group A streptococci were discussed above in the section on the Streptococcal Disease Laboratory. In the winter of 1955 and 1956, an outbreak of approximately 6,500 cases of acute nephritis occurred in Japan; Dr. Rammelkamp established that type 12 group A streptococcus was the epidemic strain.

Dr. Rammelkamp felt strongly that poststreptococcal acute glomerulonephritis was a self-limited disease and rarely, ever, progressed to chronic nephritis. His feeling was based in part on two follow-up studies he carried out. The first was a study of 61 patients with untreated type 12 infections observed during the nephritis epidemic at Bainbridge in 1952. Twelve patients with acute nephritis and 47 without nephritis were studied 15 to 48 months after the type 12 infection. One patient was considered to have chronic nephritis. This patient had had mild poststreptococcal hematuria with occasional systolic pressure above 140 mm Hg. In the second study, Dr. Rammelkamp evaluated 42 persons who had had post-scarlet fever nephritis 5 to 20 years earlier. None of these persons had evidence of chronic nephritis. Also, he and Schmidt were unable to detect type-specific antibody to nephritogenic types in the sera of persons with chronic nephritis. Lively debate between Drs. Rammelkamp and David P. Earle took place over several years around the issue of progression of acute glomerulonephritis to chronic nephritis. The other major studies of poststreptococcal nephritis supported by the CSSD were those of Drs. Wannamaker and Dillon, described above in the epidemiology of skin infections.

In connection with a meeting of the CSSD 3 March 1969, a symposium on "Skin Infections and Nephritis" was held jointly with the Commission on Cutaneous Diseases. Mr. David Taplin, of the


312

latter Commission, presented the problem of pyogenic skin infections with a potential threat of nephritis in servicemen in Southeast Asia.22 Reports were also made on the large outbreaks of nephritis following skin infections in Trinidad (Dr. Tom Parker, Central Public Health Laboratory, London, and Drs. David Earle, John Finklea, and Elizabeth Potter, Northwestern University) and the ongoing studies of Drs. Wannamaker in Minnesota and Dillon in Alabama. The peculiar biologic characteristics of cutaneous streptococci were discussed by Maxted, Central Public Health Laboratory, London.

The work of Drs. Rammelkamp, Wannamaker, and Dillon in elucidating the epidemiology, clinical course, and natural history of poststreptococcal acute glomerulonephritis is one of the outstanding achievements of the CSSD.

22. Allen, A. M., Taplin, D., and Twigg, L. Cutaneous streptococcal infections in Vietnam. Arch. Dermatol. 1971, 104, 271-280.

Balkan Nephropathy

In 1960, the existence of endemic nephropathy in sharply localized areas in Yugoslavia was brought to Dr. Rammelkamp's attention by a visit from Dr. Jacob Gaon of the medical faculty of the University of Sarajevo.

The high prevalence of chronic renal disease in areas that had high rates of "Trench" nephritis in both world wars was particularly intriguing to Dr. Rammelkamp. Intensive epidemiological, clinical, and laboratory studies were carried out by Drs. Rammelkamp, Robert Griggs, and Philip Hall in cooperation with Yugoslavian epidemiologists and nephrologists. The disease involved thousands of native people living along the tributaries of the Danube River in several Eastern European countries. In Yugoslavia, it was established that the disease was chronic, frequently led to death from uremia, and the initial lesions involved the renal tubules. Epidemiological studies suggested an environmental rather than genetic cause. The disease occurred predominantly in farmers and their children and could be related to the farming of specific fields. Dr. Hall developed a relatively simple and specific diagnostic test that could identify early disease (radio immunodiffusion of ß-2 microglobulin in urine). Development of this test took a year longer than anticipated when urine specimens, carefully collected by Dr. Hall in October 1964, were stolen from the luggage compartment of an airport bus in London. He and Dr. Dammin were the first to use biopsy material to describe the histopathology of early stages of the disease. Association of the disease with transitional cell tumors of the renal pelvis and ureters was established.

Based on the epidemiological and pathophysiological observations, hypothetical etiologic agents were investigated. These included lead, cadmium, arsenic, leptospira, plant exotoxin, silica salts, and bacterial infection. None of these agents could be associated with the disease. These studies, supported by the CSSD through 1971, have continued into the 1990s under the direction of Dr. Hall, Case Western Reserve University.

Transfer Factor

Basic studies on transfer factor by Drs. Tillett and Lawrence of New York University were supported through the CSSD from 1949 until it was discontinued. Dr. Tillett remained the principal investigator during this entire time, but it was clear early on that Dr. Lawrence was a prime mover. These studies had their genesis in the observations by Dr. Merrill W. Chase that the cellular transfer of tuberculin was possible in guinea pigs. At Dr. Tillett's suggestion, Dr. Lawrence was able to successfully transfer cutaneous delayed hypersensitivity to tuberculin from immune human donors to nonimmune recipients using blood leucocytes. This then led to the transfer of delayed sensitivity to streptococcal products in humans. This was prompted by interest in rheumatic fever and the possibility that cardiac damage could be the result of inflammatory hypersensitivity reactions of the delayed type. Transfer in humans was readily accomplished using intact streptococci, streptokinase and streptodornase (SK-


313

SD), and group A streptococcus M protein. Although the role of delayed hypersensitivity in streptococcal infections and rheumatic fever has never been delineated, the studies by Drs. Lawrence and Tillett opened up the scope of the entire field. The perfection of in vitro assays of cellular immunity and the discovery of the lymphokines advanced the field still further and led subsequently to the understanding that cellular immunity was at the core of understanding the mechanisms of allograft rejection; tumor immunity; prevention and recovery from intracellular infections caused by viruses, mycobacteria, and fungi; and some types of autoimmune responses.

It is of interest to note that Drs. Lawrence and Tillett, challenged by doubtfulness of Dr. Charles Smith of the CARP, developed a coccidioidin-specific transfer factor that transferred delayed reactivity and cellular immunity to coccidioidin from immune to nonimmune subjects. This form of therapy was shown to be of benefit in the management of patients with disseminated, amphotericin-resistant coccidioidomycosis.

Dr. Lawrence's reminiscences of the work on transfer factor and the CSSD are recorded in Appendix 7.

THE STAPHYLOCOCCUS

The first contracts for support of staphylococcal research were awarded by the CSSD in 1958 and 1959 to Dr. Cluff, The John Hopkins University, Dr. Ekstedt, Northwestern University, and Dr. Wannamaker. Dr. Rammelkamp incorporated staphylococcal studies in his streptococcal con tract at this time also. Dr. Keiichi Goshi, Medical College of Virginia, was supported from 1963 to 1965. Dr. Joseph El. Johnson, University of Florida, assumed responsibility for Dr. Cluff's contract when Dr. Cluff moved to the University of Florida in 1966. In addition, Dr. Dillon's studies of impetigo included definition of the role of staphylococci in impetiginous infections. Research related to the staphylococcus was in three areas: hospital epidemiology, host response to infection, and the biology of the organism.

Hospital Epidemiology

Drs. Rammelk amp, Mortimer, and Emanuel Wolinsky carried out a series of studies at Cleveland Metropolitan General Hospital that provided new and basic knowledge on the mechanisms of transmission of pathogenic staphylococci in the hospital setting. Their initial studies were conducted in a specifically designed newborn nursery unit to determine whether infant-to-infant spread was direct (heavy droplets projected short distances) or indirect (airborne droplet nuclei or dust). (These studies were carried out at a time when almost all newborns in this hospital became colonized by the time of their hospital discharge.) An index infant, known to be a nasal carrier of bacteriophage-typable strain of staphylococcus, was introduced into the unit. Uninfected newborns were admitted to one of six bassinets set at fixed distances from the index baby. Nurses who handled the uninfected infants had no direct contact with the index case. Ninety-five uninfected infants were admitted over an 8-week period. These brilliantly conceived studies showed that infant-to-infant spread was rare but there was a high rate (35%) of acquisition of strains carried by two of the three nurses. This and subsequent studies showed that the major mechanism of transmission was from the hands of personnel both to an infant and among infants. Handwashing by personnel markedly reduced spread but still permitted a significant amount of transmission.

A study of transmission of staphylococci from mothers to their newborn infants indicated that this was an infrequent occurrence during the 4 or 5 days of hospital stay, but that about one third of the infants acquired their mother's organism after returning home. Other studies in the nursery at Cleveland Metropolitan general Hospital indicated that fomites were not important vectors for transmission


314

unless they were contaminated by large numbers of staphylococci from open draining lesions. Intervention in a nursery epidemic by application of bacitracin ointment to the umbilicus and groin of newborns was demonstrated to control the epidemic with disappearance of the epidemic strain from the nursery.

Dr. Rammelkamp's group also studied the importance of the carrier state as a source of staphylococci in wound sepsis. Two hundred sixty-nine patients in male and female surgical wards were studied over a 2-year period. It was demonstrated that nasal and skin carriage were significant risk factors for wound colonization and wound sepsis. Skin carriage was the most important carrier site for wound colonization, but profuse nasal carriage put patients at increased risk of wound sepsis. The results indicated that measures designed to control the carrier state or to isolate the wound from the external environment should reduce wound sepsis by approximately 50%.

Dr. Cluff and coworkers carried out extensive studies at The John Hopkins Hospital in the epidemiology of staphylococcal infections in hospitalized patients, nursing mothers, pediatric patients, and hospital personnel. One of their interesting but unexplained observations was a seasonal variation in staphylococcal postsurgical wound infections. Over a 4-year period, the rate of infections was highest in January of each year. There was no evidence of similar distribution of infections by season in other hospital patients or in hospital personnel. Their longitudinal studies documented the disappearance of the type 80 / 81 strain, the "virulent" epidemic strain of the late 1950s, and its replacement in the hospital by the dominance of another strain, type 54. They speculated that increased use of neomycin for preoperative preparation of the bowel was responsible for the emergence of the new type. Occasioned by a marked increase in isolations of Staphylococcus aureus from the stools of pediatric patients, Dr. Cluff studied the intestinal flora of 38 children in a Baltimore orphanage. These studies, conducted longitudinally over a 6-month period, showed that S. aureus was present in only 4% of the cultures. S. albus in combination with a Gram-negative bacillus was present in 72% of the specimens. It was also demonstrated that only 13% of the children had persistence of the same stool flora over a 3-month period.

Host Response to Infection

Dr. Ekstedt studied natural and acquired resistance to the staphylococcus in mice. He showed that mice were protected from infection by immunization with whole cell vaccines from either living or killed cells. Cell walls, crude fractions, teichoic acid, and the Smith surface antigen also offered protection under certain experimental conditions. Germ-free mice were naturally highly resistant to infection. Dr. Ekstedt produced a form of runt disease in neonatal mice by repeated intraperitoneal injection of washed, killed staphylococci during the first 48 hours after birth. (Injection of killed streptococci also caused runt disease.) Germ-free mice were resistant to the runting phenomenon but could be induced to runt by adding homologous antiserum to the vaccine. Dr. Ekstedt also identified a serum antistaphylococcal factor in human, horse, and rabbit sera as a water-soluble globulin; it was not present in bovine serum. This factor had a direct lethal and lytic action on S. aureus and certain other bacteria.

Dr. Goshi evaluated the relationship of serum anti-alpha hemolysin to a variety of localized and more general staphylococcal skin infections. He concluded that there was no correlation between the level of anti-alpha hemolysin and either chronicity and healing of infection or phagocytosis and bacterial killing.

Drs. Wannamaker and Quie, using a rabbit model with necrotic skin lesions induced by subcutaneous injection of S. aureus, evaluated the effect of rabbit, bovine, and human platelets injected into the lesions. An obvious and consistent enhancement of infection occurred. This enhancement was also present in animals that had recovered from infection with a staphylococcal antibody response. A full-thickness experimental burn model in rabbits was developed by Drs. Wannamaker and Bascom F. Anthony to evaluate bacterial interference in mixed infections. Several strains of staphylococci were equally capable of colonizing and preventing superinfection by other inoculated staphylococci. Cross infection was also prevented. They demonstrated that this resistance was a local phenomenon, because


315

new burns on an animal could be infected with a second strain of staphylococcus. Heat-killed organisms did not cause interference. Although the mechanism of interference was not established, they concluded it was not by direct antagonism, nor was there any evidence of a humoral or tissue factor. Drs. Wannamaker and Adnan Dajani studied experimental skin infections in the hamster as a model for impetigo. They determined that the inoculum size required for infection was much greater for staphylococci than for group A streptococci and that there was great variation among staphylococcal phage types in their ability to cause infection.

Dr. Cluff and coworkers also used rabbit models for a series of experiments evaluating the effects of endotoxin, nonspecific inflammation, and anti-α-hemolysin immunity. Endotoxin, derived from Escherichia coli or S. flexneri, transiently increased the infectivity of pathogenic staphylococci but not of nonpathogenic organisms. The endotoxin effect was inhibited by α-hemolysin antibody if the latter was administered within 4 hours of the endotoxin. The increased susceptibility could be transferred to normal recipients via whole blood but not plasma. Transfer could not be made to endotoxin-tolerant animals. Endotoxin also inhibited leucocyte migration into the peritoneum after injection of staphylococci. The effect of endotoxin could be duplicated by the use of benzenes or nitrogen mustard when they caused leukopenia. They attributed the endotoxin effect to the resultant granulocytopenia. Nonspecific skin inflammation caused by thermal, chemical, or bacterial injury; arthus reaction; or tuberculin was more susceptible than normal skin to infection with intracutaneously injected staphylococci. However, if inflammation was present more than 2 to 3 days before injection, there was often increased resistance to infection. Repeated skin infections also enhanced infectivity and the extent and severity of infection. Rabbits immunized against α-hemolysin showed inhibition of necrosis and reduced growth of staphylococci in the experimental skin lesions. Renal abscesses after intrarenal injections of staphylococci were also prevented by α-hemolysin antibody.

Dr. Johnson, at the University of Florida, evaluated the effectiveness of lysostaphin in the rabbit burn model. He demonstrated that intravenous lysostaphin improved staphylococcal infections as effectively as methicillin treatment. Topical ointment was partially effective.

Studies in human hosts were rather limited. Dr. Cluff studied human cutaneous reaction to α-hemolysin or its toxoid. All subjects had demonstrable antibody to α-hemolysin. The skin reaction observed was biphasic, with early wheal and erythema followed by induration. The early response was similar to that elicited with ragweed or timothy antigens, ie, a polymorphonuclear response. The secondary response of induration was histologically not distinguishable from that of tuberculin, ie, a perivascular mononuclear response. The size of the secondary response was inversely related to the magnitude of the anti-α-hemolysin serum titer. Drs. Quie and Wannamaker compared serum levels of α-hemolysin and staphylokinase antibodies in children and adults with staphylococcal lesions, in normal persons and in maternal cord sera. They demonstrated placental transmission of both antibodies, active antibody to both by 2 years of age, and similar antibody responses after either infection or colonization.

Dr. Quie and c workers identified the inability of polymorphonuclear leucocytes to kill ingested S. aureus in patients with chronic granulomatous disease of childhood. This x-linked disease is characterized by recurrent severe infections, hepatosplenomegaly, and eczematoid skin lesions. The leucocytes from these children demonstrated normal in vitro phagocytosis, but the usual degranulation did not occur and the organism persisted intact in the leucocyte. It was subsequently shown that there is a defect within the phagocyte in oxidative metabolism and production of reactive oxygen radicals during phagocytosis.

Biology of the Staphylococcus

Drs. Quie and Wannamaker were curious about the mechanism of the Muller phenomenon, the appearance of numerous discrete satellite areas of clearing around colonies of coagulase positive staphylococci grown on agar plates containing rabbit serum and an indicator such as hemoglobin or whole red cells. They determined that the phenomenon could be duplicated in a sterile system by supernates


316

of staphylococcal broth cultures. They could also reproduce the phenomenon when purified plasminogen was substituted for whole serum. The Muller factor was demonstrated to be identical with previously described staphylokinase. Their experiments with both rabbit and human sera showed that human sera usually failed to produce (inhibited) the Muller phenomenon in the sterile system. A method for quantitative measurement of the inhibitor was developed. They concluded that the heat-stable inhibitor, in the gammaglobulin fraction of serum, was probably antistaphylokinase.

Drs. Quie and Ralph Williams investigated the antiphagocytic effects of staphylococcal protein A. Strains producing large amounts of protein A tended to be resistant to phagocytosis. Protein A itself inhibited phagocytosis in in vitro systems. They demonstrated that protein A combines nonspecifically to the Fc portion of human immunoglobulin (Ig) G and blocks or alters the opsonic site. Dr. Quie later showed that protein A affects nonspecific heat-labile opsonins as well as specific opsonins. In other work, he also described microcolonies (G variants) of S. aureus that were not pathogenic for mice. These organisms were readily engulfed by phagocytes but showed little cytotoxicity. He suggested that the G variants may be persistent in latent infections.

Dr. Dajani, in Wannamaker's laboratory, described a bactericidal staphylococcal product from phage type 71 that was effective against streptococci of groups A, C, and D, pneumococci, and corynebacteria. The product did not lyse organisms, but caused cessation of protein and DNA synthesis, and disintegrated RNA with cytoplasm dissolution, leaving cell-wall ghosts. The product, a heat-resistant and trypsin-sensitive protein of high molecular weight, was considered to be a bacteriocin. Dr. Dajani demonstrated that the bacteriocin could be neutralized by both immune and nonimmune sera. The nonimmune factor was heat labile and present in all human and guinea pig sera tested. The immune serum factor was heat stable.

Although the staphylococcal research sponsored by the CSSD did not have the major impact of its streptococcal research, several fundamental observations in the field were made and are included in current texts. There are the transmission studies by Dr. Rammelkamp and coworkers, the studies of immunity by Dr. Ekstedt, the risk factors for hospital infections described by Dr. Cluff, and the role of staphylococci in bullous impetigo elucidated by Dr. Dillon. The work of Dr. Quie in phagocytosis not only was important relative to staphylococci, but also in launching his outstanding career in the field.

STUDIES ON MISCELLANEOUS SUBJECTS

Dr. Hamburger, of the University of Cincinnati College of Medicine, studied the effect of streptokinase and streptofornase (streptococcal deoxyribonuclease [SK-SD]) in experimental meningitis in monkeys. Early experiments determined the doses of SK-SD that could be tolerated after intrathecal or intracisternal injection. Difficulty was encountered in establishing reproducible infection in monkeys using a variety of bacteria. Pneumonococcus type 1 was too virulent and Haemophilus influenzae not virulent enough. Pseudomonas aeruginosa proved to be most satisfactory and was used in experiments that demonstrated that SK-SD had some effect in reducing the exudative response in meningitis. Finally, experiments showed the importance of streptodornase in the enzymatic digestion in vitro of experimentally produced meningeal exudates.

Dr. Stetson, of New York University, pursued a variety of studies while under contract to the CSSD. The first of these involved the motility of leucocytes; he showed that the mechanism of movement was due to the alternating formation of crystal masses in pseudopods and then their solution, with result ing locomotion. He then studied the effects of radiation injury on host defenses, including the probable lack of a role of bacterial endotoxins in the illness resulting from whole-body irradiation in mice. Finally, he studied the role of murine isoantigens in homograft rejection.

Dr. Lewis M. Thomas, of New York University, held a contract for several years to study the pathogenesis of rheumatic fever. He elected to do this by investigating connective tissue pathology and


317

physiology and several experimental models in immunopathology. First, he studied the human placenta as a homograft. This was followed by the demonstration of the similar actions of papain and vitamin A on cartilage matrix, suggesting that vitamin A had its effect by activating proteolytic enzymes. Allergic encephalomyelitis, immune paralysis following excessive doses of pneumococcal polysaccharides, hemotransplantation and phagocytosis, and leukocyte metabolism were also included in his investigations. His studies on the role of lysosomes in tissue injury and the effect of cortisone in stabilizing lysosomes suggested a mechanism for the "antiinflammatory" action of cortisone. These observations were extended to studies of the role of lysosomes in endotoxin shock, traumatic shock, hypersensitivity reactions, streptococcal infection, and Shwartzman and Arthus reactions; all suggested that instability of lysosomes (or their counterparts, the granules of leukocytes), with release of lysosomal hydrolases into tissues or blood, may be important in the pathogenesis of tissue damage. Dr. Thomas also investigated the role of two mycoplasma species, M. gallisepticum and M. neurolyticum, in the central nervous system diseases of turkeys and mice, respectively, showing that these organisms, without cell walls, produce lesions by damaging blood vessels. Finally, he studied the relationship of the cell-wall carbohydrate of group H streptococci to group A carbohydrate.

Dr. Wood, of Johns Hopkins University, had a contract entitled "Factors influencing the phagocytic capabilities of polymorphonuclear leukocytes." The purpose was to identify the nonspecific phagocytosis-promoting factor (PPF) in rat serum that causes Streptococcus pneumoniae and Streptococcus pyogenes to be ingested at an accelerated rate by homologous leukocytes and the comparative phagocytic capabilities of granulocytes obtained from normal rats and from rats with chronic alloxan-induced diabetes mellitus. These studies showed that the phagocytosis-promoting effect of normal serum may be due to the combined opsonizing action of low titer antibodies to somatic antigens shared by many bacterial species and to some of the components of the complement system fixed to the bacterial cell surfaces as a result of the somatic antigen-antibody reactions. The studies in diabetic rats suggested that the depression of antiba aerial defenses that occurs in the hyperglycemic, nonacidotic, diabetic host is due to the hypersomolar'ty of the inflammatory exudate, resulting from the hyperglycemia.

PUBLICATIONS

1943

Boisvert, P L., Dawson, M. H., Schwentker, F. F., and Trask, J. D. Epidemic rheumatic fever. Ann. Intern. Med. 1943, 19,107-111.

Bloomfield, A. L., and Rantz, L. A. An outbreak of streptococcic septic sore throat in an army camp; clinical and epidemiologic observations. J. Am. Med. Assoc. 1943, 121, 315-319.

Schwentker, F. F. Survey of hemolytic streptococci in certain army camps. Army Med. Bull. 1943, 65, 94-104.

Schwentker, F. F. Relation between scarlet fever morbidity and streptococcus carrier rates. Am. J. Hyg. 1943, 38, 207-210.

1944

Rantz, L. A. Group A hemolytic streptococcus antibodies. III. A study of the simultaneous infection of men by a single type. Arch. Intern. Med. 1944, 73, 238-240.

1945

Rantz, L. A. Public health and preventive aspects of hemolytic streptococcal infections. Calif. West. Med.
1945, 63, 211-213.

Rantz, L. A., Boisvert, P J., and Spink, W. W. Etiology and pathogenesis of rheumatic fever. Arch. Intern. Med. 1945, 76, 131-138.

Rantz, L. A., and Randall, E. A modification of the technic for determination of the antistreptolysin titer. Proc. Soc. Exp. Biol. Med. 1945, 59, 22-25.

Rantz, L. A., Spink, W. W., Boisvert, P., and Coggeshall, H. The treatment of rheumatic fever with penicillin. J. Pediat. 1945, 26, 576-582.


318

1946

Dole, V. P. A dialyzable medium for cultivation of group A hemolytic streptococci. Proc. Soc. Exp. Biol. Med. 1946, 63, 122-126.

Hartman, T. L. Sulfonamide sensitivity determinations of hemolytic streptococci isolated from patients before and after treatment with sulfadiazine. Bull. Johns Hopkins Hosp. 1946, 79, 342-348.

Rantz, L. A., Boisvert, P. J., and Spink, W. W. Hemolytic streptococcal sore throat: Antibody response following treatment with penicillin, sulfadiazine, and salicylates. Science 1946, 103, 352-353.

Rantz, L. A., Boisvert, P. J., and Spink, W. W. The Dick test in military personnel: With special reference to the pathogenesis of the skin reaction. N. Engl. J. Med. 1946, 235, 39-43.

Rantz, L. A., Randall, E., Spink, W. W., and Boisvert, P J. Sulfonamide and penicillin resistance of group A hemolytic streptococci. Proc. Soc. Exp. Biol. Med. 1946, 62, 54-57.

Rantz, L. A., Rantz, H. H., Boisvert, P. J., and Spink, W. W. Streptococcic and nonstreptococcic disease of the respiratory tract, epidemiologic observations. Arch. Intern. Med. 1946, 77, 121-131.

Rantz, L. A., Boisvert, P. J., and Spink, W. W. Hemolytic streptococcic and nonstreptococcic diseases of the respiratory tract, a comparative clinical study. Arch. Intern. Med. 1946, 78, 369-386.

Rantz, L. A., Spink, W. W., and Boisvert, P. J. Abnormalities in the electrocardiogram following hemolytic streptococcus sore throat. Arch. Intern. Med. 1946, 77, 66-7 9.

Spink, W. W., Rantz, L. A., Boisvert, P J., and Coggeshall, H. Sulfadiazine and penicillin for hemolytic streptococcus infections of the upper respiratory tract: An evaluation in tonsillitis, nasopharyngitis and scarlet fever. Arch. Intern. Med. 1946, 77, 260-294.

1947

Elliott, S. D., and Dole, V P An inactive precursor of streptococcal proteinase. J. Exp. Med. 1947, 85, 305-320

Johnson, R. D., and Hartman, T. L. Sulfadiazine resistant streptococcal infections in a civilian community. J. Clin. Invest. 1947, 26, 325-328.

Rantz, L. A. The natural history of hemolytic streptococcus sore throat. Calif. Med. 1946, 65, 1-20.

Rantz, L. A., and Randall, E. Antibacterial precipitating antibodies in group A hemolytic streptococcus sore throat. Am. J. Med. 1947, 2, 551-567.

Rantz, L. A., Spink, W. W., and Boisvert, P. J. Hemolytic streptococcic sore throat. The course of the acute disease. Arch. Intern. Med. 1947, 79, 272-290.

Rantz, L. A., Boisvert, P. J., and Spink, W. W. Hemolytic streptococcic sore throat. The poststreptococcic state. Arch. Intern. Med. 1947, 79, 401-435.

Swift, H. F. Sharp interfacial precipitin reactions in capillary pipettes. Science 1947, 105, 49-50.

1948

Rantz, L. A., Boisvert, P. J., and Clark, W. H. Relationship of serological types of group A hemolytic streptococci to toxin formation and antibody response. Stanford Med. Bull. 1948, 6, 55-65.

Rantz, L. A., and Boisvert, P. J. Streptococcal fibrinolysin (streptokinase); a study of this substance and its antibody in group A hemolytic streptococcus sore throat. Am. J. Med. 1948, 5, 24-32.

Rantz, L. A., Randall, E., and Rantz, H. H. Antistreptolysin "O"; study of this antibody in health and in hemolytic streptococcus respiratory disease in man. Am. J. Med. 1948, 5, 3-23.

1949

Rantz, L. A., Randall, E., and Rantz, H. H. Immunization of human beings with group A hemolytic streptococci. Am. J. Med. 1949, 6, 424-432.

1950

*Denny, F. W., Wannamaker, L. W., Brink, W. R., Rammelkamp, C. H., Jr., and Custer, E. A. Prevention of rheumatic fever. Treatment of the preceding streptococcic infection. J. Am. Med. Assoc. 1950, 143, 151-153.

*Stollerman, G. H., and Bernheimer, A. W. Inhibition of streptolysin S by the serum of patients with rheumatic fever and acute streptococcal pharyngitis. J. Clin. Invest. 1950, 29, 1147-1155.

*Wannamaker, L. W., Denny, F. W., Rammelkamp, C. H., Jr., and Brink, W. R. Use of Maxted's method for group classification of hemolytic streptococci. Proc. Soc. Exp. Biol. Med. 1950, 73, 467-469.


319

1951

*Brink, W. R., Rammelkamp, C. H., Jr., Denny, F. W., and Wannamaker, L. W. Effect of penicillin and aureomycin on the natural course of streptococcal tonsillitis and pharyngitis. Am. J. Med. 1951,10, 300-308.

*Hahn, E. O., Houser, H. B., Rammelkamp, C. H., Jr., Denny, F. W., and Wannamaker, L. W. Effect of cortisone on acute streptococcal infections and post-streptococcal complications. J. Clin. Invest. 1951, 30, 274-281.

*Streptococcal Disease Laboratory, Francis E. Warren Air Force Base; Commission on Acute Respiratory Diseases, Armed Forces Epidemiological Board and Department of Preventive Medicine, School of Medicine, Western Reserve University. Prevention of rheumatic fever. U. S. Armed Forces Med. J. 1951, 2, 607-613.

*Wannamaker, L. W., Rammelkamp, C. H., Jr., Denny, F. W., Brink, W. R., Houser, H. B., Hahn, E. O., and Dingle, J. H. Prophylaxis of acute rheumatic fever, by treatment of the preceding streptococcal infection with various amounts of depot penicillin. Am. J. Med. 1951, 10, 673-695.

1952

*Houser, H. B., and Eckhardt, G. C. Recent developments in the prevention of rheumatic fever. Ann. Intern. Med. 1952, 37, 1035-1043.

Lawrence, H. S. The cellular transfer in humans of delayed cutaneous reactivity to hemolytic streptococci. J. Immunol. 1952, 68, 159-178.

*Rammelkamp, C. H., Jr. Prevention of rheumatic fever. Bull. Rheum. Dis. 1952, 2, 13-14.

*Rammelkamp, C. H., Jr., Houser, H. B., Hahn, E. O., Wannamaker, L. W., Denny, F. W., and Eckhardt, G. C. "The prevention of rheumatic fever." In Rheumatic Fever, A Symposium, edited by L. Thomas. Minneapolis, MN: University of Minnesota Press, 1952, 304-315.

*Rammelkamp, C. H., Jr., Wannamaker, L. W., and Denny, F. W. The epidemiology and prevention of rheumatic fever. Bull. N. Y. Acad. Med. 1952, 28, 321-334.

*Rammelkamp, C. H., Jr., Weaver, R. S., and Dingle, J. H. Significance of the epidemiological differences between acute nephritis and acute rheumatic fever. Trans. Assoc. Am. Physician 1952, 65, 168-175.

*Rammelkamp, C. H., Jr., and Denny, F. W. "Prevention of rheumatic fever." In Monographs in Medicine, edited by W. B. Bean. Baltimore, MD: William & Wilkins, 1952, p. 295.

*Rammelkamp, C. H., Jr., Wannamaker, L. W., and Denny, F. W. "Studies on the epidemiology of rheumatic fever in the armed services." In Rheumatic Fever, A Symposium, edited by L. Thomas. Minneapolis, MN: University of Minnesota Press, 1952, 72-89.

1953

*Brock, L. L., and Siegel, A. C. Studies on the prevention of rheumatic fever: The effect of time of initiation of treatment of streptococcal infections on the immune response of the host. J. Clin. Invest. 1953, 32, 630-632.

Clark, E. J., and Houser, H. B. Comparative effects of 3-hydroxy-2-phenylcinchoninic acid (HPC) and aspirin on the acute course of rheumatic fever and the occurrence of rheumatic valvular disease. Am. Heart J. 1953, 45, 576-588.

*Chamovitz, R., and Catanzaro, F. J. Evaluation of dibenzylethylene-diamine penicillin G in the prevention of rheumatic fever by treatment of the preceding streptococcal illness. In Antibiotics Annual, 1953-54. New York: Medical Encyclopedia, 1953, p. 113.

*Denny, F. W., Wannamaker, L. W., and Hahn EO. Comparative effects of penicillin, aureomycin and terramycin on streptococcal tonsillitis and pharyngitis. Pediatrics 1953, 11, 7-13.

*Dingle J. H., Rammelkamp C. H., Jr., and Wannamaker, L. W. Epidemiology of streptococcal infections and their nonsuppurative complications. Lancet 1953, 1, 736-738.

Finnerty J. J., The use of streptokinase-streptodornase in the treatment of thoracic empyema. Surg. Gynecol. Obstet. 1953, 97, 220-232.

Hamburger, M., and Biehl, J. P., Some effects of injecting sterile solutions of streptokinase-streptodornase into the sub-arachnoid space of normal rhesus monkeys. J. Clin. Invest. 1953, 32, 391-393.

*Houser, H. B., Eckhardt, G. C., Hahn, E. O., Denny, F. W., Wannamaker, L. W., and Rammelkamp, C. H., Jr. Effect of aureomycin treatment of streptococcal sore throat on the streptococcal carrier state, the


320

immunologic response of the host and the incidence of acute rheumatic fever. Pediatrics 1953, 12, 593-606.

*Rammelkamp, C. H., Jr. Glomerulonephritis. Proc. Inst. Med. Chic. 1953, 19, 17.

*Rammelkamp, C. H., Jr., and Weaver, R. S. Acute glomerulonephritis. The significance of variations in the incidence of the disease. J. Clin. Invest. 1953, 32, 345-358.

*Wannamaker, L. W., Denny, F. W., Perry, W. D., Rammelkamp, C. H., Jr., Eckhardt, G. C., Houser, H. B., and Hahn, E. O. The effect of penicillin prophylaxis on streptococcal disease rates and the carrier state. N. Engl. J. Med. 1953, 249, 1-7.

1954

*Catanzaro, F. J., Stetson, C. A., Morris, A. J., Chamovitz, R., Rammelkamp, C. H., Jr., Stolzer, B. L., and Perry, W. D. The role of the streptococcus in the pathogenesis of rheumatic fever. Am. J. Med. 1954, 17, 749-756.

*Chamovitz, R., Catanzaro, F. J., Stetson, C. A., and Rammelkamp, C. H., Jr., Prevention of rheumatic fever by treatment of previous streptococcal infections. N. Engl. J. Med. 1954, 251, 466-471.

*Denny, F. W., Jr. The prophylaxis of streptococcal infections. In Streptococcal Infections, edited by M. McCarty. New York: Columbia University Press, 1954, pp. 176-196.

*Dingle, J. H. The clinical pattern of streptococcal infection in man. In Streptococcal Infections, edited by M. McCarty, New York: Columbia University Press, 1954, pp. 120-129.

*Houser, H. B., Clark, E. J., and Stolzer, B. L., Comparative effects of aspirin, ACTH and cortisone on the acute course of rheumatic fever in young adult males. Am. J. Med. 1954, 16, 168-180.

McCarty, W. R. The enzymatic-surgical treatment of chronic infections of the feet in diabetic and arteriosclerotic patients. Surg. Clin. North Am. 1954, 34, 2-8.

*Rammelkamp, C. H., Jr. Acute hemorrhagic glomerulonephritis. In Streptococcal Infections, edited by M. McCarty. New York: Columbia University Press, 1954, pp. 197-207.

*Rammelkamp, C. H., Jr., Stetson, C. A., Krause, R. M., Perry, W. D., and Kohen, R. J. Epidemic nephritis. Trans. Assoc. Am. Physicians 1954, LXVII, 276-282.

*Rammelkamp, C. H., Jr., and Stolzer, B. L. The treatment and prevention of rheumatic fever. Pediatr. Clin. North. Am. 1954, 1, 265-274.

*Stetson, C. A., Jr. The relation of antibody response to rheumatic fever. In Streptococcal Infections, edited by M. McCarty. New York: Columbia University Press, 1954, pp. 208-218.

*Stolzer, B. L., Houser, H. B., and Clark, E. J. Comparative effects of aspirin, ACTH and cortisone on the antistreptolysin "O" titer and gamma globulin concentration in rheumatic fever. J. Lab. Clin. Med. 1954, 44, 229-234.

*Wannamaker, L. W. The epidemiology of streptococcal infections. In Streptococcal Infections, edited by M. McCarty. New York: Columbia University Press, 1954, pp. 157-175.

1955

*Catanzaro, F. J., Brock, L., Chamovitz, R., Perry, W. D., Siegel, A. C., Stetson, C. A., Rammelkamp, C. H., Jr., Houser, H. B., Stolzer, B. L., Wannamaker, L. W., and Hahn, E. O. Effect of oxytetracycline therapy of streptococcal sore throat on the incidence of acute rheumatic fever. Ann. Intern. Med. 1955, 42, 345-357.

*Chancey, R. L., Morris, A. J., Conner, R. H., Catanzaro, F. J., Chamovitz, R., and Rammelkamp, C. H., Jr. Studies of streptococcal prophylaxis: Comparison of oral penicillin and benzathine penicillin. Am. J. Med. Sci. 1955, 229, 165-171.

Clark, K. L., Jervey, L. P, Jr., Freiman, D. G., and Hamburger, M. Studies in experimental meningitis in rhesus monkeys. III. The effect of intracisternal injection of streptokinase and streptodornase on the exudate of experimental meningitis. J. Infect. Dis. 1955, 97, 305-310.

Hamburger, M., Clark, K. L., Biehl, J. P, and Jervey, L. P, Jr., Studies in experimental meningitis in rhesus monkeys. I. The pathogenic effect of various bacteria recovered from human cases. J. Infect. Dis. 1955, 97, 39-47.

Jervey, L. P, Jr., Clark, K. L., Freiman, D. G., and Hamburger, M. Studies in experimental meningitis in rhesus monkeys. II. The importance of streptodornase in the enzymatic digestion in vitro of experimentally produced meningeal exudate. J. Infect. Dis. 1955, 97, 299-304.


321

Lawrence, H. S. The transfer in humans of delayed skin sensitivity to streptococcal M substance and to tuberculin with disrupted leucocytes. J. Clin. Invest. 1955, 34, 219-230.

*Rammelkamp, C. H., Jr. Prevention of acute nephritis. Ann. Intern. Med., 1955, 43, 511-517.

*Rammelkamp, C. H., Jr. The natural history of streptococcal infections. Bull. N. Y. Acad. Med. 1955, 31, 103-112.

*Rammelkamp, C. H., Jr. Epidemiology of Streptococcal Infections. Harvey Lectures. Ser. 51. New York: Academic Press, 1955-56, pp. 113-142.

Seal, J. R. Oral penicillin prophylaxis of streptococcal infections. Am. J. Publ. Health 1955, 45, 662-672.

Seal, J. R., Mogabgab, W. J., Friou, G. J., and Banta, J. E. Penicillin prophylaxis of epidemic streptococcal infections. I. The epidemic and the effects of prophylaxis on the clinical manifestations of acute streptococcal and nonstreptococcal respiratory infections. J. Lab. Clin. Med. 1954, 44, 727-753

Seal, J. R., Mogabgab, W. J., Friou, G. J., and Banta, J. E. Penicillin prophylaxis of epidemic streptococcal infections. II. The effects of small and large doses of oral penicillin on epidemic streptococcal infections and on carriers of group A streptococci. J. Lab. Clin. Med. 1954, 44, 831-859.

*Siegel, A. C., Rammelkamp, C. H., Jr., and Griffeath, H. I. Epidemic nephritis in a school population. The relation of hematuria to group A streptococci. Pediatrics 1955, 15, 33-44.

Stetson, C. A., Rammelkamp, C. H., Jr., Krause R. M., Kohen, R. J., and Perry, W. D. Epidemic acute nephritis: Studies on etiology, natural history and prevention. Medicine 1955, 34, 431-450.

*Stolzer, B. L., Houser, H. B., and Clark, E. J. Therapeutic agents in rheumatic carditis. AMA Arch. Intern. Med. 1955, 95, 677-688.

1956

Lawrence, H. S. The delayed type of allergic inflammatory response. Am. J. Med. 1956, 20, 428-447.

Lawrence, H. S., and Pappenheimer, A. M., Jr. Transfer of delayed hypersensitivity to diphtheria toxin in man. J. Exp. Med. 1956, 104, 321-336.

*Morris, A. J., Chamovitz, R., Catanzaro, F. J., and Rammelkamp, C. H., Jr. Prevention of rheumatic fever by treatment of previous streptococcic infections. J. Am. Med. Assoc. 1956, 160, 114-116.

*Mortimer, E. A., Jr., and Rammelkamp, C. H., Jr. Prophylaxis of rheumatic fever. Circulation 1956, 14, 1144-1152.

*Rammelkamp, C. H., Jr. Streptococcal infection in relation to rheumatic fever and nephritis. Trans. Stud. Coll. Physicians. Phila. 1956, 23, 3.

Seal, J. R. Mass prophylaxis of epidemic streptococcal infections. Report on the use of penicillin prophylaxis in the navy during the winter of 1954 to 1955. Antibiotics Annual 1955-1956, 202-216.

1957

Barkulis, S. S., and Jones, M. F. Studies of streptococcal cell walls I. Isolation, chemical composition and preparation of M protein. J. Bacteriol. 1957, 74, 207-216.

*Davis, J., and Schmidt, W. C. Benzathine penicillin G. Its effectiveness in the prevention of streptococcal infections in a heavily exposed population. N. Engl. J. Med. 1957, 256, 339-342.

*Denny, F. W., Jr. Sore throat, hemolytic streptococcal. In Current Therapy. Philadelphia, PA: W. B. Saunders, 1957, p. 100.

*Denny, F. W., Jr., Perry, W. D., and Wannamaker, L. W. Type-specific streptococcal antibody. J. Clin. Invest. 1957, 36, 1092-1100.

Lawrence, H. S. Similarities between homograft rejection and tuberculin-type allergy: A review of recent experimental findings. Ann. N. Y. Acad. Sci. 1957, 64, 826-835.

*Morris, A. J., and Rammelkamp, C. H., Jr. Benzathine penicillin G in the prevention of streptococcic infections. J. Am. Med. Assoc. 1957, 164, 664-667.

*Perry, W. D., Siegel, A. C., Rammelkamp, C. H., Jr., Wannamaker, L. W., and Marple, E. C. Transmission of group A streptococci. I. The role of contaminated bedding. Am. J. Hyg. 1957, 66, 85-95.

*Perry, W. D., Siegel, A. C., and Rammelkamp, C. H., Jr. Transmission of group A streptococci. II. The role of contaminated dust. Am. J. Hyg. 1957, 66, 96-101.

Quinn, R. W., Denny, F. W., and Riley, H. D. Natural occurrence of hemolytic streptococci in normal school children. Am. J. Public Health 1957, 47, 995-1008.


322

*Rammelkamp, C. H., Jr., Microbiologic aspects of glomerulonephritis. J. Chronic Dis. 1957, 5, 28-33.

*Schmidt, W. C. The quantitative precipitin reaction of type 19 M protein antigen of group A streptococci and antistreptococcal rabbit sera. J. Immunol. 1957, 78, 178-184.

*Schmidt, W. C. Bacterial infections of the nasopharynx. In Pediatric Clinics of North America. Philadelphia, PA: W. B. Saunders, 1957, pp. 139-154.

*Sherwood, R. W., Gronbeck, C., and Denny, F. W., Jr. Reactions from multiple injections of benzathine penicillin G. J. Am. Med. Assoc. 1957, 165, 667-670.

1958

*Catanzaro, F. J., Rammelkamp, C. H., Jr., and Chamovitz, R. Prevention of rheumatic fever by treatment of streptococcal infections. II. Factors responsible for failures. N. Engl. J. Med. 1958, 259, 51-57.

Rammelkamp, C. H., Jr. The Lewis A. Conner Memorial Lecture. Rheumatic heart disease—a challenge. Circulation 1958, 17, 842-851.

*Rammelkamp, C. H., Morris, A., Catanzaro, F. J., Wannamaker, L. W., Chamowitz, R., and Marple, E. C. Transmission of group A streptococci. III. The effect of dying on the infectivity of the organism for man. J. Hyg. 1958, 56, 280-287.

*Schmidt, W. C., and Rammelkamp, C. H., Jr. Etiology and pathogenesis of glomerulonephritis. Adv. Intern. Med. 1958, 9, 181-205.

Vaisman, S., Rakita, L., Mortimer, E. A., Jr., Guasch, J., Schuster, A., Vignau, A., Roberts, R.B., Krause, R. M., and Rammelkamp, C. H., Jr. A new approach to the treatment of acute rheumatic fever. Trans. Assoc. Am. Physicians 1958, 71, 274-280.

1959

Benacerraf, B., Kivy-Rosenberg, E., Sebestyen, M. M., Zweifach, B. W. The effect of high doses of x-irradiation on the phagocytic, proliferative, and metabolic properties of the reticulo-endothelial system. J. Exp. Med. 1959, 110, 49-64.

Crea, M. A., and Mortimer, E. A., Jr. The nature of scarlatinal arthritis. Pediatrics 1959, 23, 879-884.

Mortimer, E. A., Jr., and Rammelkamp, C. H., Jr. Prevention and treatment of rheumatic valvulitis. Postgrad. Med. 1959, 25, 578-583.

Mortimer, E. A., Jr., Vaisman, B. S., Vignau, I. A., Guasch, L. J., Schuster, C. A., Rakita, L., Krause, R. M., Roberts, R., and Rammelkamp, C. H., Jr. The effect of penicillin on acute rheumatic fever and valvular heart disease. N. Engl. J. Med. 1959, 260, 101-112.

1960

*Chamovitz, R., Rammelkamp, C. H., Jr., Wannamaker, L. W., and Denny, F. W., Jr. The effect of tonsillectomy on the incidence of streptococcal respiratory disease and its complications. Pediatrics 1960, 26, 355-367.

Ekstedt, R. D., and Stollerman, G. H. Factors affecting the chain length of group A streptococci. I. Demonstration of a metabolically active chain-splitting system. J. Exp. Med. 1960, 112, 671-686.

Ekstedt, R. D., and Stollerman, G. H. Factors affecting the chain length of group A streptococci. II. Quantitative M-anti-M relationships in the long chain test. J. Exp. Med. 1960, 112, 687-698.

Ekstedt, R. D., and Yotis, W. W. Studies on staphylococci. II. Effect of coagulase on the virulence of coagulase negative strains. J. Bacteriol. 1960, 80, 496-500.

Ekstedt, R. D., and Yotis, W. W. Studies on staphylococci. III. Further studies on purification and mechanism of action of an antibacterial human serum factor. J. Bacteriol. 1960, 80, 719-725.

Kushner, I., and Schmidt, W. C. The prevention of rheumatic fever. Ohio State Med. J. 1960, 56, 657-662.

Lawrence, H. S. Homograft sensitivity. An expression of the immunologic origins and consequences of individuality. Physiol. Rev. 1959, 39, 811-859.

Lawrence, H. S., Rapaport, F. T., Converse, J. M., and Tillett, W. S. Transfer of delayed hypersensitivity to skin homografts with leukocyte extracts in man. J. Clin. Invest. 1960, 39, 185-198.

Quie, P G., and Wannamaker, L. W. An unusual staphylococcal product and its host interactions. Univ. Minn. Med. Bull. 1960, 32, 125-133.

Quie, P G., and Wannamaker, L. W. The plasminogen-plasmin system of newborn infants. Am. J. Dis. Child. 1960, 100, 836-843.


323

Schmidt, W. C. Type-specific antibody formation in man following injection of streptococcal M protein. J. Infect. Dis. 1960, 106, 250-255.

Wannamaker, L. W., and Ayoub, E. M. Clinical progress. Antibody titers in acute rheumatic fever. Circulation 1960, 21, 598-614.

Wannamaker, L. W. The continuing challenge of streptococcal infections and their complications. Minn. Med. 1960, 43, 39-43.

Wolinsky, E., Lipsitz, P .J., Mortimer, E. A., Jr., and Rammelkamp, C. H., Jr. Acquisition of staphylococci by newborns, direct versus indirect transmission. Lancet 1960, 2, 620-622.

1961

Cluff, L. E. Staphylococcal infections. Trans. Am. Acad. Ophthalmol. Otolaryngol. 1961, Jan-Feb, 33-43.

Conti, C. R., Cluff, L. E., and Scheder, E. P. Studies on the pathogenesis of staphylococcal infection. IV. The effect of bacterial endotoxin. J. Exp Med. 1961, 113, 845-860.

Johnson, J. E., Cluff, L. E., and Goshi, K. Studies on the pathogenesis of staphylococcal infection. I. The effect of repeated skin infections. J. Exp. Med. 1961, 113, 235-248.

Goshi, K., Cluff, L. E., Johnson, J. E., and Conti, C. R. Studies on the pathogenesis of staphylococcal infection. II. The effect of non-specific inflammation. J. Exp. Med. 1961, 113, 249-257.

Goshi, K., Cluff, L. E., and Johnson, J. E. Studies on the pathogenesis of staphylococcal infection. III. The effect of tissue necrosis and antitoxic immunity. J. Exp. Med. 1961, 113, 259-270.

Mortimer, E. A., Jr., Fischer, P, Jenkins, N., and McGirr, D. Staphylococcus in the nursery. Am. J. Nurs. 1961, 61, 56-59.

Quie, P. G., and Wannamaker, L. W., Staphylococcal Muller phenomenon: Relationship to the plasminogen-plasmin system. J. Bacteriol. 1961, 82, 770-783.

*Rammelkamp, C. H., Jr., and Stolzer, B. L. The latent period before the onset of acute rheumatic fever. Yale J. Biol. Med. 1961/2, 34, 226-238.

Wannamaker, L. W., and Pierce, H. C. Family outbreak of acute nephritis associated with type 49 streptococcal infection. Lancet 1961, 81, 561-571.

Wannamaker, L. W. Theoretical and practical implications of the epidemiologic differences between acute rheumatic fever and acute nephritis. N. C. Med. J. 1961, 22, 485-492.

1962

Ayoub, E. M., and Wannamaker, L. W. Evaluation of the streptococcal desoxyribo-nuclease B and diphosphopyridine nucleotidase antibody tests in acute rheumatic fever and acute glomerulonephritis. Pediatrics 1962, 29, 527-538.

Cohen, L. S., Fekety, F. R., and Cluff, L. E. Studies of the epidemiology of staphylococcal infection. IV. The changing ecology of hospital staphylococci. N. Engl. J. Med. 1962, 266, 367-372.

Cohen, L. S., Fekety, R. F., and Cluff, L. E. Studies of the epidemiology of staphylococcal infection. V. The reporting of hospital-acquired infection. J. Am. Med. Assoc. 1962, 180, 805-808.

Cohen, L. S., and Cluff, L. E. A study of the intestinal flora in a closed pediatric community. Am. J. Hyg. 1962, 76, 262-266.

Gonzaga, A. J., and Rammelkamp, C. H., Jr. Diphosphopyridine nucleotidase and acute glomerulonephritis. Arch. Intern. Med. 1962, 110, 615-618.

Guasch, J. L., Vignau, A. I., Mortimer, E. A., Jr., and Rammelkamp, C. H., Jr. Studies of the role of continuing or recurrent streptococcal infection in rheumatic valvular heart disease. Am. J. Med. 1962, 244, 290-296.

Klainer, L. M., Agrawal, H. S., Mortimer, E. A. Jr., and Wolinsky, E. Bacitracin ointment and neonatal staphylococci. Am. J. Dis. Child. 1962, 103, 564-568.

*Krause, R. M., Rammelkamp, C. H., Jr., Denny, F. W., Jr., and Wannamaker, L. W. Studies of the carrier state following infection with group A streptococci. I. Effect of climate. J. Clin. Invest. 1962, 41, 568-574.

*Krause, R. M., and Rammelkamp, C. H., Jr. Studies of the carrier state following infection with group A streptococci. II. Infectivity of streptococci isolated during acute pharyngitis and during the carrier state. J. Clin. Invest. 1962, 41, 575-578.

Mortimer, E. A., Jr., Lipsitz, P. J., Wolinsky, E., Gonzaga, A. J., and Rammelkamp, C. H., Jr. Transmission


324

of staphylococci between newborns. Importance of the hands of personnel. Am. J. Dis. Child. 1962, 104, 289-295.

Potter, E. V., Stollerman, G. H., and Siegel, A. C. Recall of type specific antibodies in man by injections of streptococcal cell walls. J. Clin. Invest. 1962, 41, 301-310.

Quie, P. G. Current concepts regarding staphylococcal disease. Minn. Med. 1962, 45, 718-722.

Quie, P. G., Wannamaker, L. W. Demonstration of an inhibitor of the Muller phenomenon in human sera: Its identification as antistaphylokinase. J. Clin. Invest. 1962, 41, 92-100.

Rammelkamp, C. H., Jr. Armed Forces Epidemiological Board activities of the Commission on Streptococcal and Staphylococcal Diseases. Mil. Med. 1962, 127, 1007-1008.

Sanders, E. Inhibition of coagulase reaction of a pathogenic staphylococci by heparin in vitro. Proc. Soc. Exp. Biol. Med. 1962, 109, 185-188.

Wolinsky, E., Gonzaga, A. J., and Mortimer, E. A., Jr. The mother as a source of neonatal staphylococci. N. Engl. J. Med. 1962, 267, 535-538.

Wolinsky, E., and Hines, J. D. Neurotoxic and nephrotoxic effects of colistin in patients with renal disease. N. Engl. J. Med. 1962, 266, 759-762.

1963

Cohen, I. R., and Stollerman, G. H. Non-type specific resistance to group A streptococci in germ free and conventional mice. Proc. Soc. Exp. Biol. Med. 1963, 114, 202-205.

Ekstedt, R. D. Studies on immunity to staphylococcal infection in mice. I. Effect of dosage, viability, and interval between immunization and challenge on resistance to infection following injection of whole cell vaccines. J. Infect. Dis. 1963, 112, 143-151.

Ekstedt, R. D. Studies on immunity to staphylococcal infection in mice. II. Effect of immunization with fractions of Staphylococcus aureus prepared by physical and chemical methods. J. Infect. Dis. 1963, 112, 152-157.

Goshi, K., Cluff, L. E., and Norman, P. S. Studies on the pathogenesis of staphylococcal infection. V. Purification and characterization of staphylococcal alpha hemolysin. Bull. Johns Hopkins Hosp. 1963, 112, 15-30.

Goshi, K., Cluff, L. E., and Norman, P. S. Studies on the pathogenesis of staphylococcal infection. VI. Mechanism of immunity conferred by anti-alpha hemolysin. Bull. Johns Hopkins Hosp. 1963, 112, 31-47.

Goshi, K., Smith, E. W., Cluff, L. E., and Norman, P S. Studies on the pathogenesis of staphylococcal infection. VII. Characterization of the dermal reaction to purified alpha hemolysin in normal and immune animals. Bull. Johns Hopkins Hosp. 1963, 113, 183-201.

Houser, H. B. Activities of the Committee on Prophylaxis of Streptococcal Infections in the Armed Forces. Mil. Med. 1963, 128, 888-889.

Lawrence, H. S., Rapaport, F. T., Converse, J. M., and Tillett, W. S. A mechanism of homograft rejection. IInd. Int. Symp. Immunopathol. 1962, 204-209.

Smith, E. W., Goshi, K., Norman, P. S., and Cluff, L. E. Studies on the pathogenesis of staphylococcal infection. VIII. The human cutaneous reaction to injection of alpha hemolysin. Bull. Johns Hopkins Hosp. 1963, 113, 247-260.

1964

Ekstedt, R. D., and Nishimura, E. T. Runt disease induced in neonatal mice by sterile bacterial vaccines. J. Exp. Med. 1964, 120, 795-804.

Fekety, F. R., Jr. The epidemiology and prevention of staphylococcal infection. Medicine 1964, 43, 593-613.

Gonzaga, A., Mortimer, E. A., Jr., Wolinsky, E., and Rammelkamp, C. H., Jr. Transmission of staphylococci by fomites. J. Am. Med. Assoc. 1964, 189, 711-715.

Griggs, R. C., and Hall, P. W. Investigations of chronic endemic nephropathy in Yugoslavia. Ren. Metab. Epidemiol. Some Ren. Dis. Proc. 1963, 312-328.

Minchew, B. H., Hook, E. W., Petersdorf, R. G., Johnson, J. E., III, and Cluff, L. E. Studies of the epidemiology of staphylococcal infection, VII. Infection in hospital personnel. Bull. Johns Hopkins Hosp. 1964, 114, 313-324.


325

Quie, P. G., and Wannamaker, L. W. Serum antibodies in staphylococcal disease. Pediatrics 1964, 33, 63-70.

Rammelkamp, C. H., Jr., Mortimer, E. A., Jr., and Wolinsky, E. Transmission of streptococcal and staphylococcal infections. Ann. Int. Med. 1964, 60, 753-758.

Schneider, W. F., Chapman, S., Schulz, V. B., Krause, R. M., and Lancefield, R. C. Prevention of streptococcal pharyngitis among military personnel and their civilian dependents by mass prophylaxis. N. Engl. J. Med. 1964, 270, 1205-1212.

Thornton, G. F., Fekety, F. R., and Cluff, L. E. Studies of the epidemiology of staphylococcal infection. VIII. Seasonal variation. N. Engl. J. Med. 1964, 271, 1333-1337.

1965

Cluff, L. E. Cellular reactions in the pathogenesis of staphylococcal infection. Ann. N. Y. Acad. Sci. 1965, 128, 214-230.

Dillon, H. C., Jr., and Wannamaker, L. W. Physical and immunological differences among streptokinases. J. Exp. Med. 1965, 121, 351-371.

Hall, P. W., III, Dammin, G. J., Griggs, R. C., Fajgelj, A., Zimonjic, B., and Gaon, J. Investigation of chronic endemic nephropathy in Yugoslavia. II. Renal pathology. Am. J. Med. August 1965, 39, 210-217.

Lewis, G. W., and Cluff, L. E. Synovitis in rabbits during bacteremia and vaccination. Bull. Johns Hopkins Hosp. 1965, 116, 175-190.

Mortimer, E. A., Jr. (Introduced by Charles H. Rammelkamp, Jr.) Production of L forms of group A streptococci in mice. Proc. Soc. Exp. Biol. Med. 1965, 119, 159-163.

Mulholland, J. H., and Cluff, L. E. The effect of endotoxin upon susceptibility to infection: The role of the granulocyte. Bacterial Endotoxins 1965, 211-229.

Vaisman, S. B., Guasch, J. L., Vignau, A. I., Correa, E. T., Schuster, A. C., Mortimer, E. A., Jr., and Rammelkamp, C. H., Jr. Failure of penicillin to alter acute rheumatic valvulitis. J. Am. Med. Assoc. 1965, 194, 1284-1286.

Vignau, A. I., Correa, E. T., Guasch, J. L., Schuster, A. C., Patri, A. M., Vaisman, S. B., and Mortimer, E. A., Jr. The effects of indomethacin on rheumatic fever. Arthritis Rheum. 1965, 8, 501-510.

1966

Ayoub, E. M., and Wannamaker, L. W. Streptococcal antibody titers in Sydenham's chorea. Pediatrics 1966, 38, 946-956.

Drachman, R. H., Root, R. K., and Wood, W. B., Jr. Studies on the effect of experimental nonketotic diabetes mellitus on antibacterial defense. I. Demonstration of a defect in phagocytosis. J. Exp. Med. 1966, 124, 227-240.

Mortimer, E. A., Jr. Wolinsky, E., and Hines, D. The effect of rooming-in on the acquisition of hospital staphylococci by newborn infants. Pediatrics 1966, 37, 605-609.

Mortimer, E. A., Jr., Wolinsky, E., Gonzaga, A. J., and Rammelkamp, C. H., Jr. Role of airborne transmission in staphylococcal infections. Br. Med. J. 1966, 1, 319-322.

Quie, P. G., Pierce, H. C., and Wannamaker, L. W. Influence of penicillinase-producing staphylococci on the eradication of group A streptococci from the upper respiratory tract by penicillin treatment, Pediatrics. 1966, 37, 467-476.

1967

Anthony, B. F., Kaplan, E. L., Chapman, S. S., Quie, P G., and Wannamaker, L. W. Epidemic acute nephritis with reappearance of type-49 streptococcus. Lancet 1967, 2, 787-790.

Anthony, B. F., Giebink, G. S., and Quie, P. G. Neomycin-resistant staphylococci in a rural outpatient population. Am. J. Dis. Child. 1967, 113, 664-669.

Anthony, B. F., and Wannamaker, L. W. Bacterial interference in experimental burns. J. Exp. Med. 1967, 125, 319-336.

Anthony, B. F., Perlman, L. V., and Wannamaker, L. W. Skin infections and acute nephritis in American Indian children. Pediatrics 1967, 39, 263-279.

Ayoub, E., and Wannamaker, L. W. The fate of group A streptococci following phagocytosis. In vitro phagocytic studies of isotope-labeled streptococci. J. Immunol. 1967, 99, 1099-1105.


326

Dillon, H. C., Jr. The treatment of streptococcal skin and soft tissue infections. Int. Congr. Chemother. 1967, 13-23.

Dillon, H. C., Jr. Pyoderma and nephritis. Annu. Rev. Med. 1967, 18, 207-218.

Dillon, H. C., Jr., Moody, M. D., Maxted, W. R., and Parker, M. T. The epidemiology of impetigo and acute glomerulonephritis, results of serological typing of group A streptococci. Am. J. Epidemiol. 1967, 86, 710-723.

Mortimer, E. A., Jr., and Vastine, E. L. Production of capsular polysaccharide (hyaluronic acid) by L colonies of group A streptococci. J. Bacteriol. 1967, 94, 268-271.

Quie, P. G., White, J. G., Holmes, B., and Good, R. A. In vitro bactericidal capacity of human polymorphonuclear leukocytes: Diminished activity in chronic granulomatous disease of childhood. J. Clin. Invest. 1967, 46, 668-679.

Top, F. H., Jr., Wannamaker, L. W., Maxted, W. R., and Anthony, B. F. M antigens among group A streptococci isolated from skin lesions. J. Exp. Med. 1967, 126, 667-685.

Wannamaker, L. W., and Yasmineh, W. Streptococcal nucleases. I. Further studies on the A, B, and C enzymes. J. Exp. Med. 1967, 126, 475-496.

Wannamaker, L. W., Hayes, B., and Yasmineh, W. Streptococcal nucleases. II. Characterization of DNAse D. J. Exp. Med. 1967, 126, 497-508.

1968

Ayoub, E. M., and McCarty, M. Intraphagocytic beta-N-acetylglucosaminidase properties of the enzyme and its activity on group A streptococcal carbohydrate in comparison with a soil bacillus enzyme. J. Exp. Med. 1968, 127, 833-851.

Chilgren, R. A., Hong, R., and Quie, P. G. Human serum interactions with Candida albicans. J. Immunol. 1968, 101, 123-132.

Dillon, H. C., Jr. Impetigo contagiosa: Suppurative and non-suppurative complications. I. Clinical bacteriologic, and epidemiologic characteristics of impetigo. Am. J. Dis. Child. 1968, 115, 530-541.

Dillon, H. C., Reeves, M. S., and Maxted, W. R. Acute glomerulonephritis following skin infection due to streptococci of M-type 2. Lancet 1968, 1, 543-545.

Dudding, B. A., and Ayoub, E. M. Persistence of streptococcal group A antibody in patients with rheumatic valvular disease. J. Exp. Med. 1968, 128, 1081-1098.

Hill, M. J., and Wannamaker, L. W. The serum opacity reaction of Streptococcus pyogenes. General properties of the streptococcal factor and of the reaction in aged serum. J. Hyg. Cambridge 1968, 66, 37-47.

Kaplan, E. L., Laxdal, T., and Quie, P. G. Studies of polymorphonuclear leukocytes from patients with chronic granulomatous disease of childhood, Bactericidal capacity for streptococci. Pediatrics 1968, 41, 591-599.

Laxdal, T., Messner, R. P., Williams, R. C., Jr., and Quie, P. G. Opsonic, agglutinating and complementfixing antibodies in patients with subacute bacterial endocarditis. J. Lab. Clin. Med. 1968, 71, 638-653. Messner, R. P, Laxdal, T., Quie, P G., Williams, and R. C., Jr. Serum opsonin, bacteria and polymorphonuclear leukocyte interactions in subacute bacterial endocarditis anti-gammaglobulin factors and their interactions with specific opsonins. J. Clin. Invest. 1968, 47, 1109-1120.

Messner, R. P, Laxdal, T., Quie, P. G., and Williams, R. C., Jr. Rheumatoid factors in subacute bacterial endocarditis-bacterium, duration of disease or genetic predisposition? Ann. Intern. Med. 1968, 68, 746-756.

Nelson, J., Ayoub, E. M., and Wannamaker, L. W. Streptococcal anti-desoxyribonuclease B, Microtechnique determination. J. Lab. Clin. Med. 1968, 71, 867-873.

Quie, P. G., Messner, R. P., and Williams, R. C., Jr. Phagocytosis in subacute bacterial endocarditis. Localization of the primary opsonic site to Fc fragment. J. Exp. Med. 1968, 128, 553-570.

Top, F. H., Jr., and Wannamaker, L. W. The serum opacity reaction of Streptococcus pyogenes. The demonstration of multiple, strain-specific lipoproteinase antigens. J. Exp. Med. 1968, 127, 1013-1034.

Top, F. H., Jr., Wannamaker, L. W. The serum opacity reaction of Streptococcus pyogenes, Frequency of production of streptococcal lipoproteinase by strains of different serological types and the relationship to M protein production. J. Hyg. Cambridge 1968, 66, 49-58.


327

Williams, R. C., Jr., and Quie, P. G. Studies of human C-reactive protein in an in vitro phagocytic system. J. Immunol. 1968, 101, 426-432.

Wolfson, J. J., Quie, P. G., Maxdal, S. D., and Good, R. A. Roentgenologic manifestations in children with a genetic defect of polymorphonuclear leukocyte function, chronic granulomatous disease of childhood. Radiology 1968, 91, 37-48.

1969

Ayoub, E. M., and Hoyer, J. Anaphylactoid purpura, streptococcal antibody titers and beta-1c-globulin levels. J. Pediatrics 1969, 75,193-201.

Danjani, A. S., and Ayoub, E. M. Mycoplasmacidal effect of polymorphonuclear leukocyte extract. J. Immunol. 1969,102, 698-702.

Dajani, A. S., and Wannamaker, L. W. Demonstration of a bactericidal substance against beta-hemolytic streptococci in supernatant fluids of staphylococcal cultures. J. Bacteriol. 1969, 97, 985-991.

Dossett, J. H., Kronvall, G., Williams, R. C., Jr., and Quie, P. G. Antiphagocytic effects of staphylococcal protein A. J. Immunol. 1969, 103, 1405-1410.

Houser, H. B. Report of the 1968 seminar on prophylaxis of streptococcal infection in the Armed Forces. Mil. Med. 1969, 135, 1526-1528.

Quie, P G. Microcolonies (G-variants) of Staphylococcus aureus. Yale J. Biol. Med. 1969, 41, 394-403.

1970

Cushing, A. H., and Mortimer, E. A., Jr. A hamster model for streptococcal impetigo. J. Infect. Dis. 1970, 122, 224-226.

Dajani, A. S., and Wannamaker, L. W. Experimental infection of the skin in the hamster simulating human impetigo. I. Natural history of the infection. J. Infect. Dis. 1970, 122, 196-204.

Dajani, A. S., Gray, E. D., and Wannamaker, L. W. Effect of bactericidal substance from Staphylococcus aureus on group A streptococci. I. Biochemical alterations. Infect. Immun. 1970, 1, 485-490.

Dajani, A. S., Gray, E. D., and Wannamaker, L. W. Bactericidal substance from Staphylococcus aureus. Biological properties. J. Exp. Med. 1970, 131, 1004-1015.

Derrick, C. W., Reeves, M. S., and Dillon, H. C., Jr. Complement in overt and asymptomatic nephritis after skin infection. J. Clin. Invest. 1970, 49, 1178-1187.

Derrick, C. W., and Dillon, H. C., Jr. Further studies on the treatment of streptococcal skin infection. J. Pediatr. 1970, 77, 696-700.

Dillon, H. C., Jr. Streptococcal skin infection and acute glomerulonephritis. Postgrad. Med. J. 1970, 46, 641-652.

Dillon, H. C., Jr. The treatment of streptococcal skin infections. J. Pediatr. 1970, 76, 676-684.

Dudding, B. A., Burnett, J. W., Chapman, S. S., and Wannamaker, L. W. The role of normal skin in the spread of streptococcal pyoderma. J. Hyg. Cambridge 1970, 68, 19-28.

Ferrieri, P., Dajani, A. S., Chapman, S. S., Jensen, J. B., and Wannamaker, L. W. Appearance of nephritis associated with type 57 streptococcal impetigo in North America. N. Engl. J. Med. 1970, 283, 832-836.

Kaplan, E. L., Anthony, B. F., Chapman, S. S., Ayoub, E. M., and Wannamaker, L. W. The influence of the site of infection on the immune response to group A streptococci. J. Clin. Invest. 1970, 49, 1405-1414.

Wannamaker, L. W., Skjold, S., and Maxted, W. R. Characterization of bacteriophages from nephritogenic group A streptococci. J. Infect. Dis. 1970, 121, 407-418.

1971

Dajani, A. S., Hill, P. L., and Wannamaker, L. W. Experimental infection of the skin in the hamster simulating human impetigo. II. Assessment of various therapeutic regimens. Pediatrics 1971, 48, 83-89.

Dillon, H. C., and Wannamaker, L. W. Skin infections and acute glomerulonephritis. Report of a symposium. Mil. Med. 1971, 136, 122-127.

1972

Dajani, A. S., Ferrieri, P., and Wannamaker, L. W. Antibody responses to group A streptococcal infections in the hamster. Infect. Immun. 1972, 6, 913-917.

Dajani, A. S., Ferrieri, P., and Wannamaker, L. W. Natural history of impetigo. II. Etiologic agents and bacterial interactions. J. Clin. Invest. 1972, 51, 2863-2871.


328

Federer, G. M., and Chapman, S. S. Simplified fluorescent-antibody staining method for primary plate isolates of group A streptococci. Appl. Microbiol. 1972, 24, 160-161.

Ferrieri, P., Dajani, A. S., Wannamaker, L. W., and Chapman, S. S. Natural history of impetigo. I. Site sequence of acquisition and familial patterns of spread of cutaneous streptococci. J. Clin. Invest. 1972, 51, 2851-2862.

Frasch, C. E., and Chapman, S. S. Classification of Neisseria meningitidis Group B into distinct serotypes. I. Serological typing by a microbactericidal method. Infect. Immun. 1972, 5, 98-102.

Frasch, C. E., and Chapman, S. S. Classification of Neisseria meningitidis group B into distinct serotypes. II. Extraction of type-specific antigens for serotyping by precipitin techniques. Infect. Immun. 1972, 6, 127-133.

Frasch, C. E., and Chapman, S. S. Classification of Neisseria meningitidis group B into distinct serotypes. IV. Preliminary chemical studies on the nature of the serotype antigen. Infect. Immun. 1972, 6, 674-681.

Glezen, W. P, Lindsay, R. L., DeWalt, J. L., and Dillon, H. C., Jr. Epidemic pyoderma caused by nephritogenic streptococci in college athletes. Lancet 1972, 1, 301-304.

Quie, P. G. Bactericidal function of human polymorphonuclear leukocytes, E. Mead Johnson Award Address. Pediatrics 1972, 50, 264-270.

Quie, P. G. Disorders of phagocyte function. Curr. Probl. Pediatr. 1972, 2, 1-54.

Wannamaker, L. W. Perplexity and precision in the diagnosis of streptococcal pharyngitis. Am. J. Dis. Child. 1972, 124, 352-358.

1973

Dajani, A. S. Neutralization of phage type 71 staphylococcal bacteriocin by immune and nonimmune sera. J. Infect. Dis. 1973, 128, 494-499.

Dajani, A. S. Rapid identification of beta hemolytic streptococci by counterimmunoelectrophoresis. J. Immunol. 1973, 110, 1702-1705.

Dajani, A. S., and Wannamaker, L. W. Kinetic studies on the interaction of bacteriophage type 71 staphylococcal bacteriocin with susceptible bacteria. J. Bacteriol. 1973, 114, 738-742.

Estensen, R. D., Hill, H. R., Quie, P G., Hogan, N., and Goldberg, N. D. Biological sciences, cyclic GMP and cell movement. Nature 1973, 245, 458-460.

Ferrieri, P, Dajani, A. S., and Wannamaker, L. W. Benzathine penicillin in the prophylaxis of streptococcal skin infections, A pilot study. J. Pediatr. 1973, 83, 572-577.

Forsgren, A., and Quie, P. G. Effects of staphylococcal protein A on heat labile opsonins. J. Immunol. 1974, 112, 1177-1180.

Frasch, C. E., and Chapman, S. S. Classification of Neisseria meningitidis group B into distinct serotypes. III. Application of a new bactericidal-inhibition technique to distribution of serotypes among cases and carriers. J. Infect. Dis. 1973, 127, 149-154.

Kaplan, E. The throat culture, its techniques, pitfalls, limitations and meaning. Conn. Med. 1973, 37, 45-48.

McGullough, J., Carter, S. J., and Quie, P G. Effect of anticoagulants and storage on granulocyte function in bank blood. Blood 1974, 43, 207-217.

Quie, P. G. Infections due to neutrophil malfunction. Medicine 1973, 52, 411-417.

Quie, P. G., and David, A. T. Interaction of Staphylococcus aureus with human polymorphonuclear leukocytes. Microbiol. Immunol. 1973, 1, 195-201.

Quie, P. G., and Hill, H. R. Granulocytopathies. Dis. Month. 1973, August, 1-32.

Shapera, R. M., Hable, K. A., and Matsen, J. M. Erythromycin therapy twice daily for streptococcal pharyngitis. J. Am. Med. Assoc. 1973, 226, 531-535.

*Listed under publications of the Strep Lab.


329

SECTION 4—APPENDIX 1

COMMISSION MEMBERSHIP

Commission on Hemolytic Streptococcal Infections (1941 to 1946)
Commission on Streptococcal Diseases (1948 to 1960)
Commission on Streptococcal and Staphylococcal Diseases (CSSD) (1960 to 1973)

Directors

Martin H. Dawson 1941 to 1942
Chester S. Keefer 1942 to 1946
William S. Tillett 1948 to 1954
Charles H. Rammelkamp, Jr. 1954 to 1957;1959 to 1968
Armine T. Wilson 1957 to 1959
Lewis W. Wannamaker 1968 to 1973

Deputy Directors

Floyd W. Denny, Jr. 1958 to 1963
Lewis W. Wannamaker 1963 to 1968
Richard M. Krause 1968 to 1973

Members and Associate Members


Member

Associate Member

Anthony, Bascom F., M.D.,
University of California, Los Angeles

 

1970 to 1973

Avery, Oswald T., M.D.,
Vanderbilt University

1948 to 1954

 

Ayoub, Elia M., M.D.,
University of Florida

 

1971 to 1973

Barkulis, Samuel S., M.D.,
University of Illinois

 

1954 to 1959

Bernheimer, Alan W., Ph.D,
New York University

1954 to 1966

 

Bliss, Eleanor A., Sc.D,
John Hopkins University

1941 to 1945

 

Bloomfield, Arthur L., M.D.,
Stanford University

1942 to 1945

 

Boisvert, Paul L., M.D.,
Yale University

1942 to 1944

 

Bunim, Joseph J., M.D.,
New York University

1949 to 1954

 


330

 


Member

Associate Member

Chapman, S. Stephen, M.D.,
University of Minnesota

 

1968 to 1971

Cluff, Leighton E., M.D.,
John Hopkins Hospital

1960 to 1973

1957 to 1960

Coffey, Julia M.
New York State Department of Health

1941 to 1945

 

Cooke, Jean V, M.D.,
Washington University

1941 to 1945

 

Coons, Albert H., M.D.,
Harvard Medical School

 

1954 to 1959

Dawson, Martin H., M.D.,
Columbia University

1941 to 1944

 

Denny, Floyd W., Jr., M.D.,
Vanderbilt University

1954 to 1971

1952 to 1954

Dick, George F., M.D.,
University of Chicago

1941 to 1945

 

Dillon, Hugh C., Jr., M.D.,
University of Alabama

1969 to 1973

1968 and 1969

Dubos, Rene J., M.D.,
The Rockefeller Institute

1958 to 1960

 

Eagle, C. Phillip Harry, M.D.,
Albert Einstein College of Medicine

 

1949 to 1954

Ebert, Robert H., M.D.,
University of Chicago

 

1954 to 1957

Fox, Eugene N., Ph.D.,
University of Chicago

 

1968 to 1973

Glaser, Robert, M.D.,
University of California

 

1957 to 1960

Gotschlich, Emil C., M.D.,
University of Connecticut Medical Center

 

1971 to 1973

Hamburger, Morton, Jr., M.D.,
University of Cincinnati

 

1948 to 1954

Hirsch, James G., M.D.,
The Rockefeller Institute

1963 to 1970

 

Hook, Edward W., M.D.,
University of Virginia

 

1962 to 1968

Houser, Harold B., M.D.,
Western Reserve University

1962 to 1973

1954 to 1957

Kaplan, Melvin H., M.D.,
Western Reserve University

 

1954 to 1971

Keefer, Chester S., M.D.,
Boston University

 

1941 to 1946

Koenig, M. Glenn, M.D.,
Vanderbilt University

 

1964 to 1973

Krampitz, Lester O., Ph.D.,
Western Reserve University

 

1954 to 1957

Krause, Richard M., M.D.,
The Rockefeller Institute

1963 to 1973

1960 to 1963

Kuttner, Ann G., Ph.D.,
Irvington House

1941 to 1946

 


331

 


Member

Associate Member

Lancefield, Rebecca C., Ph.D.,
The Rockefeller Institute

1954 to 1973

 

Lawrence, H. Sherwood, M.D.,
New York University

 

1956 to 1973

Lockwood, John S., M.D.,
University of Pennsylvania

1941 to 1946

 

Lyall, Harold W., Ph.D.,
New York State Department of Health

1941 to 1945

 

Lyons, Champ, M.D.,
Harvard Medical School

1941 to 1945

 

Lyttle, John D., M.D.,
Columbia University

1941 to 1945

 

Markowitz, Milton, M.D.,
University of Connecticut


1971 to 1973

McCarty, Maclyn, M.D.,
The Rockefeller Institute

1954 to 1973


1950 to 1954

Meleney, Frank L., M.D.,
Columbia University

1941 to 1945

 

Miller, C. Phillip, M.D.,
The University of Chicago

1948 to 1954

 

Moody, Max D., M.D.,
National Communicable Disease Center

 

1968 to 1971

Morse, Stephen, M.D.,
The Rockefeller Institute

 

1964 to 1968

Mortimer, Edward A., M.D., University of New Mexico


1969 to 1973

1962 to 1969

Quie, Paul G., M.D.,
University of Minnesota

 

1964 to 1973

Rammelkamp, Charles H., Jr., MD
Western Reserve University

1948 to 1973

 

Rantz, Lowell A., M.D.,
Stanford University

1941 to 1945

 

Rogers, David E., M.D.,
Vanderbilt University

1958 to 1968

 

Rose, Harry M., M.D.,
Columbia University

1941 to 1945

 

Schmidt, Willard C., M.D.,
University of Rochester

 

1956 to 1972

Schwentker, Francis, P, M.D.,
The Rockefeller Institute

1941 to 1942

 

Seal, John R., M.D., CDR, MSC, USN,
Great Lakes Naval Training Center

 

1956 to 1958

Seastone, Charles V, M.D.,
University of Wisconsin

 

1942

Seegal, David, M.D.,
Columbia University

1941 to 1945

 

Sherman, James M., Ph.D.,
Cornell University

1941 to 1945

 

Slade, Hutton D., M.D.,
Northwestern University

 

1957 to 1961



332

Smith, Lawrence W., M.D.,
Philadelphia, Pennsylvania

1941 to 1944

 

Spink, Wesley W., M.D.,
University of Minnesota

1941 to 1946

 

Stetson, Chandler A., M.D.,
New York University

 

1954 to 1966

Stollerman, Gene H., M.D.,
Northwestern University

1970 to 1973

1956 to 1970

Swift, Homer F., M.D.,
The Rockefeller Institute

1942 to 1946

 

Thomas, Lewis, M.D.,
New York University

1958 to 1963

1963 to 1970

Tillett, William S., M.D.,
New York University


1941 to 1946
1948 to 1966

 

Top, Franklin H., M.D.,
Wayne State University

1942 to 1945

 

Trask, James D., M.D.,
Yale University

1941 to 42

 

Updyke, Elaine L., Sc.D.,
National Communicable Disease Center

1957 to 1966

 

Vosti, Kenneth L., M.D.,
Stanford University

 

1970 to 1973

Wannamaker, Lewis W., M.D.,
University of Minnesota

1954 to 1973

 

Wesselhoeft, Conrad, M.D.,
Boston, Massachusetts

1941 to 1946

 

Wiley, Grove G., M.D., Alfred I. duPont Institute

 

1960 to 1971

Wilson, Armine T., M.D.,
Alfred I. duPont Institute

1948 to 1964

 

Wise, Robert I., M.D.,
Jefferson Medical College

 

1958 to 1966

Wolinsky, Emanuel, M.D.,
Case Western Reserve University

1971 to 1973

1968 to 1971

Wood, Harrison F., M.D.,
Yale University

 

1957 to 1963

Wood, W. Barry, M.D.,
John Hopkins University

1950 to 1954

1948 to 1950


333

SECTION 4—APPENDIX 2

SURVEY OF SITES TO LOCATE THE STREPTOCOCCAL DISEASE LABORATORY

The choice of Fort Francis E. Warren, Wyoming, as the site for the location of the Streptococcal Disease Laboratory (later Warren Air Force Base) was a very important determinant of the success of the Laboratory. The document describing the survey of sites for that location is included here in its entirety.

10 October 1948

To: The Surgeon General, Department of the Army (through Preventive Medicine Division)
Subject: Survey of sites for location of study of streptococcal diseases and rheumatic fever in the Rocky Mountain Area

1. During World War II, a high incidence of streptococcal infection and rheumatic fever occurred in posts in the Rocky Mountain area. With certain of these posts having been reopened for the training of troops, the probability is very good that streptococcal infections will again occur in epidemic form in them. The experience at Fort Francis E. Warren, Wyoming, during the Spring of 1948, where approximately 45 cases of rheumatic fever occurred in a total student population of about 4500, is a strong indication of what may be expected unless means can be devised for prevention.

It has been considered highly desirable to set up a long term study of streptococcal infections and rheumatic fever at a post in the epidemic area in order to study the reasons why these diseases occur so commonly there, to devise and test possible prophylactic measures, and to make a detailed clinical and epidemiological study of the relationship of streptococcal infection to rheumatic fever.

In order to select the most advantageous site for this study a tour of the following posts in the Rocky Mountain area was made between 9 and 13 October 1948: Fort Francis E. Warren, Wyoming (9, 10 and 11 Oct.); Lowry Field, Colorado (11 and 12 Oct.); Camp Carson, Col. (13 Oct.). The investigating party consisted of the following members: Dr. William S. Tillett, Director, Commission on Streptococcal Diseases, Army Epidemiological Board; Dr. John H. Dingle, Director, Commission on Acute Respiratory Diseases, A.E.B.; Dr. Charles Rammelkamp, Commission on Acute Respiratory Diseases, A.E.B.; Colonel Thomas E. Patton, M.C., Preventive Medicine Division, Office of the Surgeon General; Major Louis Kossuth, M.C., Air Surgeons Office; Colonel Pluennoko, M.C., Surgeon, Technical Training Command, U.S.A.F.; Lt. William Brink, M.C.; and Dr. Colin M. MacLeod, President, Army Epidemiological Board.

2. Of the three posts visited, it was considered that Fort Francis E. Warren affords certain important advantages not shared by Lowry Field and Camp Carson, which would appear to make it the most suitable site for the study. Fort Warren is used by the Technical Training Command of the Air Force for training in a wide variety of skills. These include the following: administrative courses (stenographers, clerk typists); engineering construction and equipment; engineers (draftsmen and surveyors); automotive maintenance; utilities (plumbers, carpenters). The following is a list of the present courses with load and flow:

Table I

Course
No.

Course

Load

Entry

Duration

Site of Training

013

Diesel mechanics

120

4 wks

16 wks

Indoors

050

Carpenter

300

4

12

Outdoors mainly

014

Automotive (Sept.)

1200

1

25

Indoors

059

Construction tech

20 (up to 144)

6

28

60% outdoors

070

Draftsmen

300

6

18

Indoors

078

Electrician

120

6

18

Indoors

081

Engineman operator

240

4

16

Outdoors

107

Photolithographer

12

6

12

Indoors

164

Plumber

70-80

4

16

Indoors

166

Powerman

20-42

6

18

70% indoors

201

Sheet metal

120

6

18

Indoors

213

Stenographers

220

2

26

Indoors

227

Surveyors

60

6

18

80% outdoors

256

Welders

20

4

16

Indoors

319

Construction equip mechanics

60

16

32

90% indoors

322

Refrigeration mechanics

20

4

12

Indoors

359

Heavy construction operators

350

4

16

90% outdoors

405

Clerk typist (Aug.)

1850

1

12

Indoors

727

Water supply

12

4

8

90% indoors

4805

Officers-Automotive repair

3

3

10

Indoors


From Table I it can be seen that training takes place both indoors and outside, depending on the course; that certain large classes (e.g., automotive maintenance, stenographers) will be on the post for approximately 6 months, whereas the large clerk typist course lasts for 12 weeks only.

Students coming to Fort Warren derive from Lackland and Shepard Fields, in the main. They have had 13 weeks basic training there. Other students are on detached service from other Air Force installations (seasoned troops), or are the so-called career plan students. The last two groups are relatively small.

Troops are housed in cantonment type barracks, in general close to the school buildings. Floor spacing of 72 sq. ft. per man is in practice now, but with conversion to a 2 shift basis shortly, space per man will be reduced to 60 sq. ft. The present hospital facilities are sufficient for a post population up to 12,000 men which is the maximum projected at present.

Instructors are both military and civilian, there being some 350 of the latter now. Classrooms are either converted barracks or large machine shops. In the latter, the men are widely separated except for certain phases of automotive maintenance, whereas in the barrack school rooms, contact is fairly close, in general.

Adequate laboratory space for the study can be provided in a hospital ward building adjacent to the present laboratory. In addition, alterations, construction of laboratory benches and installation of refrigerating equipment can be carried out with a minimum of delay through use of the classes in drafting, the plumbers and carpenters schools and the school in refrigeration equipment. The study at Fort Warren, therefore, could be got underway promptly.

The acting Commandant (Col. Paul), Director of Training (Col. Lay) and Post Surgeon (Col. Cullen) have all expressed great interest in the study. Colonel J. C. B. Elliott, Commandant was absent from Fort Warren at the time of our survey. His support for the proposed study is given in the 1st Endorsement to "Memo from Surgeon Fort Warren to CO Fort Warren Wyo dtd 5 Oct 48. Subj: Factors Pertinent to the Consideration of Establishing a Research Laboratory at this station." A copy of this endorsement is attached, as well as the original memorandum from Colonel J.K. Cullen.

3. Lowry Field, Col., is divided into 2 training areas designated as Lowry 1 and Lowry 2, separated by about 1 mile, with capacities of 4,000 and 8,000 men, respectively. These 2 areas are fairly well isolated from each other because of distance and type of training. Most of the students in Lowry 1 are drawn from Lackland Field and are recruits who have finished 13 weeks basic training. Two of the largest schools formerly at Lowry Field (automotive mechanics and clerk typists) have been transferred to Fort Warren, and final plans have not yet been put into effect for the new courses and schedules at Lowry Field. Table II shows the projected courses for Lowry Field with load, entry, duration and site of training.


335

Table II

Course


Load

Entry

Duration

Site of Training

Armament Technician

1496

1 wk

22 wks

Indoors

RCT Technician

620

1 wk

31 wks

Indoors

Comptroller (6 courses)

370

2 wk

12 wks

Indoors

Fire fighting (crash fire)

376

1 wk

8 wks

50% outdoors

Intelligence

506

6 mos

 

Indoors

Photographers

1244

1 wk

30 wks

30% outdoors

Transportation officers

18

 

 

 

Radio Operators
(now at Scott Field)

1856

1 wk

32 wks

Indoors


The inflow is expected to be 863 men/month beginning 1 January 1949, without the Radio Operator School. The ratio of new recruits to seasoned men is expected to be 2:1. There is a possibility that 2,000 one-year enlistees may be sent to Lowry Field between 1 January 1949 and October 1,950. If these come to Lowry, the number of regular students will be correspondingly reduced.

In addition to the school population at Lowry Field, there are approximately 1000 men in "tenant organization," e.g., Air Rescue Units, etc.

Men are housed in cantonment type barracks, with allocation of 72 sq. ft. per man at present. The projected training schedule is not expected to result in overcrowding.

Laboratory facilities could be provided by alterations to a hospital ward building which is available. This would provide adequate space. Alterations would be made from funds regularly allocated to the post for building and maintenance.
At present, hospitalization is being carried out at the Station Hospital of Lowry Field. We were informed, however, that serious attention is being given to a plan to use the facilities of Fitzsimmons General Hospital, Denver, to hospitalize soldiers from Lowry Field. If this plan comes into effect, it would throw serious difficulties in the way of the contemplated study because of the physical separation from Lowry Field.

General Beam, Commandant, and Colonel Neiss, Post Surgeon expressed themselves as being anxious to support a study of streptococcal diseases at Lowry Field. However, because of uncertainties in the hospitalization program it is considered that Lowry Field is at present less advantageous for institution of the study than Fort Warren.

4. Plans for training troops at Camp Carson have not yet reached a stage which permits formulation of plans for the study of streptococcal diseases there. In any case, it appears likely that it would be less advantageous than either Fort Warren or Lowry Field because much of the training of men sent to Camp Carson is carried on at Camp Halea considerable distance removed from Camp Carson. The lack of information on projected training, strength, and flow of troops, however, make it impossible at the present time to outline a plan for the study of a streptococcal diseases there. It should be noted that ample laboratory space could be provided in the present hospital building, which is of permanent construction, and that General Sherman, Commandant and Colonel Beringer, Post Surgeon are in full sympathy with the purposes of the study.

Acknowledgement is made to the following officers for their very courteous assistance in carrying out this survey: Colonel J.C.B. Elliott, Commandant, Lt. Col. Paul, Acting Commandant, Lt. Col. Lay, Director of Training and Colonel John Cullen, Post Surgeon, Fort Warren; General Beam, Commandant, Colonel O. K. Neiss, Post Surgeon and Colonel Dixon, Director of Training, Lowry Field; General Sherman, Commandant and Colonel Beringer, Post Surgeon, Camp Carson.

Respectfully submitted,

Colin M. MacLeod, M.D.
Consultant to the Secretary of the Army
President, Army Epidemiological Board


336

SECTION 4—APPENDIX 3

PICTURES OF THE LABORATORY AND PERSONNEL

Few photographs of the Strep Lab were found, so most of those located are included here. The photos on the following pages demonstrate snow drifts several weeks following the large storm of December 1948 and suggest the harsh nature of a Wyoming winter.

Dr. Rammelkamp's laboratory at Western Reserve University School of Medicine in the fall of 1948.

Seated, left to right: Drs. Charles H. Rammelkamp, Jr., and John H. Dingle. Standing: Drs. William R. Brink, Lewis W. Wannamaker, and Floyd W. Denny, Jr., With the exception of Dr. Dingle, these individuals formed the original professional staff of the Streptococcal Disease Laboratory. The three military officers were undergoing training in laboratory procedures before the opening of the Wyoming laboratory.


337

The appearance of the rear entrance of the laboratory in January 1949, following an unusually severe Wyoming blizzard.


338

Another view of the doors to the rear entrance to the Laboratory.


339

The three original army officers standing at the front entrance of the Laboratory.

Taken at the same time as the two preceding photos. Left to right: Drs. Floyd W. Denny, Jr., Lewis W. Wannamaker, and William R. Brink.


340

Same setting as prior photo.

Left to right: Drs. Lewis W. Wannamaker, Charles H. Rammelkamp, Jr., and William R. Brink.


341

The professional staff of the Laboratory in 1950.

Seated: Dr. Charles H. Rammelkamp, Jr. Standing, left to right: Drs. Harold B. Houser, Floyd W. Denny, Jr., Lewis W. Wannamaker, and Edward O. Hahn.


342

The professional staff of the Laboratory in 1952.

First row, left to right: Drs. L. Loring Brock, Harold B. Houser, and William D. Perry. Back row, left to right: Drs. Chandler A. Stetson, Bertrand L. Stolzer, Alan C. Siegel, Charles H. Rammelkamp, Jr., Lewis W. Wannamaker, Edward O. Hahn, and Earl C. Marple.


343

SECTION 4—APPENDIX 4

ARTICLE IN CHEYENNE, WYOMING, NEWSPAPER

This article appeared in a Cheyenne, Wyoming, newspaper. Unfortunately, no date accompanies the article but it almost certainly appeared early in 1949. It was accompanied by the first photograph in Appendix 3.

Doctor C.H. Rammelkamp Heads Rheumatic Fever Laboratory

Doctor C.H. Rammelkamp, Associate Professor of Preventive Medicine and Medicine at Western Reserve University Medical School in Cleveland, Ohio, will head the rheumatic fever laboratory at Fort Warren, it was announced recently.

This laboratory is a joint project of the Commission on Acute Respiratory Diseases, Western Reserve University, and the Streptococcal Disease Commission of New York University under the direction of Doctor Tillett, Chairman of the Streptococcal Disease Commission and Professor of Medicine, New York University Medical School.

The purpose of this lab is to determine why streptococcal diseases are prevalent in this area and to take measures to prevent such infectious diseases. The study of these infectious diseases are important for two reasons (1) they will interfere with the training of men during the acute episode, (2) and because a small proportion of such infections are followed by a heart disease.

The lab will be set up for approximately five years. During this period Dr. Rammelkamp's staff expects to conduct research on why heart diseases occur after the infections and try to devise methods to prevent its [sic] occurrence.

Dr. Rammelkamp states "that the staff has received marvelous cooperation from Colonel Elliott, Colonel Cullen and their staff. The laboratory was built and equipped within six weeks after it was decided to have the location here." This post was selected after a survey of a number of Air Force bases and Army posts in this area. It was chosen because of the ideal conditions for study that existed here and the high interest of the hospital personnel.

Doctor Rammelkamp graduated from the University of Chicago Medical School in 1937. Following his graduation he served a year and a half as an intern in Washington University. The doctor has taken courses in surgery at the University of Chicago and chest surgery at Washington University in St. Louis. He attended Harvard University to study infectious streptococcal diseases. After this he spent three and one-half years working with penicillin at Boston University.

The doctor became a consultant of the Secretary of War and was assigned to Fort Bragg, N.C., with the Commission on Acute Respiratory Diseases of the Army Epidemiological Board for the investigation of influenza and streptococcal diseases in the army. He then attended Western Reserve University Medical School where he is now the Associate Professor of Preventive Medicine and Medicine. At the present time Dr. Rammelkamp is again the consultant of the Secretary of War, a member of the Streptococcal Disease Commission and the Director of the Rheumatic Fever Laboratory here at Fort Warren.

The staff includes three army officers, one full time civilian, two enlisted personnel, and six to eight technicians and secretaries. A Doctor Custer will arrive about the first part of the month to take over the duties of acting director in Dr. Rammelkamp's absence.


344

The three army officers include 1st Lts. William R. Brink, Floyd W. Denny, and Lewis W. Wannamaker.

Lieutenant Brink will cover the clinical aspects of the study. He graduated from Duke University Medical School, Durham, N.C. The lieutenant has had 21 months hospital training at Williamsport Hospital in Pennsylvania. He attended Western Reserve University Medical School to study the particular type of training that he is assigned here to do.

Lieutenant Denny, a graduate of Vanderbilt University in Nashville, Tenn., has had 27 months of hospital training as a civilian at Vanderbilt University. His work is mainly concerned with determining where the men in the service contact influenza and find out whether it is associated with the climate here or not.

Lieutenant Wannamaker, the person in charge of the research laboratory, is a graduate of Duke University Medical School. His 21 months of hospital training are distributed between Duke Hospital and Willard Parker Hospital in the New York City.

A local Cheyenne girl, Mary Riner, will be the chief technician. She received her training in Cleveland, Ohio also. The hospital has assigned personnel to cover the administrative part of the work.


345

SECTION 4—APPENDIX 5

FOLLOW-UP OF THE PROFESSIONAL STAFF
OF THE STREPTOCOCCAL DISEASE LABORATORY

All professional personnel of the Strep Lab were contacted in 1990, except those known to be deceased. Summaries from this correspondence are included below, along with excerpts of letters with comments about the Laboratory experience.

1. William R. Brink, M.D., left the Strep Lab in December of 1949, finished a residency in internal medicine at the Mayo Clinic, and entered private practice in Williamsport, Pennsylvania. He retired in 1987 and now lives in Kitty Hawk, North Carolina, with his wife Margene. In October 1990, he wrote the following reminiscences of the early days of the Strep Lab:

It's great that you and Hal Houser are writing a history of the Streptococcal Disease Laboratory. I'll be anxiously awaiting a copy of the final monograph.

I thought I might give you a summary of what took place before we decided on establishing the lab at Fort Francis E. Warren. You probably know most of it.

Lewis and I arrived in Cleveland on February 1, 1948. After some preliminary meetings with Drs. Dingle, Rammelkamp, Feller, Hodges and Badger, we met with a group from the Army Epidemiology Board. They decided to set up a commission with Dr. Rammelkamp as the director of the research study. The members of the commission, as I remember them, were Dr. William Tillett and Dr. Colin MacLeod from New York, Dr. Barry Wood from Baltimore, Dr. Rebecca Lancefield from New York, Dr. Wesley Spink from Minneapolis, Dr. Coburn and Dr. Dornberger from Chicago, Dr. Max Finland from Boston, Dr. Dingle and Dr. Rammelkamp from Cleveland and Dr. Morton Hamburger from Cincinnati.

We went to Chicago in April or May of 1948 and visited and went through the labs of Dr. Coburn and Dr. Dornberger. In August or September of 1948, Dr. Dingle, Dr. Rammelkamp, Dr. Tillet, Dr. MacLeod, and a major from the Armed Forces Epidemiology Board, along with Lewis Wannamaker and I went to Lowry Field in Denver. After a day there we went down to Camp Carson and spent a day with General George Sherman IIIthe commanding officer at Camp Carson. He mistakenly thought we were there to see if the Camp was to be reopened. It had been closed because of a massive strep outbreak the year before with several hundred cases of rheumatic fever. He set us up in a beautiful suite at the Broadmoor Hotel in Colorado Springs. Actually we were there to see if it was a good place to set up the research lab. We then went to Francis E. Warren. This, of course, turned out to be the ideal place to have the lab. It is relatively isolated, had 12,000 personnel, all had been through their basic training, and were going to be there at least six months. In addition, they had a very high incidence of strep infections and rheumatic fever.

While in Cleveland Dr. Rammelkamp asked me to review all the articles I could find that related to strep infections and rheumatic fever. I spent a lot of time in the medical library and reviewed some 2000 articles. Two caught my attention. One was by Dr. Jenesild from Sweden. He had treated a series of strep infections very early in their course with penicillin. He had treated them so soon after onset of their infections that some of them got the same strep type infection againat a later date.

I wrote him and asked him if any of his first group had gotten rheumatic fever. He wrote back and stated as far as he knew none had gotten rheumatic fever.

The second article was one that was in the New England Journal of Medicine. I think it was about 1941 or 1942. They reported on 1002 cases of rheumatic fever. The thing that struck me about the article was that no cases of glomerulonephritis were reported in the group they studied.

I discussed these and other articles I had reviewed with Dr. Dingle, Dr. Rammelkamp and Dr. Feller at a two hour afternoon meeting.

Finally on December 8, 1948 Lewis and I arrived at Cheyenne, Wyomingin a snow storm. We went to work setting up the lab. As you may remember in early January 1949 we had one of the big blizzards of the


346

century (Operation Snowlift they called it). A portion of the roof on the North end of the lab collapsed under the weight of the snow. In order to get the lab under way Rammel and I spent a couple of nights cutting up beef hearts and preparing media plates for the strep cultures.

As you may remember in April 1949 Dr. Armine Wilson from the A.I. Dupont Research Institute in Dela-ware spent a month with us, doing some research work.

In July Margene began working at the lab as a serology technician!!! [Note: Subsequently, she became his wife and the Margene mentioned in his introduction above.]

2. L. Loring Brock, M.D., took fellowships in cardiology at the Universities of Colorado and Washington after leaving the Strep Lab in 1953. He then entered the practice of internal medicine and cardiology in Denver and became interested in health promotion and rehabilitation. He was the Director of the Rehabilitation Unit of the Colorado Heart Association from 1957 to 1978. He subsequently moved to Bigfork, Montana, where he is the Director of the Health Promotion Center in the Flathead Valley.

3. Frank J. Catanzaro, Sr., M.D., entered a practice of cardiology in St. Louis after leaving the Strep Lab in 1955. In 1960 he became Chief of Cardiology at the Cochran Veterans Administration Hospital associated with Washington University. In 1966 he became Director of Medical Education and Chief of Medicine of Missouri Baptist Hospital. He is now Medical Director of that hospital.

4. Robert Chamowitz, M.D., entered a fellowship in gastroenterology after leaving the Strep Lab and has been in a solo practice of gastroenterology in Pittsburgh since that time. In January 1991 he wrote of his great admiration of Dr. Stetson and the benefits he received from working in the Strep Lab. He remains grateful for the contributions to his career made by Dr. Rammelkamp.

5. Ernest J. Clark, M.D., left Warren Air Force Base in 1952 but remained a member of the Air Force until he retired in 1978. He served in military installations in England, Germany, and the United States, including Hawaii. He had several tours in the Office of The Surgeon General of the Air Force. As a Brigadier General, in 1975, he became Director of Professional Services, the post he held until retirement. He now lives in Monument, Colorado.

6. Edward A. Custer, M.D., entered private practice in Palo Alto, California, after a short tour of duty at the Strep Lab. He retired in 1983.

7. Floyd W. Denny, Jr., M.D., left the Strep Lab in 1951 to spend a 2-year fellowship with Dr. Lewis Thomas at the University of Minnesota. He spent 2 years as a junior faculty members in pediatrics at Vanderbilt from 1953 to 1955, when he returned to the Departments of Pediatrics and Preventive Medicine at Western Reserve University. He remained there until the late fall of 1960, when he became Professor and Chairman of Pediatrics at the University of North Carolina. He resigned the chair in 1981 and is now Director of the Program for Health Promotion and Disease Prevention of the University of North Carolina School of Medicine.

8. George C. Eckhardt, M.D., left the Strep Lab in 1952 to enter private pediatric practice in California. He subsequently joined the Permanente Medical Group. He retired in 1982 and now lives in Chico, California.

9. Edward O. Hahn, M.D., entered the solo practice of internal medicine in Cleveland after leaving the Strep Lab. He retired in 1983 and now lives in Thomaston, Maine.

10. Harold B. Houser, M.D., left the Strep Lab in 1952 to start an Arthritis and Rheumatism Foundation Fellowship with Harry Feldman at the State University of New York at Syracuse. In 1954, as Field Director, he established the Laboratory on Housing and Illness, AFEB at Sampson Air Force Base, New York, under the auspices of the CARD. He left Syracuse in 1958 to join the Department of Preventive Medicine at Western Reserve University where he has remained. He was appointed Professor of Epidemiology and Chairman of the Department of Biometry in 1974. Since 1985, he has been Chairman of the Department of Epidemiology and Biostatistics.

11. Robert J. Kohen, M.D., was only tangentially related to the Strep Lab, since he was stationed at the Bainbridge Naval Training Station and assisted Dr. Rammelkamp with studies on glomerulonephritis. We have not been able to locate him, but it is reported that he is deceased.


347

12. Richard M. Krause, M.D., had an interesting association with the Strep Lab and the Commission. This and excerpts of a letter from him are included in Appendix 7.

13. Earl C. Marple joined the Strep Lab in 1949 as a Master Sergeant and chief administrator and remained with the Lab until it closed. His remarkable talents were indicated by promotion to Major and nomination for a Legion of Merit Award. Major Marple died 19 February 1966.

14. Alton J. Morris, M.D., returned to a medical residency at Barnes Hospital and then to the University of Colorado for a fellowship with Gordon Meiklejohn and Bob Glazer. He then entered the private practice of rheumatology in Springfield, Illinois, following which he developed the hemodialysis program and laboratory at Southern Illinois University School of Medicine, where he was a Professor. Later he went to Eastern Tennessee State University as Program Director, Professor of Medicine, and Chief of Rheumatology. He now practices rheumatology in Kingsport, Tennessee.

15. William D. Perry, M.D., returned to St. Louis, Missouri, in the practice of internal medicine. He died in May 1990.

16. Charles H. Rammelkamp, Jr., M.D., was the primary mover of the Strep Lab and the CSSD during most of its existence. Appendix 10 is devoted in part to the accomplishments of this remarkable man.

17. Willard C. Schmidt, M.D., returned to Western Reserve University School of Medicine where he remained on the faculty until 1973. After entering the private practice of allergy and infectious diseases in Ithaca, New York, for 5 years, he received a Masters of Public Health from Johns Hopkins School of Hygiene and Public Health. In 1979, he became Health Commissioner of Thompkins County, New York. He retired in 1985 and now lives in Ithaca.

18. Alan C. Siegel, M.D., practiced pediatrics in Winnetka, Illinois, after leaving the Strep Lab. He was on the staff of Children's Memorial Hospital where he worked closely with Drs. Stollerman and Eloise Johnson on problems of the streptococcus and rheumatic fever. He died on 8 December 1968.

19. Chandler A. Stetson, M.D., returned to New York University after his tour of duty at the Strep Lab. He subsequently became Professor and Chairman of Pathology there. In 1972, he became Dean of the University of Florida School of Medicine. He died on 25 May 1977.

20. Bertrand L. Stolzer, M.D., entered the practice of rheumatology in Pittsburgh after leaving the Strep Lab. He practices at St. Margaret Memorial Hospital (Doris Palmer Arthritis Center), which is a part of the University of Pittsburgh. In October of 1990, he wrote of the following experience:

Incidentally, I paid a visit to Warren Air Force Base in September, 1990 and found only a few familiar areas remaining. The old hospital is now an air police station; the Strep Lab is gone; the Officer's Club is about the same and the base is a tranquil missile site. One of the medical officers had no knowledge of the base having been the site for the Streptococcal Disease Laboratory in the past and little knowledge of the role streptococcal disease played in this area.

21. Lewis W. Wannamaker, M.D., was a very important member of the Strep Lab and member of the CSSD. Following his untimely death in 1983, the 86th Ross Conference on pediatric research entitled "Management of Pharyngitis in an Era of Declining Rheumatic Fever" was dedicated to him. The memorial to Dr. Wannamaker in that publication is in Appendix 10.


348

SECTION 4—APPENDIX 6

LANDMARK ARTICLE

The most notable accomplishment of the Strep Lab was the study demonstrating that the treatment of a streptococcal infection would prevent the subsequent occurrence of rheumatic fever. The first report of the study was published by the Journal of the American Medical Association on 13 May 1950. The Journal recognized the significance of this article by designating it as a Landmark Article and reprinted it in its entirety, along with a commentary by Dr. Bisno, both of which are reproduced here, with permission of the journal.

Prevention of Rheumatic Fever
Treatment of the Preceding Streptococcic Infection

Capt. Floyd W. Denny
Capt. Lewis W. Wannamaker
Capt. William R. Brink
Medical Corps, Army of the United States
Charles H. Rammelkamp Jr., M.D.
Cleveland
and
Edward A. Custer, M.D.
Palo Alto, Calif.

The prevention of acute rheumatic fever by the prompt treatment of streptococcic infections with penicillin has been attempted in this study. The results obtained show that this attempt was successful, and, because of their importance, these results are presented here in a preliminary report.

The significance of an adequate means of prevention may be realized when it is considered that rheumatic fever develops in an estimated 200,000 to 250,000 persons in the general population of the United States yearly.1 Figures for the Armed Services similarly show a high incidence, with an average of 7,300 cases annually for the seven year period from 1942 through 1948.2 The gravity of the disease itself is emphasized by the estimate of Paul that at least 460,000 persons in the country today have rheumatic heart disease.3 Not only is rheumatic fever a menace to health, but it is also a serious economic problem. A conservative estimate of the cost of each case that occurs in the Armed Services is $16,000.2

DESCRIPTION OF THE STUDY

The study was conducted at Fort Francis E. Warren, in southeastern Wyoming. The Fort is an air force technical training base where approximately 80 per cent of the men are trainees who report after twelve weeks of basic training at a southwestern base. The study began Jan. 24, 1949 and ran continuously until July 1, 1949, except for a ten day period in April. Although the average strength of the base during the study was 8,000 men, the actual number exposed to infection was much greater because the men remained in school only eight to thirty-two weeks.

All patients admitted to the hospital for disease of the respiratory tract were seen within a few hours by one of the members of the professional staff of the laboratory. Those having exudate on the tonsils or on the pharyngeal wall were included in the study group. A total of 1,634 such patients were observed.


349

A total of 798 patients whose Air Force serial numbers ended in an even digit received penicillin treatment, and 804 patients whose serial numbers ended with an odd digit comprised the control group and received no specific treatment. Prior to March 3, 1949 the treatment consisted of 300,000 units of crystalline procaine penicillin G (suspended in peanut oil containing 2 per cent aluminum monostearate) given intramuscularly as soon after admission as possible. This dose was repeated in seventy-two hours. After March 3 the following change was made in the dosage schedule: 300,000 units were administered at the time of admission and again in forty-eight hours, and 600,000 units were given ninety-six hours after the initial dose. Of the 798 patients who received penicillin, 253 were treated before March 3. Eighty-eight per cent of the treated patients received the first penicillin within sixty hours after the onset of the symptoms of the streptococcic illness.

Follow-up studies for the detection of rheumatic fever were performed between the third and fourth weeks after the initial infection, without knowledge of the serial numbers of the patients or of their previous treatment. Those patients suspected of having acute rheumatic fever were hospitalized until
a satisfactory diagnosis was established. Rigid criteria for diagnosis were followed. A modification of the classification of Jones5 was used. This classification may be seen in the following tabulation:

Major Manifestations

Carditis
a. Definite cardiac enlargement
b. Appearance of a significant murmur heretofore not present
c. Friction rub
d. Heart block or other electrocardiographic findings indicative of carditis
e. Cardiac failure
Migrating polyarthritis
History of recurrences
Chorea
Subcutaneous nodules

Minor Manifestations

Fever
Abdominal pain
Arthralgia
Skin rash
a. Erythema marginatum
b. Erythema multiforme
Epistaxis
Pulmonary changes
Nonspecific electrocardiographic changes
Elevated erythrocyte sedimentation rate (20 or above considered abnormal)
Anemia

For a diagnosis of definite acute rheumatic fever a patient had to have two major manifestations or one major and two minor manifestations. For a diagnosis of probable acute rheumatic fever a patient had to have one major and one minor, one major or two minor manifestations. Instances of abdominal pain, epistaxis, pulmonary changes and anemia were encountered but did not contribute to the classification of these patients. No patient with chorea or subcutaneous nodules was encountered. Only persons in whom acute rheumatic fever developed between ten to thirty-five days after the onset of the observed streptococcic infection are included in this report.

Throat cultures and blood specimens were obtained from the patients on admission and again at the time of the follow-up examination. Strains of beta hemolytic streptococci isolated from cultures


350

were grouped and typed according to the method of Lancefield.6 Antistreptolysin O titration was performed on acute and convalescent serums according to a modification of the method of Hodge and Swift.7

RESULTS

Of the 798 patients that were treated with penicillin, definite acute rheumatic fever developed in only 2. In contrast, the disease developed in 17 of the untreated patients (table 1), a difference which could be due to chance only 6 times in 10,000. Of the 2 patients in the treated group who became ill with rheumatic fever, 1 was treated within eight hours after the onset of the symptoms of streptococcic disease and the second approximately seventy-two hours after the onset.

Probable acute rheumatic fever developed in 2 patients in the treated group and in 6 patients in the untreated group. Of the 2 patients in the treated group, 1 received penicillin forty-eight hours after the onset of symptoms of streptococcic disease and the second one hundred and eight hours after the onset. Whether the time of treatment of the initial infection is related to the development of poststreptococcic nonsuppurative complications cannot be determined at this time.

The effect of penicillin treatment on the presence of betahemolytic streptococci in cultures of the throat is shown in table 2. In the treated group the number of persons having streptococci was reduced from 78.3 per cent on admission to 18.1 per cent at the time of the follow-up examination. The untreated group showed a reduction from 81.7 per cent to only 52.7 per cent.

The development of antistreptolysin O in the treated and untreated groups was also different. In the treated group only 51 per cent of the patients showed a rise in titer of two or more tubes, while 73 per cent of the untreated patients showed a similar rise. Tests of significance support the validity of these differences.

The prevention of rheumatic fever, the inhibition of antibody and the partial eradication of streptococci in the group of patients treated with penicillin assume more significance when the composition of

Table 1.Cases of Rheumatic Fever Found at the Follow-Up Examination in the Treated and Untreated Groups

 

Number of Patients

Treated

Untreated

Definite rheumatic fever

2

17*

Probable rheumatic fever

2

6

Total

4

23

*Test of significance shows that probability is 0.0006.

Test of significance shows that probability is 0.0002.

Table 2.Persistence of Group A Beta Hemolytic Streptococci in the Treated and Untreated Groups

 

Treated
(Percentage)

Untreated
(Percentage)

Persons with Group A beta hemolytic steptococci on admission

78.3

81.7

Persons with group A beta hemolytic streptococci in follow-up examination

18.1

52.7


351

the treated group and that of the control group are compared. That the two groups were comparable is demonstrated in table 3, in which various features are presented. Moreover, a large proportion of the illnesses in both groups were streptococcic in origin, since group A betahemolytic streptococci were isolated from 80 per cent of all cultures made at admission and since 73 per cent of the untreated patients showed an antistreptolysin response of two or more tubes.

COMMENT

The data presented concerning the incidence of rheumatic fever in the treated and control groups establish the fact that penicillin therapy of acute streptococcic infections will almost completely pre-vent the subsequent occurrence of rheumatic fever. These results emphasize again the close relation-ship between streptococcic disease and rheumatic fever.

Attempts to prevent the occurrence or the recurrence of rheumatic fever during the last decade have centered around the streptococcic disease that precedes most cases of acute rheumatic fever. Coburn,8 Kuttner and Reyersbach9 and Hodges10 showed that sulfonamide drugs, given prophylactically, not only reduced the incidence of streptococcic disease but also reduced the occurrence of rheumatic fever. This would seem to be a practical means of prevention in two situations: (a) in closed groups in which the incidence of streptococcic disease is extremely high and (b) in select groups, such as patients with inactive rheumatic fever or rheumatic heart disease, in which the danger of recurrence is great. This method of prevention has not proved to be practical for the general population, however, because of the toxicity of the sulfonamide drugs, the high percentage of sulfonamide-resistant strains of streptococci that develop and the difficulty that is entailed in mass prophylaxis.8

Treatment after the development of the streptococcic infection has been another approach to the problem. Sulfonamide drugs have proved to be ineffective when used in this manner.11 Experience with penicillin has been conflicting. Weinstein, Bachrach and Perrin12 treated 225 patients with streptococcic disease with penicillin; in 7 of these patients rheumatic fever subsequently developed. This observation supports Finland's13 conclusion, from a review of the literature, that penicillin is not effective when used in this manner for the prevention of rheumatic fever. On the contrary, Massell, Dow and Jones14 employed penicillin to treat ten clinical and five subclinical hemolytic streptococcic infections in patients hospitalized for rheumatic fever or rheumatic heart disease; the patients failed to exhibit subsequent recurrences. Jersild15 has shown that poststreptococcic complications, including nephritis,

Table 3.Comparability of Treated and Untreated Groups

 

798
Treated Patients
(Percentage)

804
Untreated Patients
(Percentage)

Age (years):

 

 

17-19

61.0

62.0

20 and over

39.0

38.0

Previous history of rheumatic fever

3.5

4.4

Tonsils present

72.7

70.7

Cervical nodes enlarged or tender

50.1

46.3

Leucocyte count 13,000 or over at admission

54.7

56.3

Persons with group A beta hemolytic streptococci at admission

78.3

81.7

Antistreptolysin O titer of 125 units or less at admission

70.3

69.1

Follow-up obtained

80.7

82.8


352

are reduced after penicillin treatment of the initial illness, but he makes no statement about the occurrence of rheumatic fever.

The theory has been advanced that rheumatic fever is associated with a peculiar response to an unknown antigen-antibody reaction. Kilbourne and Loge16 showed that early and intensive penicillin therapy against streptococcic disease suppressed the production of antistreptolysin O. It has been shown here that adequate treatment with penicillin not only suppresses the antistreptolysin response but also prevents rheumatic fever. Whether the antibody suppression is only a reflection of the inhibition of some more basic process in the mechanism of rheumatic fever or is in itself the responsible factor is entirely speculative at this time.

Exudate on the tonsils or oropharynx was used as the sole means of selection of patients to be included in this study because it was a rapid, easily standardized method. It was thought that such a criterion would include the majority of streptococcic infections of the respiratory tract, since various studies have shown that exudative lesions of the throat appear in 60 to 90 per cent of streptococcic infections,17 particularly in a population experiencing epidemic rates of streptococcic illnesses. The isolation of group A streptococci from 80 per cent of the patients and the demonstration of an increase in the antistreptolysin O titer in 73 per cent of the control group indicate that the majority of the patients actually had streptococcic disease. A few undoubtedly had nonstreptococcic exudative tonsillitis.

If the incidence of rheumatic fever is to be reduced materially by early treatment with penicillin, it becomes necessary that streptococcic infections be diagnosed accurately and early. In some cases the clinical findings alone will permit an almost certain diagnosis of streptococcic infection. Characteristically, such illnesses present a sudden onset of sore throat with pain on swallowing, fever and other constitutional reactions, diffuse redness and edema of the soft palate, tonsils and oropharynx, discrete or confluent exudate and large or tender cervical lymph nodes. Supportive data may be obtained from the laboratory. Many patients will have an elevated total leukocyte count. Cultures of the pharynx will almost always show a predominant growth of beta hemolytic streptococci. Depending on the availability and use of the preceding criteria, a large percentage of streptococcic respiratory infections can be reliably and rapidly diagnosed, particularly during an epidemic period. Treatment with penicillin can thus be instituted immediately.

SUMMARY

Evidence is presented to indicate that rheumatic fever can be prevented by the treatment of streptococcic disease with penicillin. A total of 798 patients with streptococcic infections were treated with penicillin; in only 2 did acute rheumatic fever subsequently develop. Of 804 untreated patients, the disease developed in 17. Penicillin therapy likewise suppresses the antistreptolysin O response and eradicates the streptococci in many cases.

1. Swift, H. F.: Rheumatic fever, in Cecil, R. L. A Textbook of Medicine. Philadelphia: W. B. Saunders Company, 1947, p. 168.

2. Department of Preventive Medicine, Surgeon General's Office.

3. Paul, J. R. The Epidemiology of Rheumatic Fever and Some of Its Public Health Aspects. New York: Metropolitan Life Insurance Company, 1943.

4. Thirty-two patients were excluded from the analysis because they were treated with aqueous penicillin by the ward physician for various reasons. In none of these patients did acute rheumatic fever subsequently develop.

5. Jones, T. D. The diagnosis of rheumatic fever. J. Am. Med. Assoc. 1944, 126, 481.

6. Swift, H. F. Wilson, A. T., and Lancefield, R. C. Typing group A hemolytic streptococci by M precipitin reactions in capillary pipettes. J. Exp. Med. 1943, 78, 127.

7. Hodge, B. E., and Swift, H. F. Varying hemolytic and constant combining capacity of streptolysins: Influence on testing for anti-streptolysins. J. Exp. Med. 1993, 58, 277.


353

8. Coburn, A. F. The prevention of respiratory tract bacterial infections by sulfadiazine prophylaxis in the United States Navy. J. Am. Med. Assoc. 1944, 126, 88.

9. Kuttner, A. G., and Reyersbach, G. The prevention of streptococcal upper respiratory infections and rheumatic recurrences in rheumatic children by the prophylactic use of sulfanilamide. J. Clin. Invest. 1943, 22, 77.

10. Hodges, R. G. The use of sulfadiazine as a prophylactic against respiratory disease. N. Engl. J. Med. 1944, 231, 817.

11. Commission on Acute Respiratory Diseases. A study of a food-borne epidemic of tonsillitis and pharyngitis due to beta-hemolytic streptococcus, type 5. Bull. Johns Hopkins Hosp. 1945, 77, 143.

12. Weinstein, L., Bachrach, L., and Perrin, T. S. Studies of the influence of penicillin on the immune reactions in streptococcal pharyngitis. J. Clin. Invest. 1949, 298, 817.

13. Finland, M. Use of penicillin in infections other than bacterial endocarditis. Adv. Int. Med. 1947, 2, 350.

14. Massell, B. F., Dow, J. W., and Jones, T. D. Orally administered penicillin in patients with rheumatic fever. J. Am. Med. Assoc. 1948, 138, 1030.

15. Jersild, T. Penicillin therapy in scarlet fever and complicating otitis. Lancet 1948, 1, 671.

16. Kilbourne, E. D., and Loge, J. P. The comparative effects of continuous and intermittent penicillin therapy on the formation of antistreptolysin in hemolytic streptococcal pharyngitis. J. Clin. Invest. 1948, 27, 418.

17. Rantz, L. A., Boisvert, P J., and Spink, W. W. Hemolytic streptococcic and nonstreptococcic diseases of the respiratory tract. Arch. Int. Med. 1946, 78, 369.


This investigation was supported through the Commission on Acute Respiratory Diseases, Armed Forces Epidemiological Board, Office of the Surgeon General, Washington, D. C.

From the Streptococcal Disease Laboratory, Fort Francis E. Warren, Wyo., and the Department of Preventive Medicine, Western Reserve University School of Medicine, Cleveland.

The Rise and Fall of Rheumatic Fever*

Alan L. Bisno, MD

IN THIS week's issue, the editors of JAMA have republished an article that stands clearly as a landmark in modern medical history. The article, which first appeared in The Journal 35 years ago, presents convincing evidence that acute rheumatic fever may be prevented by penicillin therapy for the antecedent streptococcal throat infection. This study and a succeeding one on the same topic published the next year1 emerged from the famous Streptococcal Disease Laboratory, which functioned at the Fort Warren, Wyo, air force technical training base in the years shortly after the end of World War II. The laboratory, under the leadership of, the late Dr Charles H. Rammelkamp, Jr, included among its ranks a number of young investigators destined to make indelible contributions to the field of infectious diseases. Numbered among these were Dr Floyd W. Denny, the senior author of the 1950 JAMA article, the late Dr Lewis W. Wannamaker, and other luminaries. Indeed, the meticulous epidemiologic and clinical data that emerged from Fort Warren remain today as the basis for many of our concepts regarding streptococcal pharyngitis and its sequels.

The recognition that acute rheumatic fever is a consequence of preceding group A streptococcal upper respiratory tract infection and that adequate treatment of such infection with penicillin is spectacularly effective in prevention led to development of our current strategies for control of rheumatic fever and rheumatic heart disease. These strategies have been reaffirmed once again by the recent publication of the latest revision of the American Heart Association's recommendations for primary and secondary prevention of rheumatic fever.2 The now-familiar recommendations relating to primary


354

prevention call for accurate diagnosis of streptococcal tonsillopharyngitis by use of the throat culture, followed by therapy for a minimum of ten days with penicillin or, in allergic patients, with erythromycin.

Decline of Rheumatic Fever in the United States

In rereading the Fort Warren article, one is struck by the estimates of 200,000 to 250,000 new cases of rheumatic fever developing in the United States annually in the late 1940s, with an average of more than 7,000 new acute rheumatic fever cases annually in the military alone. In those days, whole sanatoriums, such as the famous Irvington House in New York, were devoted to the care of children felled by acute rheumatic fever and severe forms of rheumatic carditis.

The situation in the 1940s contrasts remarkably with that in the 1980s. For many decades, there has been a steady decline in the occurrence of acute rheumatic fever in North America and western Europe. Within the past two decades, this decline has appeared to accelerate, so that in many parts of the United States today, acute rheumatic fever has become a truly rare disorder. Admission of a suspected case to the wards of a major teaching hospital is cause for a grand rounds presentation and for trotting out the more senior clinicians, who regale the house staff with experiences from the bad old days of yore.

The exact incidence of acute rheumatic fever in the United States at this time is difficult to ascertain. Rheumatic fever registries maintained by many states in the past have largely been abandoned.3 There have, however, been a number of detailed investigative studies carried out in various geographic locales, and the trends they document are most impressive. As recently as two decades ago, careful surveys yielded average annual acute rheumatic fever incidence rates among children and adolescents (aged 5 to 19 years) in Baltimore, Md,4 and Nashville, Tenn,5 of approximately 25 per 100,000 population. In the Nashville study, the incidence rate among black children aged 10 to 14 years for the years 1963 to 1969 was 55.5 (all rates expressed per 100,000 population per annum). The acute rheumatic fever incidence among schoolchildren in the borough of Manhattan during 1963 to 1965 was estimated at 61, with rates in the most congested Puerto Rican districts of 78 to 79.6

These figures contrast sharply with the most recent survey data. Land and Bisno7 found an annual acute rheumatic fever incidence rate for schoolchildren in Memphis-Shelby County, Tennessee, during 1977 to 1981 of 1.88. Among white children residing in the suburbs, the rate had fallen to 0.49, ie, one case per 200,000 children per year! These startling figures have been confirmed elsewhere. In his continuing studies of Baltimore, Gordis8 found the incidence rate of first attacks in children and teenagers had by 1977 to 1981 fallen to 0.5. Similar unprecedentedly low rates have recently been reported for Fairfax County, Virginia,9 and for the state of Rhode Island.10

Possible Reasons for the Waning of Acute Rheumatic Fever

The reasons for the dramatic decline of rheumatic fever incidence in North America, western Europe, and, more recently, in the most highly developed areas of the Far East11 remain speculative. There is no convincing evidence of a parallel decline in the incidence of group A streptococcal pharyngitis. Indeed, streptococci continue to be isolated in a sizable percentage of children presenting for treatment of simple sore throat.

Continuous antimicrobial prophylaxis has been highly effective in preventing recurrences of acute rheumatic fever in patients with a prior history of the disease. It is difficult, however, to attribute the bulk of the decline in first attacks of acute rheumatic fever to antibiotic therapy for strep throat, because the decline appears to antedate the antibiotic era. We know, moreover, that one third or more of acute rheumatic fever cases occur after strep throats that are asymptomatic or at least so mild as to have been overlooked and thus not preventable by antibiotics. Many other relatively mild cases of pharyngitis, particularly those occurring in indigent families, undoubtedly never come to medical attention. In many other cases, failure of compliance with orally prescribed antibiotics makes the efficacy of primary prevention highly problematic.


355

Although household crowding and other, less well-defined socioeconomic factors appear to influence markedly the incidence of rheumatic fever, it is difficult to see how such factors could explain the precipitous drops in occurrence of the disease that have been observed over the past 20 years in cities such as Baltimore.

Finally, there is considerable epidemiologic evidence to suggest that group A streptococci may vary in their rheumatogenic potential and that currently prevalent streptococcal serotypes may be less apt to initiate the disease. The well-known rheumatogenic serotypes circulating at Fort Warren (eg, types 5, 14, and 24) gave rise to acute rheumatic fever with a relatively constant attack rate approximating 3% in recruits with untreated exudative tonsillopharyngitis.12 Those serotypes are rarely encountered nowadays in isolates submitted to this writer's laboratory from various areas of the United States, and the types currently causing pharyngitis in many centers have not been strongly epidemiologically related to acute rheumatic fever. Data supporting the concept of relative rheumatogenicity of group A streptococci cannot be summarized here, but the reader is referred to comprehensive reviews published elsewhere.13,14

Rheumatic Fever in the Third World

While rheumatic fever has become a rare disease in many parts of the United States, and particularly so in the affluent suburbs, the disease continues to devastate many of the poorer and most densely populated areas of the globe. In the Indian subcontinent, southeast Asia, the Arab world, and in certain areas of Africa and Latin America, rheumatic fever remains one of the leading causes of cardiovascular morbidity and mortalityoften the leading cause. To cite only two examples, the annual acute rheumatic fever incidence rate among children in Sri Lanka from 1972 to 1978 averaged 142,15 while as late as 1980, rheumatic heart disease patients accounted for 40% of all cardiac admissions to a major Indian teaching hospital.11 Indeed, the incidence of acute rheumatic fever may actually have risen in certain of the tropical Third World countries, because it was widely written and assumed early in this century that rheumatic fever was rare in the tropics.16

The duality in the global epidemiology of rheumatic fever raises legitimate questions regarding strategies currently being employed for acute rheumatic fever control in both settings. The strategies employed for management of acute pharyngitis by physicians in this country were developed in the days when acute rheumatic fever was a familiar and ever-present hazard. Are they still valid in an era of declining acute rheumatic fever incidence?

Management of Strep Throat: A Reassessment

The cornerstone of diagnosis of streptococcal pharyngitis for many decades has been the throat culture. This procedure has been advocated by authorities because the broad overlap in signs and symptoms of streptococcal and viral pharyngitis precludes confident distinction between the two on clinical grounds alone in many cases. The throat culture has been roundly criticized, however, on several counts. First and foremost, it cannot differentiate with certainty between acutely affected individuals, who require antibiotic therapy, and asymptomatic carriers, who do not. Second, when a single throat swab is performed (as is conventional), there is an approximate 10% rate of false-negativity.17 Third, the culture adds expense and time delay to the management of this extremely common clinical problem.

Advocates of the throat culture point out that, even though its use is associated with a modest degree of overtreatment, the throat culture has a negative predictive value in excess of 95%. Thus, a negative culture allows the physician confidently to rule out strep throat and thus withhold antibiotics in the 70% or more of patients with pharyngitis whose cultures are negative. In an era when blunderbuss penicillin use for prevention of acute rheumatic fever is no longer defensible, this is a critical point. The issue of sensitivity has probably been overblown, because the few false-negatives likely represent random sampling errors in patients with weakly positive cultures; the risk of acute rheu-


356

matic fever ensuing in such patients, most of whom are probably carriers, may well be minuscule. The cost of throat culture, while admittedly a factor, need not be exorbitant if screening is limited to group A streptococci and if determinative bacteriologic procedures and detailed antimicrobial testing on other microbes are avoided. Such cultures can, moreover, be used more sparingly in children younger than 3 and in older adults, because both groups have a relatively low incidence of streptococcal pharyngitis and of rheumatic fever.

Even when throat cultures are performed assiduously, the information obtained is often not used appropriately. A recent survey of Rhode Island physicians and laboratories,10 for example, revealed that 157,000 throat cultures were performed in 1980 for a population of less than 1 million. Eighty-seven percent of responding primary care physicians stated that they started antimicrobial therapy before culture results were known, and 39% continued antibiotic therapy even if the cultures were negative. Some 44% of respondents indicated that they often did not receive culture results in time to influence therapy. These data are indeed disturbing and raise questions as to the cost-effectiveness of throat cultures as currently employed by many primary care practitioners.

The Fort Warren investigators18,19 showed that, although prompt penicillin therapy was effective in ameliorating the symptoms of strep throat, such improvement was often not striking, because the disease itself was self-limited within a few days. They also showed20 that a brief delay in initiation of therapy did not increase appreciably the risk of acute rheumatic fever. Thus, most authorities have felt that immediate treatment was not mandatory except in the minority of children with high fever, significant toxic reaction, or evidence of suppurative complications. Apparently, the profession does not agree.

This dilemma may be resolved with the appearance on the market of kits that allow rapid detection (within minutes to less than an hour) of group A streptococcal antigen and do not require overnight incubation.21,22 The exact sensitivity of these tests in everyday practice remains to be determined. None is reliable in detecting 1+ cultures (ten colonies or less), but such sensitivity may not be required, given the rarity of acute rheumatic fever and the high proportion of carriers among patients with such weakly positive cultures. If currently available kits or future modifications can be definitely established to have adequate sensitivity for general clinical purposes (and emerging data appear quite favorable), then the physician will be able to make a definitive determination of the need for therapy on the day the patient is seen and even, if desired, before the patient leaves the office.

Once the diagnosis of streptococcal pharyngitis is established, the issue of therapy arises. Because of its demonstrated efficacy (dating back to the landmark report of Denny et al) in prevention of acute rheumatic fever, penicillin is considered the drug of choice. For many years, benzathine penicillin G
has been considered the preferred dosage form. The prolonged penicillinemia obtained after a single injection obviates problems of patient compliance and ordinarily results in high rates of eradication of group A streptococci from the pharynx. The injection is painful, however, and parenteral penicillin injections have been associated with fatal hypersensitivity reactions at an estimated frequency of 1.5 deaths per 100,000 administrations.23 Although the exact data are not available for the risk of fatal anaphylaxis after oral penicillin use, most observers believe that oral penicillin is much less risky in this regard than is a parenteral drug. There is thus the question, given the ubiquity of strep throat and the rarity of acute rheumatic fever, of whether the risk-benefit ratio has now shifted in favor of oral therapy, especially in affluent areas where the acute rheumatic fever risk is particularly low and prospects for patient compliance are (it is hoped) somewhat higher. Indeed, many primary care physicians have already adopted this policy.

A prudent response to the changing epidemiologic scene would suggest that extensive culturing of asymptomatic family contacts of patients with strep throat is no longer necessary, unless there is a rheumatic individual in the family or the epidemiologic situation suggests a high risk of acute rheumatic fever. Moreover, the most recent American Heart Association statement2 mandates posttreatment cultures only for those patients with strep throat "who are at unusually high risk of rheumatic fever or who remain symptomatic." It goes without saying that repetitive attempts to eradicate asymptomatic throat carriage by multiple repetitive courses of antibiotics are inappropriate and usually futile.


357

Rheumatic Fever Control in the Third World

The methods of rheumatic fever control pioneered by the Fort Warren investigators and others have marked limitations when applied to the Third World. So-called primary prevention strategies may be foiled by the fact that relatively minor, self-limited illnesses such as sore throat often do not come to medical attention because of extreme poverty, competing family needs, lack of understanding of the potential significance of the illness, and limited access to medical care. Secondary prevention (ie, continuous antibiotic prophylaxis in rheumatic patients to prevent recurrences of acute rheumatic fever and progression of rheumatic heart disease) has been highly effective in selected areas. Unfortunately, organized programs of secondary prophylaxis require monetary resources and well-developed public health infrastructures, which are often lacking in just the areas of greatest need.

While a decline in acute rheumatic fever incidence similar to that observed in the west might be anticipated as socioeconomic conditions improve, such improvement is nowhere to be seen in many of the countries in which the problem is gravest. Meanwhile, untold numbers of individuals will become cardiac cripples or die of rheumatic heart disease. For this reason, the ultimate preventative measure might prove to be not an antibiotic but rather a vaccine.

During the past decade, gratifying progress has been made in purifying and characterizing streptococcal M protein, the antiphagocytic surface substance that confers upon the group A organism its virulence and that elicits type-specific antibodies in the host. These antibodies form the basis of acquired immunity to the group A streptococcus in man. Small peptides contained within the M protein molecule and composed of as few as 35 amino acids have been found to contain antigenic determinants that elicit protective antibodies.24 Moreover, certain M protein fractions elicit antibodies that opsonize streptococci of several M protein serotypes. These findings suggest that it might be possible to construct vaccines made of pools of peptides that protect against the major rheumatogenic serotypes in a given geographic area.

An exciting recent finding has been the presence of epitopes on the M protein molecule that share antigenic determinants with human heart tissue.25 Although the relevance of such antigens to the pathogenesis of rheumatic fever is unknown, it is interesting that they have been identified on streptococci belonging to serotypes known to be strongly epidemiologically associated with acute rheumatic fever. In addition to providing a possible theoretical explanation for the concept of relative rheumatogenicity of group A streptococci, identification of these cross-reactive antigens will make it possible to exclude them from future vaccine preparations, thus providing an immunizing agent of maximal safety to the host.

Only time will tell how soon the combination of antimicrobials, socioeconomic changes, and, perhaps, vaccines will finally bring rheumatic fever under ultimate control. That such a prospect is even conceivable, however, is due in large part to the pioneering efforts, only a few decades ago, of the denizens of Fort Warren, Irvington House, and the other great staging areas for a war on rheumatic fever that had some of its earliest beginnings, appropriately enough, in a camp for military recruits.

This work was supported in part by grant 84-996 from the American Heart Association and grant AI-10085 from the National Institutes of Health.

REFERENCES

1. Wannamaker LW, Rammelkamp CH Ir, Denny FW, et al: Prophylaxis of acute rheumatic fever by treatment of the preceding streptococcal infection with various amounts of depot penicillin. Am J Med 1951; 10:673-695.

2. Shulman ST, Amren DP, Bisno AL, et al: Prevention of rheumatic fever. Circulation 1984;70:1118A-1122A.


358

3. Kaplan EL: Current status of rheumatic fever control programs in the United States. Public Health Rep 1981;96:267-268.

4. Gordis L., Lilienfeld A, Rodrigues R: Studies in the epidemiology and preventability of rheumatic fever I. Demographic factors and incidence of acute attacks. J Chronic Dis 1969;21:645-654.

5. Quinn RW, Federspiel CF: The incidence of rheumatic fever in metropolitan Nashville, 1963-1969. Am J Epidemiol 1974;99:273-280.

6. Brownell KD, Bailen-Rose F: Acute rheumatic fever in children: Incidence in a borough of New York City. JAMA 1973;224:1593-1597.

7. Land MA, Bisno: AL Acute rheumatic fever: A vanishing disease in suburbia. J. Am. Med. Assoc. 1983;249:895-898.

8. Gordis L: Changing risk of rheumatic fever, in Shulman ST (ed): Management of Streptocococcal Pharyngitis in an Era of Declining Incidence of Acute Rheumatic Fever. New York, Praeger Publishers, 1984, pp 13-22.

9. Schwartz RH, Hepner Sl, Ziai M: Incidence of acute rheumatic fever A Suburban community hospital experience during the 1970s. Clin Pediatr 1983;22:798-801.

10. Holmberg SD, Faich GA: Streptococcal pharyngitis and acute rheumatic fever in Rhode Island. JAMA 1983;250:2307-2312.

11. Agarwal BL: Rheumatic heart disease unabated in developing countries. Lancet 1981;2:910-911.

12. Rammelkamp CH Jr, Denny FW, Wannamaker LW: Studies on the epidemiology of rheumatic fever in the armed services, in Thomas L (ed): Rheumatic Fever: A Symposium. Minneapolis, University of Minnesota Press, 1952, pp 72-83.

13. Bisno AL: The concept of rheumatogenic and nonrheumatogenic group A streptococci, in Read SE, Zabriskie JB (eds): Streptococcal Diseases and the Immune Response, Streptococcal Disease and the World Status. New York, Academic Press Inc, 1980, pp 789-803.

14. Stollerman CH: Nephritogenic and rheumatogenic group A streptococci. J Infect Dis 1969;120:258-263.

15. World Health Organization: Community control of rheumatic heart disease in developing countries: I. A major public health problem. WHO Chron 1980;34:336-345.

16. Markowitz M: Observations on the epidemiology and preventability of rheumatic fever in developing countries. Clin Ther 1981;4:240-251.

17. Kaplan EL: Unresolved problems in the diagnosis and epidemiology of streptococcal infections, in Wannamaker LW, Matsen JM (eds): Streptococci and Streptococcal Diseaes. New York, Academic Press Inc, 1972, pp 557-570.

18. Brink WR, Rammelkamp CH Jr, Denny FW, et al: Effect of penicillin and aureomycin on the natural course of streptococcal tonsillitis and pharyngitis. Am J Med 1951;10:300-308.

19. Denny FW, Wannamaker LW, Hahn EO: Comparative effects of penicillin, aureomycin and terramycin on streptococcal tonsillitis and pharyngitis. Pediatrics 1953;11:7-14.

20. Catanzaro FJ, Rammelkamp CH Jr, Chamovitz R: Prevention of rheumatic fever by treatment of streptococcal infections: II. Factors responsible for failures. N Engl J Med 1958;259:51-57.

21. Gerber MA, Spadaccini LJ, Wright LL et al: Latex agglutination tests for rapid identification of group A streptococci directly from throat swabs. J Pediatr 1984;105:702-705.

22. Berkowitz CD, Anthony BF, Kaplan EL, et al: A cooperative study of latex agglutination to identify group A streptococcal antigen in throat swabs of patients with acute pharyngitis. J Pediatr, in press.

23. Idsoe O, Guthe T, Wilcox RR, et al: Nature and extent of penicillin side-reactions, with particular reference to fatalities from anaphylactic shock. Bul WLO 1968;38:159-188.

24. Beachey EH, Seyer JM, Dale JB, et al: Type-specific protective immunity evoked by synthetic peptide of Streptococcus pyogenes M protein. Nature 1981;292:457-459.

25. Dale JB, Beachey EH: Multiple heart cross-reactive epitopes of streptococcal M proteins. J Exp Med 1985;161:113-122.


359

From the Department of Medicine, Division of Infectious Diseases, University of Tennessee Center for the Health Sciences, Memphis.

Reprint requests to Department of Medicine, Division of Infectious Diseases, University of Tennessee Center for the Health Sciences, 956 Court Ave, Room H308, Memphis, TN 38163 (Dr Bisno).

*A commentary on Denny FW, Wannamaker LW, Brink WR, et al: Prevention of rheumatic fever: Treatment of the preceding streptococcic infection. JAMA 1950;143:51-163.

Reprinted with permission from J. Am. Med. Assoc. 1985, 245, 534-537, 538-541 (originally published J. Am. Med. Assoc. 1950, 143-153) Landmark Articles, © 1950 / 1985, American Medical Association.


360

SECTION 4—APPENDIX 7

TRANSFER FACTOR

The commissions on streptococcal and staphylococcal infections supported parts of the work on transfer factor in the laboratories of Drs. Lawrence and Tillett of the New York University Medical Center. A section on these accomplishments is in the body of the history. Some reminiscences by Dr. Lawrence of his experiences with the commissions are included here.

Recollections of a Streptococcal Watcher
(with apologies to Lewis Thomas)
H.S. Lawrence, NYU Medical Center

What I remember chiefly about the Streptococcal Commission of the AFEB was the stimulating intellectual climate and the impressive scientific achievements of its members who at the same time comprised such a genial, friendly group strongly supportive of young investigators, such as myself. I had the good fortune to be introduced to the Strep Commission by my illustrious teacher and staunch friend, William S. Tillett, who had served as former Chairman of the Commission.

My connections to the streptococcus seemed rather tenuous at the time and limited to getting Rammelkamp's advice on treatment of my son Geoffrey's tonsillitis and yet it all began simply enough. Tillett had read of Chase's cellular transfer of tuberculin sensitivity in guinea pigs and with characteristic insight suggested that I might see if such a transfer of immunity could be brought about in humans as well. The transfer of cutaneous delayed type hypersensitivity from immune human donors to non-immune recipients was readily accomplished using blood leukocytes.

We then moved onto the transfer of delayed sensitivity to streptococcal products in humans. This adaptation arose out of our interest in rheumatic fever and the suspicion that the "altered tissue reactivity" (Tillett's apt phrase) which resulted in cardiac damage following streptococcal infection was more likely to be a result of inflammatory hypersensitivity reactions of the delayed type and cell mediated immune responses to streptococcal products rather than arising from the intercession of the serum antibodies detected in this disease.

The subsequent transfers of delayed cutaneous reactivity to intact streptococci, to SK-SD, an extracellular product close to Tillett's heart, and to streptococcal M-substance were also readily accomplished in hu-mans. This study was supported by the Streptococcal Commission of the AFEB. It was my first research grant award and what a boost in morale it was.

The award was renewed on a yearly basis and I continued to acknowledge with gratitude AFEB support in publications from 1952 up through my Harvey Lecture in 1974, and although other federal and private foundation support ensued, the Streptococcal Commission grant always held a special place in my memory.

Following the transfer of delayed reactivity to streptococcal products, I presented our results to the annual commission meeting in Washington and met O. T. Avery. He was on the same program and closed his presentation with the modest disclaimer that he feared that he had accomplished very little in the preceding yearan unbelievable suggestion which prompted vociferous disagreement from the audience. At dinner that evening I chanced to be seated opposite Avery. He confided to me that he could not understand the full meaning of our results but that he found the whole idea intriguing and was convinced that we were on to something important and should keep at it. To me this was high praise indeed, particularly since Tillett had been trained by Avery and I had been trained by Tillett, it was reassuring that I had not let my teacher down. Parenthetically, I should have told Avery, that I could not understand the full meaning of our results either, but it took me a while longer to fully realize it.

It was about this time that I met Lewis Thomas at one of the annual AFEB meetings, which I have described on the occasion of the presentation of his Kober Medal award by the Association of American Physicians, and from which I quote:


361

'I first met Lew while he was still at Minnesota when we served together on the Streptococcal Commission of the Armed Services Epidemiological Board along with many of the distinguished members of the Association here today. He had just presented his progress report on the Shwartzman reaction and the place of endotoxin as the cornerstone and central focus of all biological transactions, speaking in a flawless dialect of English and making incisive and witty good sense. The audience was at first rapt and then galvanized into thinking. That is to say thinking as Lew thinks and revelling in the sensation. Colin MacLeod was sitting nearby, and I could see in his enthusiastic reaction, reflected as well in the rest of us, that instant impact of a winner. I knew then that Lew was not long for Minnesota. Indeed, I should have had the courtesy to tell him to start packing then.

For pack he did and came to NYU as Chairman of Pathology in 1954 through the lure of Colin MacLeod, Homer Smith, Alwin Pappenheimer, Severo Ochoa, William Tillett, Bernard Davis, and Saul Farber. And with all due respect to his many friends at Minnesota, it was an offer that he couldn't refuse.' (Lawrence, H.S. Presentation of the George M. Kober Medal to Lewis Thomas, Trans. Assoc. Am. Physicians 1983, XCVI, 118-133. Reprinted with permission.)

Those were the Minnesota days with Lew Thomas and his gallant crew Bob Good, Dick Smith, Floyd Denny and our late, beloved Lew Wannamaker.

Although I enjoyed the intellectual simulation of the meetings and the good fellowship of the members greatly, I still felt a bit out of it scientificallyprobably because I was studying Delayed Type Hypersensitivity, a sort of nondescript occupation at that timeout of the mainstream and unlikely to lead anywhere. Then suddenly the scope and tempo of the whole field was transformed with the perfection of in vitro assays of cellular immunity and the discovery and exploitation of the lymphokinesevents that led to liberation from an indolent red spot in the skin as the sole endpoint of the transaction. These advances coupled with the realization that cellular immunity was at the core of understanding mechanisms of allograft rejection, tumor immunity, prevention and recovery from intracellular infections caused by viruses, mycobacteria and fungi and certain types of autoimmune responses added to the attractiveness and prestige of the field that was to evolve into Cellular Immunology.

Yet in those early days I don't think we really convinced Chuck Smith, our late and beloved doyen of coccidioidomycosis, nor other members of the Commission that serum antibody was only the signal that an intracellular infection had occurred and that cell-mediated immunity was at the heart of the mechanism of resistance to and indispensable for recovery from that disease.

Of course this idea had been in contention since Ehrlich and Metchinkoff squared off and sent it whirling down the labyrinthine corridors of time. Nevertheless, we made our report to the Commission that coccidioidin-specific Transfer Factor did indeed transfer delayed reactivity and cellular immunity to coccidioidin from immune to non-immune individuals. Subsequently several other groups went on to show that Transfer Factor immunotherapy of patients with disseminated, amphotericin-resistant coccidioidomycosis resulted in their clinical, immunological and microbiological recovery.

Surely the collective scientific contributions of the Commission members have had a most favorable impact on the health of military and civilian populations alike, however it is the imprint of the people that lingers long after the parade has passedso many friends Lew Thomas, Gus Dammin, Floyd Denny, MacLyn McCarty, Dick Krause, Paul Beeson, Ted Woodward, and of course our late stalwarts Colin MacLeod, Rammel, John Dingle, Al Stetson, Armine Wilson and Lew Wannamaker among a host of others over the yearstruly scientific gentlemen who won the grateful admiration of us all.


362

SECTION 4—APPENDIX 8

CORRESPONDENCE WITH COMMISSION MEMBERS

Recollections of associations with the CSSD were sought from several former members. Excerpts from letters received from Drs. McCarty, Krause, and Stollerman are included below.

Dr. McCarty was an Associate Member of the CSSD from 1950 to 1954 and a Member from 1954 to 1973. When asked to record in November 1990 some of his memories of the CSSD, Dr. McCarty wrote the following:

I don't know how much I can contribute to the history of the Strep Commission. I still regret that all of my files on the subject, which may have served as something of a mnemonic, seem to have been discarded as out of date by an overzealous secretary many years ago.

One memory that comes back to me in thinking about the Commission has to do with the period shortly after the war when Bill Tillett was about to become chairman. He called me to ask if I would act as his deputy while he was serving in this capacity. I had just taken over the strep lab at Rockefeller on the retirement of Homer Swift, after five years of having no responsibilities other than working at the bench, and I was fixed on the idea that I ought to avoid extracurricular activities until I had this new job well in hand. I was further motivated in this idea by the fact that I considered myself on trial in this job, having not received a promotion to member or even associate member. Taking on an active department, with Rebecca Lancefield as one of the members, and the rheumatic fever service in the hospital seemed like a big challenge to me.

In any event, I felt that I had to decline Tillett's invitation. I tried to do this diplomatically, but it was immediately evident that he was annoyed with me. In retrospect, I think it is clear that I was being over-cautious and could have easily managed to take on this activity. The upshot was that I did not become a member of the Commission until a few years later (I think in 1951 or 1952). Tillett never mentioned the matter to me again, and we ultimately resumed our friendly relations.

With regard to the contributions of the Commission and its members to science and to the military, I don't believe that I have anything new or unique to offer. Beginning with the star in its crown, the Fort Warren Laboratory, it played a major role in the study of streptococcal infections and their sequelae, which had its impact on our general knowledge of the organism and its diseases as well as on their control in both military and civilian populations. From the point of view of providing a forum for the exchange of ideas and new information, it is clear how the members of the Commission in 1973 lost no time in organizing a "Streptococcal Club" to replace at least that function. Now appropriately renamed the "Lancefield Club," it continues to do this successfully.

While writing this letter it occurred to me to look at the list of Commission members in the recent AFEB anniversary volume to confirm some of the dates. Aside from a number of howlers in the affiliations given (Jim Hirsch and Steve Morse are credited to the Rockefeller Foundation, for example), the list is informative. My dates are given as 1951-1973, more or less confirming what I wrote above. From 19711 had the title of Advisory Member, which was the compromise reached when I proposed to resign, since with Dick Krause and Becca also members I felt that Rockefeller representation needed to be deemphasized. (I at least have the correspondence on this point, and don't have to rely on memory.)

With so little that is concrete to contribute, I've probably gone on too long alreadyso I'll close with warm regards.

Dr. Krause had an unusual relationship with the CSSD. While still a medical student at the Western Reserve University (as it was then called) School of Medicine, he spent a year at the Streptococcal Disease Laboratory working primarily on the quantitation of M protein. The impetus for these studies was the apparent loss of M protein from strains of streptococci that were carried in the pharynx for long


363

periods following acute infections. After graduating from medical school and finishing his residency training in internal medicine, he went to the Rockefeller Institute for Medical Research to study with Drs. Lancefield and McCarty. He subsequently was Professor and Chairman of the Department of Epidemiology at Washington University. After returning to the Rockefeller for several years, he became Director of the Institute of Allergy and Infectious Disease of the National Institutes of Health. Dr. Krause was an Associate Member of the CSSD from 1960 to 1963. He was a member from 1963 to 1973 and the CSSD's Deputy Director from 1968 to 1973. His work was supported in part by the CSSD. He writes in November 1990 of some of his recollections of this work as follows:

You have asked about the work from my laboratory which was supported in part by the AFEB (in particular Loring Air Force Base). There were two papers published. One, the lead article in The New England Journal of Medicine. volume 270, pages 1205-1212,1964, was entitled 'Prevention of Streptococcal Pharyngitis Among Military Personnel and Their Civilian Dependents by Mass Prophylaxis.'

The spread of streptococcal disease in a population such as Loring Air Force Base was more typical of a civilian community than a military population such as a recruit training command. In the case of Loring Air Force Base the health of the military personnel is influenced in large measure by the health of members of the family as evidenced by the fact that the control of streptococcal pharyngitis among the dependents was an important feature in the control of the disease among the military. Because of the relatively high incidence of streptococcal pharyngitis, penicillin prophylaxis was administered to the children during the third week of February. Targeting this population had a remarkable impact on the subsequent decrease in streptococcal pharyngitis in the military personnel even though they had not received penicillin prophylaxis.

The next study, in many ways, was more interesting. It was published in the Journal of Laboratory and Clinical Medicine, volume 56, pages 483-494, 1966. This was entitled 'Studies on the Transmission Within Families of Group A Hemolytic Streptococci.' As noted above, epidemiologic research on group A hemolytic streptococci at Loring Air Force Base had directed attention to the role of interfamilial transmission of the organism in the persistence and spread of streptococcal disease in the community. The personnel at Loring Air Force Base, unlike that at a large recruit training center, consisted predominantly of married military personnel and their dependents. Group A hemolytic streptococcal prevalence was determined for the family contacts of index cases of streptococcal associated respiratory disease and the family contacts of index cases of non-streptococcal respiratory disease. Prevalence percentage of A-positive contacts was at least five times higher for streptococcal index cases than that for the non-streptococcal index cases. This suggests that the home was the major locus and the school the secondary locus for the spread of streptococcal disease in this community. These studies emphasize that patients with streptococcal disease are a potential hazard to other members of the family including the military personnel. Under certain circumstances the identification of streptococcal pharyngitis in one member of the family may warrant bacteriologic procedures to prevent possible spread to other family members.

From 1962 until 1975 I was receiving support for various studies from the Streptococcal / Staphylococcal Diseases Commission [CSSD]. The emphasis of the work was the immune response in rabbits and mice to the polysaccharide antigens of the hemolytic streptococci. When I started this line of investigation, at the time I moved my laboratory to St. Louis, it was my intention to look at the immune response to streptococcal vaccines in rabbits using all the new methods of immunology, moving away, in other words, from the antistreptolysin O and the other long tried and true tests as well as the quantitative perceipitin test. As part of this strategy I recruited people into the laboratory in St. Louis who had been trained in the new immunology, such as Kirk Osterland and Eng Tan who came from Henry Kunkel's laboratory, and Julian Fleishman who came from Rodney Porter's laboratory. The confluence of these new people in the lab and their assistance at looking at the immune response with the new methodologies of the sixties resulted in the end in the use of streptococcal antigens to examine mechanisms of immunity. An unexpected opportunity for this effort was the chance observation that certain rabbits produced 20-50 mg/ml of serum of homogeneous antibody to the group specific polysaccharides. Further studies using rabbits of known pedigree revealed that this response was an inherited trait.


364

With a plentiful supply of homogeneous antibodies it was possible for the first time to perform structural studies on induced antibodies rather than the myeloma proteins, the only source of homogeneous gamma globulin prior to this time.

Most important for immunogenetics, these antibodies to the streptococcal carbohydrates were used as probes for examining the inheritance of idiotypes. The concept of idiotype emerged from Oudin's studies on the use of specific antibodies as antigens. The unique antigenic element of a specific antibody is the antigen binding site. When the antibody is used as an antigen the anti-antibody is directed against this antigen binding site, and in serologic terms this is called the idiotype.

There were a number of attempts in various laboratories to show the possible inheritance of idiotypes as genetic markers but these were inconclusive. At this juncture it would require a special experimental sys-tem and probably a good ration of luck to demonstrate unequivocally that there was genetic inheritance of the idiotype, and by implication, the genes coding for the binding site. Such, in fact, proved to be the case with extensive studies published in a number of papers from the laboratory. In a study of over 133 closely related rabbits and a comparison to 97 unrelated rabbits, there was a clear familial clustering of the idiotype of the proband antibody.

A number of laboratories, after I withdrew from the field in 1975, extended the work to use idiotypy to show the regulation and modulation of immunity. For example, the idiotypic antibody (streptococcal) was used successfully to suppress specific antibody production and it was shown that it was possible to induce T and B cell immunity by anti-idiotypic antibody. These and other observations were part of the back-ground against which Neils Jerne developed his antibody network hypothesis for immune regulation.

Another line of investigation concerned the biological properties of peptidoglycan. This was the work of Jiri Rotta and was published in the JEM. He came to the laboratory in 1963 having made the prior observation that streptococcal cell walls would increase nonspecific resistance of mice to subsequent challenge by streptococci. The problem was to determine which component of the cell wall was responsible for this enhanced non-specific resistance. He conclusively showed that this was due to peptidoglycan and not to other cell wall components. He also showed that the peptidoglycan had a number of properties that were similar to endotoxin but he proved beyond doubt that the biological activities of the peptidoglycan fraction was not due to endotoxin contamination.

These were important studies because they contributed to a growing body of evidence of the importance of peptidoglycan components as possible adjuvants. As you know, there has been much done on the smallest component of peptidoglycan that serves as a powerful adjuvant. Muramic acid with several amino acids attached (muramyl dipeptide) is the smallest molecule, and several different compounds using different amino acids are now in clinical trials for adjuvant activity.

This is probably much more than you want to know, Floyd, but it did give me a chance to reminisce over a long period of support by the Commission. It was all great fun and it was the best of times, of course, at Warren Air Force Base.

Dr. Stollerman spent a short period of time at the Streptococcal Disease Laboratory to collect streptococcal strains for some of his studies at Irvington House. In later years some of his work with streptococcal M protein was supported through a contract with the CSSD. He was an Associate Member of the CSSD from 1956 to 1970 and a Member from 1970 to 1973. When asked in December 1990 to record the impact of the CSSD on his work he wrote the following:

Your letter of October 10, 1990, conjures up some of the most poignant memories of my research career. It was, in part, with the timely and valued support of the AFEB Commission on Streptococcal and Staphylococcal Diseases that I was able to focus on the problem of type specific immunity to strep M serotypes in the late 50's and early 60's while I was a Northwestern University.

I had just arrived there from Irvington House where I had become fascinated with the bactericidal test of Todd, refined by Sid Rothbard and Rebecca Lancefield, as a test-tube microcosm of the contest between group A streptococci and the phagocytes of the human host. Dr. Lancefield herself supervised my grasp of


365

that test and taught me the critical importance of the phase of virulence in which the organism had to be maintained to retain their remarkable resistance to phagocytosis, and that this phase could usually be maintained by repeated mouse passage or passage through fresh human blood.

Armine Wilson was also very helpful in supplying me with strain variants of M serotypes that either had lost the characteristic large capsules (and thus suffered some decline in resistance to phagocytosis), or had retained encapsulation but lost M protein, thus also suffering an anti-phagocytic decline.

It was while making Giemsa stains of the blood-strep mixtures at time intervals during the incubation period of the bactericidal tests that I first observed the inverse relationship of virulence and encapsulation to chain length. In the first hour of growth in either blood or plasma, chain-length shortened dramatically. In contrast, growth in the presence of homologous M antibody caused a spectacular extension of chain length, and this reaction proved to be exquisitely M type specific.

What soon became apparent to me, however, was that this chain reaction to homologous M antibody was not applicable to most strains isolated from throat cultures in community studies (made with Alan Siegel and Eloise Johnson at Childrens Memorial Hospital in Chicago). Strep throat strains rapidly lost virulence during convalescent carriage, and therefore these strains were often unencapsulated, poor in M protein content (though often still typable) and tended to grow spontaneously in longer chains. Moreover, we were beginning to recognize that only a few freshly isolated strains from children with endemic pharyngitis in civilian settings were fully developed in capsular, M protein and antiphagocytic properties when rheumatic fever was rapidly declining in prevalence.

One of these fully virulent variants still haunts me because it was an encapsulated M type 5 that caused acute rheumatic fever within 10 days in a 10 year old boy leading to mitral and aortic regurgitation, despite the treatment of the child on the tenth day with intensive penicillin therapy! A truly rheumatogenic strain was that one and it subsequently fortified my bias toward the essential role of virulence properties in the rheumatogenicity of group A strep. Strains with such properties caused epidemics of rheumatic fever at Great Lakes Naval Training Center (my studies with Paul Frank) whereas rheumatic fever became scarce and then virtually disappeared at the Childrens Memorial Hospital clinic (studies with Alan and Eloise) coincident with the disappearance of these strains. I could not help being impressed with this epidemiologic contrast. The dissociation of ARF and AGN in the subsequent Memphis studies with Alan Bisno further strengthened the conviction of strain "rheumatogenicity." Some eminent future investigators were in my lab as medical students during my sojourn at Northwestern University such as Fred Kantor (now Beeson Professor of Medicine at Yale) and Irun Cohen (now Head of the Department of Cell Biology at the Weizmann Institute), but most particularly the late Edwin Beachey who was my patient when he developed rheu-matic fever as a medical student. Dick Ekstedt and I were then studying the effects of removal of the capsule with hyaluronidase. By such treatment we released into the supernate very small quantities of the most spectacularly type-specific inhibitor of the long chain reaction we had ever encountered. It turned out to be highly purified M protein but present in such small quantities as to be undetectable except by biologic tests. But the experiments reinforced my suspicions that the purest M protein could be split off from the strep surface and subsequent vaccine development might depend on such gentle enzymatic treatment.

Our studies of purification of M protein at that time were made from hot acid extracts of M protein as crude starting material. This purified preparation, though M-antigenic (with incomplete Fruend adjuvant) was still strikingly reactogenic. When Ed Beachey joined me in Memphis, we struggled to remove this toxicity by further purification until 1976 when we finally gave up and concluded (J.C.I. and J. Immunol) that the toxic moiety was an inherent part of the same molecule that contained the type specific antigen (TSA) and that this toxic component could be removed only by splitting TSA off the outermost surface of the organism.

These studies led Ed Beachey to use dilute pepsin at suboptimal pH to prepare "Pep-M." Rebecca Lancefield had tried a pepsin approach in her early studies, but at the time the methodology for protein purification was not sufficiently advanced for much success. The arrival in my lab in Memphis in the early 70's of Itzhak Ofek from Jerusalem changed our approach. Itzhak brought with him from Issac Ginsberg's lab (at the Hadassah Dental School) purified lipoteichoic acid. Ed and I had been awed by Gibbon's studies on adherence of salivary strep to the teeth as a cause of caries. We were convinced that at the very end of the M protein molecule of group A strep would be the adherence lectin. To our astonishment, splitting off pep


366

M allowed the strep to adhere more avidly to oral membrane receptors. Moreover, the specific blocker of adherence turned out to be lipoteichoic acid! The avalanche of subsequent adherence studies is now history. Meanwhile, we had removed from the surface a piece of M protein of great purity and very little reactogenicity.

When I could get Ed Beachey to return to the "pep M" protein, he identified its molecular primary amino acid structure with the help of Jerry Seyer at the Memphis VA labs. The small peptide epitopes of the M molecule that were protective were molecularly defined and were separate from the non-type specific moieties that Ed and Jim Dale were sorting out as cardiac tissue cross reactants. Ed and I almost had a shot at organizing a vaccine study in the Soweto section of Johannesberg, South Africa in 1972 at the invitation of the South African Medical Council. All that went up in smoke in the political upheavals of that poor ghetto where the prevalence of acute rheumatic fever had reached unprecedented rates. The responsible strep strains were there for the study but vaccine plans went up in smoke in the political turmoil of that civil rights revolution.

Finally, the recent focal outbreaks of acute rheumatic fever in the U.S.A. occurred just before Ed's death, but in time for Ed's work on the molecular structure of rheumatogenic strep to be confirmed by Vince Fischetti and his group in their painstaking studies of the extended M molecule in the rheumatogenic strains collected at the Rockefeller University. The issue of a strep vaccine for selected strains of strep may still be alive. Some people are still asking surviving old-timers like me to discuss its prospects. The latest wrinkle to add is that the toxic property of M protein may be that of a "superantigen" that attaches directly to the T cell receptor! Malak Kotb, the Egyptian lady transplant immunologist who was working with Ed Beachey when he developed cancer, has been in touch with me to review my early experience with the toxicity of M protein. The old studies of the toxicity of streptococcal hemolysins and especially of cell-bound streptolysin S as well as the M protein have been reviewed. M protein, part of which is antiphagocytic and part of which may react nonspecifically with autoimmunity-regulating T lymphocytes now offer fascinating new possibilities about the pathogenesis of rheumatic fever. Stimulation and dysregulation of the strep immune response may be another ploy in the effect of M-rich strains of strep on human tonsillar tissues.

It was great to be part of the great tussle with the strep since the 40's. I will always be grateful to Colin MacLeod and to the Commission for allowing me to enter the fray.


367

SECTION 4—APPENDIX 9

COMMISSION DIRECTORS DURING WORLD WAR II

The Commission on Hemolytic Streptococcal Infections had two directors during World War II: Dr. Martin H. Dawson, College of Physicians and Surgeons, Columbia University, 1941 and 1942 and Dr. Chester S. Keefer, Boston University School of Medicine, 1942 to 1946. We do not have a picture of Dr. Dawson but the picture below was kindly furnished by Dr. Theodore Woodward.

CHESTER F. KEEFER, M.D.


368

SECTION 4—APPENDIX 10

COMMISSION DIRECTORS AFTER WORLD WAR II

William S. Tillett
Director, 1948 to 1954

Dr. Tillett had a long and distinguished career as one of the leaders of American academic medicine. His service to the military as adviser and consultant in streptococcal diseases spanned 25 years. He was a member of the Commission on Hemolytic Streptococcal Infections from 1941 to 1946 and was the first director of the Commission on Streptococcal Diseases; he remained a member until 1966. He died in 1974 at the age of 81 years.

The memorial that follows was written by Dr. Lawrence, Dr. Tillet's long-time student and colleague, and is reprinted with the permission of the Journal of Infectious Diseases.

Obituaries

It was with great sadness that I learned of Dr. William Smith Tillett's death on April 4, 1974 after a brief illness. He was a fine man, an outstanding scientist, and a beloved physician who is sorely missed by his family, his friends, his colleagues and his students.

Dr. Tillett was a gentleman of the old school: courtly, urbane, witty, and possessed of a grace and softness that was most cherished by the patients at Bellevue Hospital, to whom he was devoted. At the same time he had a common touch for humanity and its foibles, and he could put his finger on the crux of any situation in the laboratory, in the drawing room, or at meetings, for he had little patience with sham or pretence. His forthright and outspoken resolution of a problem at issue could be humorous or sober, and, being incapable of subterfuge, he cleared the air.

Dr. Tillett received his bachelor's degree from the University of North Carolina, where he was a good scholar and an All-American quarterback. After receiving his medical degree at Johns Hopkins, he enlisted in the army and saw action during World War I in France as the captain of a battalion of engineers in the Army Medical Corps.

After the war Dr. Tillett came to Rockefeller University under the aegis of Dr. O. T. Avery, whom he affectionately called "Fess" and whom he admired and revered both as a man and as a scientist. This was the beginning of a long and fruitful relationship that changed the course of Dr. Tillett's career.

He moved back to Johns Hopkins to become Director of Laboratories, and, stimulated by his observation of the lysis of clots by cultures of streptococcus that had been left standing, he began the pursuit of an idea that was to lead to the discovery of streptokinase and streptodornase.

Dr. Tillett came to New York University in 1938 as Professor and Chairman of the Department of Bacteriology and became Professor and Chairman of the Department of Medicine at Bellevue Hospital in 1939; he remained there until his retirement as Professor Emeritus in 1958. He was active in investigative programs until the age of 79.

During the period he was at New York University, Dr. Tillett's greatest achievements came to fruition; particularly outstanding were the isolation, identification and partial purification of streptokinase-streptodornase from streptococcal filtrates with Dr. Sol Sherry and the application of the principle of enzymatic debridement to purulent and thromboembolic disorders. It was also at this time that Dr. Tillett explored the use of the new drug penicillin in the treatment of pneumococcal infections. He combined his newly found enzymatic therapy with penicillin therapy to eliminate the need for surgery in the treatment of empyema.

Dr. Tillett received many honors and awards (including the Lasker and the Borden Awards) for his discovery of streptokinase-streptodornase and the application of enzymatic therapy to disease. The esteem of his colleagues was reflected in the various phases of his career; he was president of the American Society of


369

Clinical Investigation, of the Association of American Physicians, and of the Harvey Society. He was also a member of the National Academy of Sciences and chairman of the Streptococcal Commission of the Armed Forces Epidemiological Board.

After his retirement in 1958, Dr. Tillett continued to be active in the investigative academic life he loved so well and was the director of a training program in allergy and infectious diseases sponsored by the U.S. Public Health Service. He was happiest when advising a series of young investigators on their research problems.

Upon his retirement, the Department of Medicine had constructed and dedicated a suite of laboratories in Bellevue Hospital, designated the William Smith Tillett Laboratories. These laboratories and the research they foster were his pride and the only regret he was ever heard to express was that we had usurped for laboratory space a room he had set aside for "thinking."

We all miss him deeplyhis humor, his gusto, his incisive mind, and his great heart. A generous and gallant man, he helped to raise those brought low by disease and left his signature on the progress of science and humanity.

Lawrence, H. Sherwood. Obituaries: William Smith Tillett 1892-1974

Reprinted with permission of J. Infect. Dis. 1974, 130, 311-312.


370

WILLIAM SMITH TILLETT, M.D.


371

Charles H. Rammelkamp, Jr.
Director, 1954 to 1957
1959 to 1968

Dr Rammelkamp, was the Director and scientific leader of the Strep Lab during its entire existence and clearly the most important contributor to the CSSD for over 25 years. This exceptional role in the CSSD is recognized in the following memorial prepared by Dr. Robbins.

Charles H. Rammelkamp, Jr., 1911 to 1981

Charles H. Rammelkamp, Jr. died suddenly on December 6, 1981 of a ruptured abdominal aortic aneurysm at the age of 70. On the night before his death he awakened with abdominal pain and suspected what the diagnosis might be. However, with his characteristic concern for others, he did not bother anyone and waited several hours until his wife awakened at 7:00 am, her usual time. His remark to her was, "I think you had better take me to the hospital, I believe I am going into shock." At the hospital he was indeed in shock, and although surgery was done promptly, he did not recover. At the time of his premature death he had just become emeritus professor and was looking forward to a new and exciting career of scholarly activities. During his career he made exceptional contributions to clinical research, teaching and patient care. His scientific contributions were largely in the field of infectious disease, most notably early studies on the clinical application and mechanism of action of antimicrobials, i.e., sulfonamides and penicillin, and the epidemiology of streptococcal infections, the non-suppurative complications of streptococcal infections such as rheumatic fever and acute glomerulonephritis and the prevention of rheumatic fever by treatment of the streptococcal infection with penicillin.

Dr. Rammelkamp, who was known to all his friends and acquaintances as Rammel, was born in Jacksonville, Illinois, on May 24, 1911. He grew up in a family with a sister and two brothers. The environment was a scholarly one with a father who was president of Illinois College. Rammel obtained his A.B. degree (1933) at his father's college and upon graduation chose a medical career with the intention to become a general practitioner. He attended medical school at the University of Chicago (1937) after which he served as an intern in medicine at the Barnes Hospital in St. Louis (1937-1938). After one year at Barnes he returned to Chicago as an intern in surgery at the Billings Memorial Hospitals of the University of Chicago (1938-1939). His foray into surgery lasted only one year and he returned to Barnes as an Assistant Resident in Medicine (1939). It was never quite clear why he chose to spend a year as a surgical resident because he had few of the attributes usually associated with a surgeon but he seems to have enjoyed it and would often comment upon how valuable he found the experience. The course of his career was really determined in 1939 when he went to the Thorndike Memorial Laboratory of Boston City Hospital as Resident Physician. The Thorndike was an exciting place intellectually. At the time, it was populated by such luminaries as George Minot, hematologist and Nobel laureate noted for his work on pernicious anemia; Soma Weiss, teacher "extraordinaire" and cardiovascular investigator; Maxwell Finland and Chester Keefer, both of whom were distinguished infectious disease investigators. In addition there was a group of young physician-scientists who were to become leaders in academic medicine. Fortunately for the field of infectious diseases Rammel accepted a position with Chester Keefer rather than Soma Weiss. Had he joined Weiss cardiology undoubtedly would have benefited greatly.

Rammel's first task in Keefer's laboratory was to group and type beta hemolytic streptococci, a task that he found tedious and uninspiring. Nevertheless, this was the beginning of a lifelong fascination with the streptococcus and the diseases it causes. Next he chose to study an antibiotic, gramicidin, that had been discovered by Rene Dubos. Although effective in the test tube, gramicidin did not prove very useful in vivo because of its poor solubility. Along with these studies Rammel was involved in experiments with sulfonamides that were just beginning to be used clinically. His first publication dealt with sulfathiazole, the first sulfonamide to be introduced: in this country. Most of his early work concerned the pharmacology and clinical application of sulfonamides and the bacterial products, gramicidin and tyrothricin.


372

In 1940 Dr. Keefer moved to the Evans Memorial Laboratory to establish a Department of Medicine at Boston University. Rammel joined him there and soon was engaged in exploring the use of the new and exciting antibiotic, penicillin. The studies done by Rammel, Keefer, and associates on the pharmacokinetics and clinical effectiveness of penicillin were critical in providing the basis for its rational clinical use. Penicillin was a precious commodity at that time and Keefer was given responsibility for its allocation nation-ally. Thus, Rammel was strategically placed to be kept informed about all studies being conducted through-out the country. One of Rammel's more significant contributions was to devise a procedure for quantitating penicillin levels in blood and other biological fluids, a method that became universally used.

Rammel's tenure in Keefer's department was highly productive but did not last long. The United States had entered the World War II and the military was experiencing serious problems with acute respiratory disease. A Commission on Acute Respiratory Diseases had been established at Fort Bragg, North Carolina, with Dr. John Dingle as its head. Dr. Dingle recruited Rammel along with a fine group of clinical investigators and epidemiologists to conduct studies directed at elucidating the cause of acute respiratory diseases and to develop methods for their control. Rammel's special assignment was streptococcal disease but he was also involved with studies on primary atypical pneumonia (now known to be due to mycoplasma infection), influenza and other respiratory diseases. During its five year existence, the Commission published extensively on these topics. One of the more significant papers described the relationship of epidemics of influenza with the frequency of pneumonia. This has provided the basis for the influenza surveillance by the Centers for Disease Control which follows pneumonia prevalence as a surrogate for influenza. The Commission adopted a policy of communal authorship of papers; the recorded author was the Commission with only a listing of the members, so that a portion of Rammel's bibliography is not identified under his name.

With the war over, Dr. Dingle moved to Cleveland in 1946 along with several members of the Commission, including Rammel, in order to establish a Department of Preventive Medicine at Western Reserve University School of Medicine. The department made many important contributions over the years but is best known for the landmark ten year Family Study program. This careful study provided a gold mine of information about the common illnesses in families and the population at large. Although Rammel was very much involved in the design and conduct of the Family Study he became intrigued with the high prevalence of streptococcal infection and rheumatic fever in troops serving in the Rocky Mountain area. In 1949 he became the director of the Streptococcal Disease Laboratory at Warren Air Force Base in Wyoming. It was here, in a period of six years, that he and his associates conducted the classical studies on the epidemiology and clinical features of streptococcal infection that demonstrated that rheumatic fever could be prevented if the acute streptococcal infection was treated adequately with penicillin. These studies not only made it possible to prevent rheumatic fever but also provided the clinching evidence of the role of the streptococcus in its etiology. The Ft. Warren laboratory was highly productive scientifically but also served as a training ground for an unusually talented group of young physicians among whom where Lewis Wannamaker, Richard Krause, Chandler Stetson, Harold Houser, and Floyd Denny, all of whom went on to distinguished careers. The significance of their work was recognized when, in 1954, the Albert Lasker Group Award was presented to the Streptococcal Disease Laboratory.

Rammel had been puzzled by the fact that only a single case of acute glomerulonephritis had occurred among the more than 1000 cases of streptococcal infection that had been observed at the Warren Air Force Base. The organism recovered from that case was type 12. This observation he put together with earlier findings from a family outbreak of type 12 infection in which five members displayed evidence of acute kidney disease and proposed the hypothesis that type 12, and possibly others, was a nephritogenic strain of streptococcus. This hypothesis on further study did indeed prove to be correct and type 12 and a few other types are now recognized as having the peculiar capability of producing acute nephritis. He and his coworkers were interested in why some strains were nephritogenic and others were not but several lines of investigation did not yield the answer to this intriguing question.

In 1950 Rammel was asked by Dr. Joseph Wearn, then Dean of the Western Reserve Medical School, to help develop an academic program at Cleveland City Hospital (later to become Cleveland Metropolitan Gen-


373

CHARLES H. RAMMELKAMP, M.D.


374

eral Hospital [CMGH], and now MetroHealth Medical Center). Dean Wearn had negotiated with the Mayor of Cleveland a new agreement that gave the medical school appointment power for the staff and provided for new facilities including a research building. Rammel was given the titles of Professor of Medicine, Associate Director of Medicine, and Director of Research Laboratories at City Hospital. He was able to recruit a number of outstanding research oriented staff and new directors of Pediatrics and Surgery. The model he had in mind was the Thorndike Memorial Laboratory at Boston City Hospital but, as it turned out, his influence and that of the new recruits affected all aspects of the hospital's functions. Largely through his efforts the City Hospital became the fine academic institution that it is today.

Rammel continued his interest in streptococcal disease and among other activities developed, with his associates, a mail-in system for the rapid diagnosis of streptococcal pharyngitis that allowed the physician to delay treatment until there was evidence that it was indicated, thus forestalling much unnecessary treatment. He also engaged in a series of studies in Chile on the use of penicillin treatment of acute rheumatic fever and valvulitis.

In addition to the streptococcus, Rammel was interested in the staphylococcus. Along with A.J. Gonzaga, Edward A. Mortimer, Jr., and Emanuel Wolinsky, he conducted a series of classical studies on the epidemiology of staphylococcal infections in newborn nurseries. At the time, epidemics of staphylococcal infections were occurring frequently with considerable morbidity and mortality. Their studies showed, quite conclusively, that infection was transmitted on the hands of the caretakers and that simple handwashing was an effective control measure.

Although Rammel's principal scientific interests were in the field of infectious diseases and streptococcal and staphylococcal infections in particular, he brought the same degree of curiosity and scientific analysis to whatever he was concerned with. He was a strong advocate for the application of basic science to clinical problems and was concerned that basic principles were not being taught adequately in the ambulatory or outpatient setting. He devised and put into effect an ambulatory unit where students and their instructors could investigate their patients in more depth than was usual in the clinic. This became an effective and unique teaching unit in which ambulatory patients received exceptionally fine care.

Another example of Rammel's ability to combine a scientific approach with his great concern for teaching and patient care was the "Firm" system of organizing medical care. He had been impressed with the ad-vantages of the "Firm" system as practiced in Great Britain. This consists of a group headed by a senior physician and including registrars (the equivalent of residents and fellows in the U.S.) and students who are responsible for the total care, on a continuing basis, of a group of patients in the hospital and the ambulatory care. This provides for a degree of continuity of care and teaching that does not occur in the usual U.S. system. Although at first he was primarily interested in improving patient care and teaching, he immediately saw its research potential. One can introduce a certain procedure or behavior into one or more firm[s] and not the others and compare the outcome. A key feature of the program is the random assignment of patients to the firms. Since Rammel's death, this unique technique of health care research has been continued at Metro by a cadre of young physicians. Their studies have evoked interest around the country.

Rammel had a profound interest in education. His inquiring mind was always searching for more effective ways to teach. He was a major force in the construction of the innovative curriculum at Western Reserve. His particular interests were better ways of integrating basic science with clinical teaching and the application of epidemiologic principles. He was one of the architects of the so-called "basic" clerkship which was a four month period on either a medical or pediatric service and constituted the student's first intensive clinical experience. It was a long enough period so that the student could experience some continuity of patient care and contact with one group of faculty. It also provided the opportunity to do special projects and to give greater attention than is usually the case to biomedical and psychosocial processes underlying disease.


375

Rammel's concern for the education of his resident staff was great and, as already mentioned, in large part motivated the introduction of the firm system which proved so successful. He was always available to his house staff and fellows and was much concerned with their education and their personal welfare as well. As a result he was much admired and even loved by most of them.

Rammel was married to Helen Chisholm who was Chester Keefer's secretary and they had three children: Charles H., III, Colin C. and Anne K. Davies. Rammel was devoted to his family although he did not spend as much time with them as he might have because of his heavy schedule and tremendous devotion to his work. However, they had a cottage on the shore of Lake Michigan and he always found some time each year to spend there. The Rammelkamp family was close but not particularly interested in the social life of the community or faculty.

Rammel very much enjoyed association with his faculty, house staff and fellows and his colleagues through-out the country. Typically, with a cigarette in his mouth (in spite of many efforts, he never succeeded in kicking the habit), he would often be found deep in discourse with a group of colleagues that would continue to all hours. The topics discussed would deal with science, education, or intellectual subjects, to a limited extent the usual academic gossip. Although Rammel was actively engaged in many professional societies and served as an officer including being president of many, he had little interest in professional politics. Indeed, among his outstanding attributes were a lack of personal ambition for power or prestige and an unselfish concern for his colleagues no matter what their rank or position. He was a warm, enthusiastic man who evoked respect and admiration from his colleagues and peers and exceptional loyalty from those who worked with or for him.

This biography was written for the Biographical Memoirs of the National Academy of Sciences and appeared in Volume 64 of the series. It is reproduced here with permission of the National Academy of Sciences.

Selected Bibliography of Publications by Dr. Rammelkamp

1940

Rammelkamp, C. H., Jr., and Keefer, C. S. Sulfathiazole: Effect on Staphylococcus aureus in vitro. Proc. Soc. Exp. Biol. Med. 1940, 43, 664.

Rammelkamp, C. H., Jr., and Jewell, M. L. Comparative in vitro study of various sulfanilamide derivatives on typhoid-dysentery organisms. Proc. Soc. Exp. Biol. Med. 1940, 45, 169.

1941

Keefer, C. S., Rantz, L. A., and Rammelkamp, C. H., Jr. Hemolytic streptococcal pneumonia and empyema: A study of 55 cases with special reference to treatment. Ann. Intern. Med. 1941, 14, 1533.

Rammelkamp, C. H., Jr., and Jewell, M. L. Comparative study of effect of sulfadiazine with sulfathiazole on Staphylococcus aureus. Proc. Soc. Exp. Biol. Med. 1941, 48, 27.

Rammelkamp, C. H., Jr., and Keefer, C. S. Observations on the use of "gramicidin" in the treatment of streptococcal and staphylococcal infections. J. Clin. Invest. 1941, 20, 433.

1942

Rammelkamp, C. H., Jr. A method for determining the concentration of penicillin in body fluids and exudates. Proc. Soc. Exp. Biol. Med. 1942, 51, 386.

Rammelkamp, C. H., Jr., and Maxon, T. Resistances of Staphylococcus aureus to the action of penicillin. Proc. Soc. Exp. Biol. Med. 1942, 51, 386.

1943

Rammelkamp, C. H., Jr. Mode of action of gramicidin and penicillin in the treatment of infections. J. Bacteriol. 1943, 45, 66.


376

Rammelkamp, C. H., Jr., and Keefer, C. S. The absorption, excretion and distribution of penicillin. J. Clin. Invest. 1943, 22, 425.

1945

Commission on Acute Respiratory Diseases. Transmission of primary atypical pneumonia to human volunteers. J. Am. Med. Assoc. 1945, 127, 146-149.

Commission on Acute Respiratory Diseases. An experimental attempt to transmit primary atypical pneumonia to human volunteers. J. Clin. Invest. 1945, 24, 175-188.

Commission on Acute Respiratory Diseases and the New York State Department of Health. The relation between epidemics of acute bacterial pneumonia and influenza. Science 1945, 102, 451-453.

1946

Commission on Acute Respiratory Diseases. Q fever: A foreword. Introduction to a series of papers dealing with Q fever. Am. J. Hyg. 1946, 44, 1-5.

1947

Commission on Acute Respiratory Diseases. The role of the Lancefield groups of ß-hemolytic streptococci in respiratory infections. N. Engl. J. Med. 1947, 236, 157-166.

Commission on Acute Respiratory Diseases. Experimental transmission of minor respiratory illness to human volunteers by filter-passing agents. II. Immunity on reinoculation with agents from two types of minor respiratory illness and from primary atypical pneumonia. J. Clin. Invest. 1947, 26, 974-982.

1950

Denny, F. W., Wannamaker, L. W., Brink, W. R., Rammelkamp, C. H., Jr., and Custer, E. A. The prevention of rheumatic fever. Treatment of the preceding streptococcic infection. J. Am. Med. Assoc. 1950, 143, 151-153.

1951

Wannamaker, L. W., Rammelkamp, C. H., Jr., Denny, F. W., Brink, W. R., Houser, H. B., Hahn, E. O., and Dingle, J. H. Prophylaxis of acute rheumatic fever by treatment of the preceding streptococcal infection with various amounts of depot penicillin. Am. J. Med. 1951, 10, 673-695.

1953

Rammelkamp, C. H., Jr., and Weaver, R. S. Acute glomerulonephritis. The significance of the variations in the incidence of the disease. J. Clin. Invest. 1953, 3, 345-358.

Wannamaker, L. W., Denny, F. W., Perry, W. D., Rammelkamp, C. H., Jr., Eckhardt, G. C., Houser, H. B., and Hahn, E. O. The effect of penicillin prophylaxis on streptococcic disease rates and the carrier state. N. Engl. J. Med. 1953, 249, 1-7.

Dingle, J. H., Badger, G. F., Feller, A. E., Hodges, R. G., Jordan, W. S., Jr., and Rammelkamp, C. H., Jr. A study of illness in a group of Cleveland families. I. Plan of study and certain general observations. Am. J. Hyg. 1953, 58, 16-30.

1955

Stetson, C. A., Rammelkamp, C. H., Jr., Krause, R. M., Kohen, R. J., and Perry, W. D. Epidemic acute nephritis. Studies on etiology, natural history and prevention. Medicine 1955, 34, 431-450.

1958

Catanzaro, F. J., Rammelkamp, C. H., Jr., and Chamovitz, R. Prevention of rheumatic fever by treatment of streptococcal infections. II. Factors responsible for failures. N. Engl. J. Med. 1958, 259, 51-57.

Rammelkamp, C. H., Jr., Morris, A. J., Catanzaro, F.J., Wannamaker, L. W., Chamovitz, R., and Marple, E. C. Transmission of group A streptococci. III. The effect of drying on the infectivity of the organism for man. J. Hyg. 1958, 53, 280-287.

Vaisman, S., Rakita, L., Mortimer, E. A., Jr., Gausch, J., Schuster, A., Vignau, A., Roberts, R. B., Krause, R. M., and Rammelkamp, C. H., Jr. A new approach to the treatment of acute rheumatic fever. Trans. Assoc. Am. Physicians 1958, 71, 274-280.

1960

Wolinsky, E., Lipsitz, P. J., Mortimer, E. A., Jr., and Rammelkamp, C. H., Jr. Acquisition of staphylococci by newborns. Direct versus indirect transmission. Lancet 1960, 279, 620-622.

1962


377

Mortimer, E. A., Jr., Lipsitz, P. J., Wolinsky, E., Gonzaga, A. J., and Rammelkamp, C. H., Jr. Transmission of staphylococci between newborns. Importance of hands of personnel. Am. J. Dis. Child. 1962, 104, 289-295.

1964

Rammelkamp, C. H., Jr., Chester, E. M. The training of the physician. A new approach to teaching ambulatory medicine. N. Engl. J. Med. 1964, 271, 349-351.

1965

Vaisman, S., Gausch, L., Vignau, A., Correa, E., Schuster, A., Mortimer, E. A., Jr., and Rammelkamp, C. H., Jr. The failure of penicillin to alter acute rheumatic valvulitis. J. Am. Med. Assoc. 1965, 194, 1284-1286.


378

Armine Taylor Wilson
Director, 1957 to 1959

Dr. Wilson, clinically trained as a pediatrician, joined Dr. Lancefield's laboratory at the Rockefeller Institute for Medical Research in 1940 and began a lifelong career as a preeminent streptococcal microbiologist. As director of the Navy's streptococcal typing laboratory, he was closely involved with streptococcal problems in the military during World War II. After discharge from the Navy, he directed the Microbiology Laboratory at the Alfred I. DuPont Institute of the Nemours Foundation in Wilmington, Delaware. He was a charter member of the reorganized CSSD in 1948 and remained a member until his death.

In 1964, because of his importance to the CSSD and their affection for Dr. Wilson, Drs. Wannamaker and Denny wrote the following article, which is reproduced with permission from Mosby-Year Book, Inc.*

An Effective Career Off the Mainstream

The field of pediatrics is so complex and encompasses such a broad area that oftentimes individuals working unobtrusively may make contributions of unusual significance which in large part go unnoticed by the mainstream of pediatrics. Dr. Armine T. Wilson, whose untimely death occurred on Dec. 7,1964, is a distinguished example of a man trained in pediatrics and dedicated to its principles who found that he could contribute most abundantly through laboratory observations.

Dr. Wilson was first attracted to pediatrics by his association with Dr. A. Graeme Mitchell, head of pediatrics at the University of Cincinnati College of Medicine. He served as chief resident at Children's Hospital in Cincinnati, 1939 to 1940. While with Dr. Mitchell, Dr. Wilson developed an interest in bacterial pheumonia in children and published data on its treatment with sulfapyridine. Dr. Oswald T. Avery, who was on the board of the Children's Hospital at that time, recognized Dr. Wilson's potential for investigation and lured him to the Rockefeller Institute for Medical Research. At this time he worked side by side with Dr. Rebecca C. Lancefield and began the association with hemolytic streptococcus which lasted his entire lifetime.

Dr. Wilson was intimately involved with Dr. Lancefield in the classical work of typing group A streptococci. Much of his subsequent investigation was directed toward elucidation of the intricate biologic properties of hemolytic streptococci, including sulfonamide resistance, antigenic structure, colonial characteristics, and properties related to phagocytosis. A contribution of unique interest to pediatricians was his investigation of the antistreptococcal properties of milk.

Evidence of his motivation to share his knowledge with students of pediatrics can be found in his concise but comprehensive section on streptococcal infections which first appeared in the 1950 edition of the Mitchell-Nelson standard Textbook of Pediatrics, with subsequent revisions until 1964. Although his natural bent was more toward investigation than formal teaching, a suppressed desire to contribute to student education also emerged in an unusual form in his production of a professional teaching film on the dynamics of phagocytosis. This meticulously prepared film has received wide acclaim and use and was officially recognized by receiving the Biological Photographic Association's "Award of Excellence, First Place" on Sept. 3, 1959.

Dr. Wilson's curiosity extended beyond the confines of streptococcus and included observations on the problems of cholera, which took him to various parts of the Near and Far East, and investigations of new methods of sterilization by ethylene oxide.

Beginning with his tour of duty in the Navy during World War II, Dr. Wilson had a continuing concern about problems of epidemiology and military medicine, and served as a member of the Commission on Streptococcal and Staphylococcal Diseases of the Armed Forces Epidemiological Board from January, 1949, until his death. He was director of this Commission from May, 1957, to May, 1959, and was instrumental in broadening its objectives to include staphylococcal diseases.


379

From the time of his discharge from active duty with the Navy, Dr. Wilson's microbiology laboratory at the Alfred I. DuPont Institute of the Nemours Foundation in Wilmington, Delaware, was an unsurpassed mecca for those-whose interests touched his own. Armine Taylor Wilson was a man of quiet wisdom and sound judgment, who in his unhurried and controlled approach to life found time to discuss problems at length and in depth. His unique contributions and his personal dedication to medicine and scientific investigation will enrich the field of pediatrics for many years to come.

*Reprinted with permission from Wannamaker, L. W., and Denny, F. W. An effective career off the mainstream. J. Pediatr. 1966, 69, 851-852.

ARMINE T. WILSON, M.D.


380

Lewis W. Wannamaker
Director, 1968 to 1973

Dr. Wannamaker, one of the most outstanding products of the Strep Lab, had a long association with the CSSD. He was a member of the CSSD from 1954 to 1973, its Deputy Director from 1963 to 1968, and its Director from 1968 to 1973. Lewis died on 24 March 1983 at the age of 59 years. Shortly before his death, he participated in a Ross Conference, entitled the "Management of Pharyngitis in a Era of Declining Rheumatic Fever." This conference was dedicated to his memory.

The memorial to Lewis by Dr. Denny accompanying the conference proceedings is reprinted be-low, with permission of Ross Laboratories.

I first met Lewis Wannamaker in 1948 in Cleveland, Ohio, where we had been assigned by the Army to study streptococcal infections and rheumatic fever under the direction of John Dingle and Charles Rammelkamp in what was then the Department of Preventive Medicine at Western Reserve University School of Medicine. We remained close friends thereafter until his untimely death on March 24, 1983. It is a privilege for me to write this memorial about this man whom I admired and respected very much.

Under the direction of and in collaboration with Rammelkamp, Lewis began to develop as a scientist. After a period of indoctrination in Cleveland, he joined "Rammel" and others in establishing the Streptococcal Disease Laboratory at Warren Air Force Base, Wyoming. There he developed expertise in and love for clinical and epidemiologic research, an affection that permeated his future investigations. He was instrumental in the many accomplishments of the Strep Lab, including the elucidation of many aspects of the epidemiology of group A streptococcal pharyngitis and the demonstration that the treatment of streptococcal pharyngitis with penicillin and other effective antimicrobial agents prevents rheumatic fever - a feat that earned the Lasker Award in 1954. I suspect it was also at the Strep Lab working with Rammelkamp that Lew developed some of the drive that helped him accomplish difficult tasks in his future career.

In 1952, Lewis joined the faculty of the University of Minnesota, where he subsequently became Professor of Pediatrics and Microbiology and Chief of the Division of Pediatric Infectious Diseases. Between 1955 and 1957 he worked with Maclyn McCarty at what was then the Rockefeller Institute for Medical Research. Laboratory skills were added to his clinical and epidemiologic armamentarium, and the stage was set for a brilliant career. This was recognized by the American Heart Association in 1958 when he was appointed a Career Investigator, a position he held until his death.

Lewis received many awards and honors, including the John Simon Guggenheim Memorial Fellowship, Helen Hay Whitney Fellowship, Outstanding Civilian Service Medal from the Army, Alexander Von Humbolt Award, Duke University Distinguished Alumnus Award, and the Josiah Macy, Jr., Foundation Faculty Scholar Award. In 1980 he received the Robert Koch prize and medal and in 1982 was elected to the Institute of Medicine, National Academy of Sciences. He was a member of many distinguished scientific societies and served on the editorial boards of several medical journals. He was a consultant to The Surgeons General of the Public Health Service and the Army. His special interest in streptococcal infections in the military was evidenced by his longtime membership on the Commission on Streptococcal and Staphylococcal Diseases of the Armed Forces Epidemiological Board; he served as director of this group for many years. Lewis was especially devoted to the American Heart Association and served as the Chairman of its Committee on Prevention of Rheumatic Fever and Bacterial Endocarditis; in 1972, he delivered the T. Duckett Jones Memorial Lecture at the annual meeting of the Association.

Lewis' laboratory at the University of Minnesota Medical School was a mecca for all who had an interest in streptococci and the diseases they cause and an international resource for characterizing streptococci. Lewis was one of the world's authorities on the biology of group A streptococci and the clinical and epidemiologic aspects of streptococcal infections. Examples of his work include the identification of several nucleases of group A streptococci and discovery of a consistent antibody response to one of these nucleases in patients with streptococcal infections; this test has become a standard laboratory method for diagnosis of streptococcal infections. He and his colleagues published classic epidemiologic studies that showed biologic differences in host response when group A streptococci infect the skin or the pharynx. Lewis' laboratory


381

LEWIS W. WANNAMAKER, M.D.


382

contributions also include new knowledge about the genetic behavior of streptococci and the role of surface factors and extracellular products in disease.

Lewis was mentor for scores of trainees now in positions of scientific leadership throughout the world. He taught by example and a quiet, determined insistence on the best efforts in research and in writing. His judgment was sought constantly by students and colleagues at Minnesota, and his door was always open. Investigators from England, Germany, Egypt, Poland, New Zealand, India, Scandinavia, and the Orient spent time in his laboratory and were in frequent communication, since Lew shared his knowledge, counsel, and judgment with scientists throughout the world.

As much as Lewis accomplished as an investigator and as a clinician, he may have been appreciated most for his qualities as a human being. He was soft spoken, kind, deliberate in his actions, and slow to anger, but in matters of principle he could be extremely obstinate. He also possessed a rich sense of humor. Some of these qualities were brought home to me by two incidents following his death. I called a mutual friend to tell him that Lew had died and his response included, among other things, "He was some kinda guy." Another mutual friend told me that, in spite of Lew's national and international prominence and influence, he had never heard one derogatory word about Lewis Wannamakera remarkable accomplishment indeed. I have never known a finer man.

Lewis is survived by his wife, Hallie; four children: Julie, Ann, Libby, and Whit; his mother; and two brothers. His family was his first priority, and Hallie was a true partner in all of his activities. Those of us who knew Lew well realized his great dependence on Hallie in everything he did; she certainly deserves much credit for his many accomplishments.

Lew participated in this Ross Conference only a month before his death and he contributed greatly to its success. We all turned repeatedly to him for counsel and guidance, which he gave in his quiet and unassuming manner. It is so very appropriate that this publication is dedicated to Lewis Wannamaker. My life was enriched immensely by my friendship with him. I join all of his many friends in paying tribute to this gentle and remarkable man.