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Chapter XII

Contents

CHAPTER XII

Diagnosis and Treatment of the Venereal Diseases

Paul Padget, M.D.

HISTORICAL NOTE

The history of the treatment of the venereal diseases in World War II may well begin on 7 June 1940.1 The development and application of the methods of treatment used in the U.S. Army prior to this time have been admirably traced and summarized by Siler,2 and need not be recapitulated. 

On 7 June 1940, a meeting of the National Research Council was held in Washington, D.C., to form a subcommittee3 on venereal disease control. The Subcommittee on Venereal Diseases by its terms of reference was charged with making general recommendations to The Surgeons General of the Army and the Navy concerning the prevention and treatment of the venereal diseases and with acting in a consultative capacity on questions in its special field that might originate from the armed services.

Following this, meetings were held at frequent intervals (six between 7 June and 19 July 1940), and on the latter date, detailed recommendations were approved concerning the diagnosis and treatment of each of the commonly recognized venereal diseases. These recommendations were submitted to the parent committee and eventually were transmitted to the respective surgeons general as the official recommendations of the National Research Council. They were subsequently incorporated in Circular Letter No. 18, Office of the Surgeon General, 10 March 1941, which became the first official statement of a policy for the treatment of these infections to come from the Office of the Surgeon General during the period of the emergency which culminated in World War II. Much later, Circular Letter No. 195, Office of the Surgeon General, 1 December 1943, ordered that the treatment of all patients

1The author is indebted to Dr. Thomas H. Sternberg and Dr. Ernest B. Howard for material on care and treatment which has been incorporated in this chapter. Acknowledgment is also made of the invaluable assistance gained from the use of the private files of Dr. Joseph Earle Moore, formerly Chairman, Subcommittee on Venereal Diseases, National Research Council.
The final editing of this chapter was completed after the death of Dr. Padget.
2Siler, J. F.: The Prevention and Control of Venereal Diseases in the Army of the United States of America. Army M. Bull. No. 67, May 1943.
3The subcommittee was composed of Dr. Joseph E. Moore, chairman, and Drs. Edwin P. Alyea, Walter Clarke, Oscar F. Cox, John F. Mahoney, and John H. Stokes, members. With the exception of Dr. Alyea, who withdrew after the 14th meeting on 11 March 1942, the members served throughout the wartime period. Dr. Perrin H. Long (later Colonel, MC, USAR) served from time to time ex officio in his capacity as chairman of the Committee on Chemotherapeutics and Other Agents, National Research Council, and as problems dealt with grew in complexity, other specialists were invited to join the subcommittee either temporarily or as permanent members.


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hospitalized for venereal disease be on the medical service or under the direction of the chief of the medical service unless there were cogent local reasons to the contrary. Distinction was thus made early between the prevention and control of venereal diseases and treatment of the infected soldier. In the field, it was sometimes the practice to separate these functions entirely and, as in the European Theater of Operations, U.S. Army, to have control and preventive measures administered by the Preventive Medicine Division, Office of the Chief Surgeon, while treatment was supervised by the appropriate consultant of the Professional Services Division, Office of the Chief Surgeon. In the Office of the Surgeon General, both preventive and therapeutic measures were eventually supervised from one office under the Preventive Medicine Service, with free exchange of consultation with the Professional Service and without losing sight of the fact that the individuals in charge of these activities were dealing with separate problems.

It is in keeping with this medical philosophy that a section on the treatment of the venereal diseases appears here. It should be noted that although, to a large extent, the venereal diseases may be grouped for preventive measures and although the two most important (gonorrhea and syphilis) at the end of the war responded to the same antibiotic (penicillin), nevertheless the several venereal diseases are wholly separate and distinct clinical entities. For purposes of diagnosis and treatment, they will be considered individually.

GONORRHEA

At the beginning of World War II, there was probably no prevalent disease comparable to gonorrhea in the wide disparity between the therapeutic recommendations of the experts and the care usually accorded the average patient. Fortunately, the new methods of treatment were so simple that by the end of the war the management of gonorrhea in the Army followed in large measure the directives prepared by the experts and issued by The Surgeon General.

Prior to the publication of Circular Letter No. 18, there was little or no uniformity of practice in the diagnosis and treatment of gonorrhea by medical officers. The older officers of the Regular Army Medical Corps, who had been trained in the disciplines described by Siler, had in general advanced to supervisory or administrative positions; the medical officers who were actually treating the patients were young physicians from civilian practice. Each of these groups had had different training and experience; most of them had little or no special knowledge of the management of patients with gonorrhea and few knew little more about the opinions of the experts than a dim awareness that the relatively new sulfonamide drugs were useful in treatment.

Circular Letter No. 18 brought a semblance of order out of the chaos which these conditions had fostered. The Army was rapidly expanding, but with unimportant exceptions, the troops were stationed in training camps within the continental United States. These camps were adequately supplied


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with cantonment-type hospitals, in which it was usual practice to have venereal disease wards to which an adequate number of medical officers were permanently assigned. All patients with gonorrhea were hospitalized, so that they came under the care of a relatively small group of medical officers. Accordingly, the information contained in Circular Letter No. 18 had to be disseminated to only a relatively small number of medical officers, many of whom had had no previous training in the management of gonorrhea, but all of whom, actually or from necessity, had a special interest in the problem. This point is important because the contrasting situation will be brought out later in the discussion of the treatment of gonorrhea on a duty status.

It was the consensus of observers during 1941 and 1942 that in general a determined and satisfactory effort was made to carry out the provisions of Circular Letter No. 18. The observed deviations were most frequently carelessness in diagnostic technique, for example, preparation and examination of smears by a relatively untrained technician using only methylene blue for staining; a tendency to prescribe larger total doses of the sulfonamides than recommended, either by giving greater individual doses or, more commonly, by a longer course of treatment; and the early and often vigorous use of local methods of treatment, especially urethral irrigation, prostatic massage, and the passage of sounds.

The provisions of Circular Letter No. 18 with regard to the diagnosis and treatment of gonorrhea are of more than passing interest. Under the heading entitled "Diagnosis in the Male," the circular says "a diagnosis of gonorrhea must not be made in the absence of laboratory confirmation * * *," although it does provide for emergency treatment without diagnosis in case laboratory facilities are not readily available. The section on the diagnosis in the female is much less definitely phrased and contains the clear implication that the history of exposure to a known case of gonorrhea may be utilized as presumptively supporting the diagnosis.

The regimen recommended for the treatment of acute gonorrhea consisted of 19 gm. of sulfathiazole to be given in 10 days (3 gm. the first day, 2 gm. daily thereafter) in cases which responded well; if the clinical response to sulfathiazole was not satisfactory by the fifth day, sulfapyridine, (3 gm. the first day, 2 gm. daily thereafter) was substituted. If this exchange proved beneficial by the 10th day, this drug was continued until a total of 15 days of chemotherapy (5 days of sulfathiazole, 10 days of sulfapyridine) had been given. If the clinical response to this regimen was not good, the patient was to be transferred (presumably to a general hospital) for special care.

The test of cure advised for the male was based upon the examination of gram-stained smears of material expressed by prostatic massage done weekly for 8 weeks. The use of culture was mentioned, but not emphasized. The test of cure advised for the female was based on smear from the urethra, cervix, and Skene's and Bartholin's glands every 2 weeks for 3 months, with cultures from the same areas monthly on the last day of the menstrual period.


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The recommended followup for both sexes included one serologic test for syphilis done 3 to 4 months after the original infection with gonorrhea. 

With the deviations noted, these procedures were followed for over a year, but in the winter of 1941-42, Dr. P. S. Pelouze, directly representing The Surgeon General, made personal visits to a number of the larger Army camps, and his report occasioned The Surgeon General to write to the chairman of the National Research Council, in part, as follows: "Dr. P. S. Pelouze has just presented to us some evidence that the recommendations of the Council on the treatment of gonorrhea may need revision in the light of recent advances in this field * * *."4

Accordingly, a revision of Circular Letter No. 18 was considered and approved by the Subcommittee on Venereal Diseases in March 1942, and this eventually appeared in Circular Letter No. 74, Office of the Surgeon General, 25 July 1942. The important changes included alteration of the criteria for diagnosis of gonorrhea in the female to bring them into line with those previously defined for the male; the recommendation of sulfathiazole or sulfadiazine as the drug of choice to be administered in a dose of 4 gm. daily for 5 days, this course to be repeated no more than once; the direction that if sulfapyridine must be used it be given in a dose of only 3 gm. daily for 5 days; a relaxation of the test of cure; a marked reduction in the period of followup (3 weeks advised, but not insisted upon); and finally the recommendation "* * * that carefully selected patients with sulfonamide-resistant infections be given ten hours of sustained fever therapy * * *" without, however, directions or suggestions as to how the selection should be made. This deficiency was partially rectified by Circular Letter No. 86, Office of the Surgeon General, 18 August 1942, which designated eight named general hospitals as fever therapy centers and implied that the final decision as to whether the patient should be treated with fever should be left to the staff of the hospital to which he was referred for this treatment.

These eight hospitals soon proved to be insufficient to care for the mounting load of patients with sulfonamide-resistant gonorrhea. The average rate of cure with the sulfonamides was falling below 75 percent, owing to the development of sulfonamide-resistant strains of the gonococcus and to the substantial number of chronic cases that probably represented relapse after inadequate self-administered treatment. Every station and general hospital had a mounting backlog of patients with chronic gonorrhea for whom the only prospect of cure and return to duty at that time lay in treatment with fever. Accordingly, at the request of The Surgeon General, a conference was held on 6 April 1943, under the auspices of the Subcommittee on Venereal Diseases on the use of combined fever and chemotherapy in the treatment of sulfonamide-resistant gonorrhea. The aim of the conference was to prepare a draft of a circular letter to be sent out by the Surgeon General's Office to

4Minutes, Fourteenth Meeting, Subcommittee on the Venereal Diseases, National Research Council, 11 Mar. 1942.


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appropriate military hospitals. The draft was approved by the Subcommittee on Venereal Diseases on 7 April 1943, forwarded to The Surgeon General, and published as Circular Letter No. 97, Office of the Surgeon General, 12 May 1943. This broadened the base of the number and type of hospitals authorized to administer fever therapy to patients with sulfonamide-resistant gonorrhea and at the same time protected the patient by defining with great care the criteria for the selection of patients and details for management of therapy. It had been found that one session of 8 hours at approximately 106 F. (rectally) would accomplish cure in about 90 percent of patients with sulfonamide-resistant gonorrhea, that half of the failures would achieve a satisfactory result from a second similar treatment, but that fever in excess of two such bouts apparently was valueless. No patient, therefore, was to be subjected to more than two 8-hour sessions of induced fever, even though manifestations of the disease persisted.

Not long afterward, Circular Letter No. 129, Office of the Surgeon General, 22 July 1943, amended Circular Letter No. 74 in two important particulars. It pointed out that prostatic massage should not be done as a test of cure of acute gonorrhea and, thereby, served to prevent a substantial number of relapses and complications occasioned by this procedure. It advised that for patients with gonorrhea treated in hospital the dose of sulfathiazole or sulfadiazine should be increased to a total of 33 gm., given as an initial dose of 4 gm. followed by 1 gm. every 4 hours night and day of 5 days. This, it was hoped, would somewhat reduce the number of sulfonamide failures.

Treatment on duty status-Prior to the advent of chemotherapy, it had been the custom in the Army to hospitalize soldiers for the treatment of gonorrhea,5 in spite of the fact that the vast majority of civilian patients with gonorrhea were treated on an ambulatory basis. The reasons given for this are well known: The Army in peacetime felt it impracticable to assign a light-duty status, the philosophy being that the soldier either was able for full duty or belonged in the hospital. During World War I, however, working quarantine was extensively employed for the treatment of selected cases of gonorrhea (especially the chronic and recalcitrant), and this procedure was later authorized by paragraph 7, AR (Army Regulations) 40-235, 11 October 1939. Quoting this regulation as authority, Circular Letter No. 18, 10 March 1941, said in part: "Even under ambulatory conditions, acute gonorrhea may be cured by appropriate measures in a large proportion of cases. Therefore, when considered desirable and local conditions permit, acute gonorrhea may be treated on an ambulatory basis in working quarantine." However, very little use was made of working quarantine or ambulatory treatment. Accordingly, Circular Letter No. 74, 25 July 1942, dealt realistically with the matter, as follows: "In the Zone of Interior and in the communications zone, venereal disease cases will ordinarily be hospitalized for treatment during the infectious stages. In order to maintain effective strength of organ-

5See footnote 2, p. 409.


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izations during combat, consideration may be given to the treatment of venereal disease cases on a duty status with their organization in the combat zone."

In the meantime, however, dissatisfied both with the large number of hospital beds occupied by patients with gonorrhea, and with the loss of time from training, certain posts in the Fourth Service Command (Camp Forrest, Tenn., was apparently the first) had undertaken the treatment of gonorrhea with the sulfonamide compounds on a duty status. The method seemed to work and, if it could be shown to be therapeutically efficient, might be used more widely. Accordingly, in November 1942, a board6 was appointed to evaluate the experiences which had so far been gained.7 The board members proceeded from the Office of the Surgeon General to posts within the Fourth Service Command where gonorrhea was being treated on a duty status. Their report recommended (1) that the policy of treating uncomplicated gonorrhea on a duty status be approved and that the adoption of such a policy wherever feasible be encouraged and (2) that because this method may not be equally practicable under all conditions its adoption not be made mandatory.

The recommendations made by this board were officially authorized in January 1943,8 and on 1 February 1943, Circular Letter No. 32, Office of the Surgeon General, gave in detail directions for the management of patients with acute gonorrhea while ambulatory.

Following this, the duty-status treatment of acute gonorrhea was undertaken on a large scale, both in the continental United States and in the oversea theaters, but the sulfonamides were so quickly thereafter replaced by penicillin that there was no opportunity to gain a large-scale evaluation of the usefulness of the method. Even a complete study, however, would have been difficult to evaluate unless the ambulatory method were a marked improvement over treatment in hospital. This is because of the declining percentage of cures already being observed among hospitalized patients and the great variation in the interest, training, and experience of the large number of unit medical officers who suddenly became responsible for the diagnosis and treatment of gonorrhea and for the evaluation of results.

Penicillin-The verbal report, early in 1943 (subsequently published in September 1943), by Mahoney and his collaborators,9 on the use of penicillin in the treatment of sulfonamide-resistant gonorrhea, rapidly removed the

6The board was composed of Brig. Gen. Henry C. Coburn, Jr.; Col. (later Brig. Gen.) Hugh J. Morgan, MC; Lt. Col. (later Col.) Thomas B. Turner, MC; Col. Alvin L. Gorby, MC; and Maj. (later Lt. Col.) Robert Dyar, MC.
7(1) Letter, Col. John A. Rogers, MC, Executive Officer, Office of the Surgeon General, to Commanding General, Headquarters, Services of Supply, 19 Nov. 1942, subject: Appointment of Board of Investigation of the Treatment of Venereal Disease on a Duty Status. (2) Letter, J. F. McGuire, The Adjutant General's Office, to The Surgeon General, 30 Nov. 1942, subject: Board of Officers.
8War Department Memorandum W40-2-43, Treatment of Individuals With Uncomplicated Gonorrhea on Duty Status, 19 Jan. 1943.
9Mahoney, J. F., Ferguson, C., Buchholtz. M., and Van Slyke, C. J.: The Use of Penicillin Sodium in the Treatment of Sulfonamide-Resistant Gonorrhea in Man. Am. J. Syph., Gonor. & Ven. Dis. 27: 525-528, September 1943.


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practical importance of determining the best way of treating with sulfonamide. It appeared that penicillin in almost any dosage effected cure in a high percentage of cases and in almost miraculous fashion. This was confirmed by Herrell and his coworkers.10

This promise of a solution for all increasingly harrassing problem of the soldier led, in May 1943, to a clinical investigation in 15 Army hospitals of the use of penicillin in the treatment of this condition. Within a relatively short time, results of the treatment with penicillin of 1,686 patients with sulfonamide-resistant gonorrhea were available. The details of this study were later published by Sternberg and Turner.11 All of the 1,686 patients were men; their ages reflected the usual distribution in the Army at the time; they had had on the average 58 gm. of a sulfonamide ending at least 5 days before penicillin was administered, and 236 had also had treatment with fever. The patients were divided into groups, each group treated with a different dose of penicillin. With a dose of 160,000 units or more, 98 percent of the patients achieved cure; as the dose was reduced below 100,000 units, the cure rate fell off rapidly. There were in all (regardless of dosage) 126 failures. Of these, 85 were re-treated, all with 100,000 units and 91.8 percent of them were cured. This raised the overall cure rate for two courses of treatment to 99 percent.

These dramatic results induced The Surgeon General, on 23 September 1943, to address a letter to the service command surgeons authorizing the use of penicillin in the treatment of sulfonamide-resistant gonorrhea. The dosage authorized was 50,000 units in doses of 10,000 units at 3-hour intervals, with permission to re-treat with 100,000 units administered in 10,000-unit doses hourly in case of failure of the first course. It must be recalled that penicillin was in excessively short supply at the time, a fact that seriously influenced the size of the dose recommended. As the supply improved, this was increased to 100,000 units given in 20,000-unit doses by TB MED (War Department Technical Bulletin) 9, 12 February 1944. About a month later, 6 March 1944, TB MED 16 authorized the use of penicillin for the treatment of sulfonamide-resistant gonorrhea in station hospitals and directed that it should be administered to patients with gonorrhea immediately after failure to respond to one course of a sulfonamide.

As the supply of penicillin increased, its use was extended. On 21 September 1944, TB MED 96 provided for complete replacement of sulfonamides by penicillin in the treatment of gonorrhea, except for those individuals who failed to respond to penicillin. This bulletin said further that the treatment of uncomplicated gonorrhea with penicillin might be carried out as a hospital or dispensary procedure, but recommended that where satisfactory medical facilities were available hospitalization be avoided. The recommended dose

10Herrell, W. E., Cook, E. N., and Thompson, L.: Use of Penicillin in Sulfonamide Resistant Gonorrheal Infections. J.A.M.A. 122: 289-292. 29 May 1943.
11Sternberg, T. H., and Turner, T. B.: The Treatment of Sulfonamide Resistant Gonorrhea With Penicillin Sodium: Results of 1,686 Cases. J.A.M.A. 126: 157-161, 16 Sept. 1944.


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was 100,000 units, given in 20,000-unit injections intramuscularly every 3 hours for those in hospital, or five injections spaced over an 8-hour period for outpatients. In the event of failure, re-treatment with the same dose was suggested, and if the failure persisted, a third course of treatment with 300,000 units given in 20,000-unit injections at 3-hour intervals was advised. In the event of failure of these three courses of penicillin, the treatment of choice would be sulfathiazole in the 33-gm. dose recommended by Circular Letter No. 129. Finally, TB MED 196, 20 August 1945, redefined the criteria for diagnosis and cure and increased the initial dose of penicillin to 200,000 units administered in four injections of 50,000 units every 2 to 3 hours, depending on whether the patient was hospitalized or being treated on duty status. Patients failing of cure after the first course were to be re-treated similarly with 200,000 units. Those patients who did not respond to these two courses were to be hospitalized for more complete urological and bacteriological investigation and, if gonococcul infection were proved, to be given at least 500,000 units of penicillin in 50,000-unit doses every 2 or 3 hours.

It was at first feared that, with the widespread use of penicillin in the treatment of gonorrhea, the gonococcus might develop penicillin resistance analogous to the sulfonamide resistance already encountered. None of the Army material, however, has proved any evidence to that effect, either clinically or in vitro, although the production of penicillin resistance in vitro has been reported by Dr. Joseph E. Moore.12 As further experience was gained, it became clear that 10 to 15 percent of patients with gonorrhea failed to respond to 100,000 units of penicillin but that most, if not all, would respond to repeated courses or increased doses. Toward the close of World War II, several cases were reported in which penicillin resistance was suspected clinically, but it was not determined whether these failures of treatment were due to true penicillin-resistant strains, to insufficient, deteriorated, or substandard penicillin, or to failure to detect the true etiological agent, thereby confusing gonorrhea with nonspecific urethritis.

And so the end of the war saw a therapeutic triumph. Penicillin in adequate dosage had solved the problem of sulfonamide-resistant gonorrhea, had provided a substitute for dangerous, troublesome, and unpleasant fever therapy, had relieved general hospitals of rapidly increasing numbers of patients with gonorrhea, and had made of the disease a relatively minor infection, with few complications and with a small noneffective rate. In 1937, complications developed in about one-fourth of all cases of gonorrhea in the U.S. Army; in 1944, complications occurred in approximately 1 percent of all cases.13

Penicillin in oil-beeswax-One remaining difficulty was the fact that the only effective method for the administration of penicillin then known was by

12Moore, Joseph Earle: Penicillin in Syphilis. Springfield, Ill.: Charles C. Thomas, 1946.
13Monthly Progress Report, Army Service Forces, War Department, 28 Feb. 1945, Section 7: Health.


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injection, preferably intramuscular; yet in the usual aqueous or saline solution, penicillin was so rapidly absorbed and excreted that in order to maintain therapeutically effective blood levels14 it had to be given no less frequently than every 3 hours.15 A number of investigators had approached this subject-one group attempting to delay excretion by blocking the kidney;16 others, to delay absorption by local vasoconstriction17 or by local application of ice packs.18 None of these methods was particularly successful. The first satisfactory method for delaying the absorption of penicillin with relative uniformity was devised by Romansky and Rittman at the Walter Reed General Hospital, Army Medical Center, Washington, D.C. These investigators found the injection of a suspension of 300,000 units of penicillin, preferably the calcium salt, in 1 cc. of a vehicle consisting of peanut oil containing 4.8 percent by weight of beeswax, was followed by assayable blood levels of penicillin from 24 to 36 hours after injection19 and produced excellent therapeutic results in patients with acute gonorrhea.20

The Surgeon General then initiated an investigation of the subject to be carried out, both clinically and in the laboratory, at the Regional Hospital, Fort Bragg, N.C. Partial confirmation of the results of the original investigators was achieved. Over 90 percent of 88 patients with acute gonorrheal urethritis were cured with a single intramuscular injection of 300,000 units of calcium penicillin suspended in the oil-beeswax vehicle.21 The substance was not entirely without its objectionable features, however. Uniform blood levels were not always obtained, and after appropriate investigation these later investigators concluded that the blood levels produced depended on both

14In October 1948, the previously accepted concept that assayable levels of penicillin concentration in the blood must be maintained in order to gain maximum therapeutic effect was being sharply questioned. At the time of the development of POB (penicillin in oil-beeswax), however, there was general acceptance of the concept that maintenance of a relatively uniform concentration of penicillin in the blood was necessary for maximum therapeutic effect.
15Rammelkamp, C. H., and Bradley, S. E.: Excretion of Penicillin in Man. Proc. Soc. Exper. Biol. & Med. 53: 30-32, May 1943.
16
Beyer, K. H., Woodward, R., Peters, L., Verwey, W. F., and Mittis, P. A.: Prolongation of Penicillin Retention in Body by Means of Para-Aminohippuric Acid. Science 100: 107-108, 4 Aug. 1944.
17Parkins, W. M., Wiley, M., Chandy, J., and Zintel, H. A.: Maintenance of the Blood Level of Penicillin After Intramuscular Injection. Science 101: 203-205, 23 Feb. 1945.
18Trumper, M., and Hutter, A. M.: Prolonging Effective Penicillin Action. Science 100: 432-434, 10 Nov. 1944.
19Romansky, M. J., and Rittman, G. E.: Method of Prolonging Action of Penicillin. Science 100: 196-198, 1 Sept. 1944.
20(1) Romansky, M.J., and Rittman, G. E.: Penicillin: Prolonged Action in Beeswax-Peanut Oil Mixture; Single Injection Treatment of Gonorrhea. Bull. U.S. Army M. Dept. No. 81: 43-49, October 1944. (2) Romansky, M. J., Murphy, R. J., and Rittman, G. E.: Single Injection Treatment of Gonorrhea With Penicillin in Beeswax-Peanut Oil; Results in 175 Cases. J.A.M.A. 128: 404-407, 9 June 1945.
21(1) Kirby, W. M. M., Leifer, W., Martin, S. P., Rammelkamp, C. H., and Kinsman, J. M.: Intramuscular and Subcutaneous Administration of Penicillin in Beeswax-Peanut Oil. J.A.M.A. 129: 940-944, 1 Dec. 1945. (2) Leifer, W., Martin, S. P., and Kirby, W. M. M.: The Treatment of Gonococcal Urethritis With Single Injections of Penicillin-Beeswax-Peanut Oil Mixtures. New England J. Med. 233: 583-586, 15 Nov. 1945. (3) Kirby, W. M. M., Martin, S. P., Leifer, W., and Kinsman, J. M.: Maintenance of Therapeutic Blood Concentrations of Penicillin for Twenty-four Hours Following Single Injections of Penicillin-Beeswax-Peanut Oil Mixtures. J. Lab. & Clin. Med. 31: 313-316, March 1946.


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the concentration of penicillin in the vehicle and the total amount administered. They also found the mixture so viscid as to require incubation at 37 C. to go through a 17-gage needle and so immiscible with water that the slightest amount of moisture in the syringe would produce a completely unmanageable gummy, sticky mass. As the war ended, it seemed that the preparation represented a large step forward but that several improvements, even perhaps an entire alteration of its composition, would be necessary before it would be suitable for widespread adoption.

NONSPECIFIC URETHRITIS

Although not officially classified as one of the venereal diseases, nonspecific urethritis22 bears consideration here because of its close association with gonococcal urethritis, both because of its etiology and because of the diagnostic confusion which it so often produced. The condition was common, amounting in various experiences from 10 to 40 percent of all cases of urethritis, but unfortunately it was never subjected to careful study. The diagnosis was made entirely by the exclusion of gonorrhea, and treatment usually began with the method that currently was being employed in the management of gonorrhea. This was commonly unsuccessful, in which case the patient was referred to the urologist and subsequently treated by various manipulative procedures at the physician's direction. These were also frequently unsuccessful, and eventually the process was allowed to run its natural course, which tended to be one of great chronicity. There probably was no disease of comparable numerical importance during World War II that was so completely neglected both as to definition of etiology and as to development of satisfactory methods of treatment.

SYPHILIS

Before and during the early stages of mobilization, that is, prior to the publication of Circular Letter No. 18, 10 March 1941, the diagnosis and treatment of early syphilis in the Army essentially followed the recommendations of the Cooperative Clinical Studies Group23 as elaborated in the standard textbooks.24 Neoarsphenamine was the arsenical drug most commonly employed; many bismuth compounds were used, although a suspension of the subsalicylate in oil was perhaps the most frequently employed; and rest periods by either design or accident tended to be more common than the experts would advise. On the whole, however, standards of practice compared favor-

22There is no useful source material on nonspecific urethritis in the official records. The material on which this section is based was assembled by Col. Paul Padget, MC, from conversations with many medical officers from 1942 to 1945 and recorded in his personal diary.
23Cooperative Clinical Studies in the Treatment of Syphilis; Early Syphilis. Ven. Dis. Inform. 13: 207-231, 20 June 1932; 253-293, 20 July 1932.
24(1) Moore, Joseph Earle: The Modern Treatment of Syphilis. Springfield, Ill.: Charles C. Thomas, 1933. (2) Stokes, John H.: Modern Clinical Syphilology. 2d edition. Philadelphia: W. B. Saunders Co., 1934.


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ably with those of the average health department clinic at the time. As in health department clinics, however, there was much less uniformity of practice in the management of the various forms of late syphilis, and from a review of old records, one has the impression that many medical officers treating patients with late syphilis were actually treating the positive blood test rather than the patient. For this, of course, the medical officers concerned should not be blamed since it was then, and unfortunately still is, likewise common in civilian practice.

In supplying the material upon which Circular Letter No. 18 was based (p. 409), the Subcommittee on Venereal Diseases made no recommendations concerning the management of syphilis which were peculiar to the Army. Instead, this material represented simply a summary of accepted good practices in the diagnosis and treatment of syphilis which were then current in best civilian practice. In this circular letter, accuracy of diagnosis was emphasized; necessity for clocklike regularity of treatment was reiterated; Mapharsen (oxophenarsine hydrochloride), at that time the only commercially available arsenoxide, was recommended as the arsenical drug of choice; and treatment at weekly intervals was to be continued for 15 to 18 months.

The 18-month system of treatment was impracticable even under the relatively static conditions of training. In view of the extent to which all practical administrative difficulties would be magnified in an oversea theater, particularly after combat was joined, the need for a shorter method for the treatment of syphilis became obvious. Accordingly, representatives from the Office of the Surgeon General had informal meetings with members of the Subcommittee on Venereal Diseases, and at a formal meeting on 27 May 1942, the subcommittee approved recommendations made by this subgroup. These were published in Circular Letter No. 74, 25 July 1942.

The principles of accurate diagnosis and the criteria for cure were not significantly changed from the form in which they appeared in Circular Letter No. 18, but the treatment scheme was compressed into 40 doses of Mapharsen and 16 doses of bismuth given over a 6-month period. By this system, Mapharsen was given in two courses of 20 injections, each twice weekly for 10 weeks separated by 6 weeks of therapy with bismuth, the additional bismuth being given in two groups of five weekly doses concurrently with the beginning of the first and the end of the second courses of Mapharsen.

According to Sternberg and Leifer,25 this treatment system was used in the management of approximately 200,000 soldiers with syphilis, with a mortality rate ascribable to treatment of about 0.003 percent. In a study of the short-term results in 3,000 soldiers with early syphilis, 72 percent of whom had been observed for more than 1 year after the completion of the 26-week treatment, they say "* * * the results appear excellent with satisfactory progress in 98.25 percent of seronegative primary, 94.48 percent of seroposi-

25Sternberg, T. H., and Leifer, W.: Treatment of Early Syphilis by Twenty-six-Week Mapharsen-Bismuth Schedule. Am. J. Syph., Gonor. & Ven. Dis. 31: 124-134, March 1947.


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tive primary, and 89.34 percent of secondary cases. There were but 18 (0.64 percent) abnormal cerebrospinal fluids among the 2,842 examined." 

Intensive arsenotherapy.-As the war progressed, this treatment scheme, later shown to be therapeutically effective by Sternberg and Leifer, became increasingly impractical. Six months under the pressure of war was, comparatively speaking, longer and more intolerable than 18 months in peacetime; biweekly injections for 20 of the 26 weeks interfered even with military training. Maintenance of uninterrupted medical control for the time necessary to complete treatment became increasingly difficult. Only 38 percent of the troops with syphilis registers who came to the European theater during March 1943 had had as much as two-thirds of the optimal amount of treatment up to the time of their embarkation.26 None had been treated in transit, which often had imposed an additional lapse of many weeks. Consequently, there was widespread pressure to persuade the Army to adopt one or another of the rapid treatment systems which were in use or could be made available. The 5-day intravenous drip method27 was particularly strongly urged because this scheme, unlike other proposed methods, had had considerable clinical use just prior to this time. The Subcommittee on Venereal Diseases reviewed the subject in detail on 13 January 1942 and 10 June 1943, and it was taken under advisement by the Committee on Medicine, National Research Council, 16 October 1942. This committee concluded:

That the intensive arsenotherapy of early syphilis (including the five-day intravenous drip method) be considered as still in the experimental stage; that the optimum time-dose relationship still requires to be established by further animal and subsequent clinical experimentation; and that at present the method cannot be recommended for routine use by the Armed Forces.

The need for a rapid treatment method was so great, however, especially in oversea theaters (fig. 56), that at its 19th meeting, 10 June 1943, the Subcommittee on Venereal Diseases bowed to the continuing pressure of the advocates of the 5-day intravenous drip technique and passed a series of recommendations which had been made at a conference on intensive arsenotherapy of early syphilis held on 19 May 1943. These recommendations read in part, as follows:

1. Owing to the relatively high mortality rate, no system of intensive arsenotherapy compressed into a period of 2 weeks or less is as yet suitable for routine adoption by the Armed Forces.

2. For the routine treatment of early syphilis in the Armed Forces the 26-week system now in use in the U.S. Army should be continued pending further information concerning intensive treatment systems.

3. It is hoped that the U.S. Public Health Service will amplify a statistical evaluation of the several methods of intensive arsenotherapy of early syphilis * * *.

26Annual Report, Senior Consultant in Dermatology, Office of the Chief Surgeon, European Theater of Operations, U.S. Army, 1943.
27Leifer, W., Chargin, L., and Hyman, H. T.: Massive Dose Arsenotherapy of Early Syphilis By Intravenous Drip Method; Recapitulation of Data (1933 to 1941). J.A.M.A. 117: 1154-1160, 4 Oct. 1941.


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FIGURE 56.-Poisoning by Mapharsen in treatment of syphilis. Fixed arsenical eruption on left side of face, neck, chest, and thigh of 6 months' duration. Patient was treated at the 20th General Hospital, China-Burma-India theater, June 1943.

4. In oversea areas, whether advanced training or combat zones, two alternative methods of intensive arsenotherapy of early syphilis, treatment compressed within a period of 2 weeks or less, may be utilized provided: (a) That patients be treated under hospitalized conditions rather than on an ambulatory basis, and (b) that treatment be administered under the direction of specially qualified personnel.

The two treatment systems recommended for early syphilis were the 5-day intravenous drip and 10-day multiple syringe technique. It was further suggested that the same intensive treatment systems might be utilized in the continental United States for selected personnel under the same conditions. An alternative 12-week system was advised in the event that hospitalization was not practicable. Detailed descriptions of the techniques of the three systems were provided.

In the Surgeon General's Office, it was decided to give this scheme an experimental trial in one large hospital before recommending it for general use in the Army, even in oversea theaters. Accordingly, in July 1943,28 a research project was set up at Fort Bragg on the use of intensive doses of Mapharsen by intravenous drip.29 The experiment was terminated in Octo-

28Memorandum, Lt. Col. Thomas B. Turner, Chief, Venereal Disease Control Branch, Preventive Medicine Division, for General Kirk, 3 July 1943, subject: Short, Intensive Treatment of Syphilis. 
29Fort Bragg was selected not only because of its size but because Capt. (later Maj.) Williard Leifer, MC, joint author of the original and numerous other papers on the 5-day intravenous-drip technique was on duty there.


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ber 1943, when the superiority of penicillin became obvious. No new information was obtained from study of the patients treated up to that time.

In the meantime, in the Office of the Chief Surgeon, European theater (which was, because of the disrupted state of communications, virtually isolated from knowledge of current developments in the Surgeon General's Office), it had been decided to try an entirely new scheme for the treatment of syphilis with Mapharsen. It was undertaken because of the utter impossibility of even approximately regular treatment under the existing conditions. Consideration was given to the known facts regarding the toxicity of Mapharsen as determined by the time-dose relationship. Theoretical considerations and experimental work with rabbit syphilis, culled from the most recent source material available on massive arsenotherapy, indicated that the total curative dose of Mapharsen for early syphilis in the human should be of the order of 20 mg. per kilogram of body weight.30 Further, it appeared that the incidence of reactions is determined almost entirely by the timedose relationship, with a very rapid rise in rate as the total interval for treatment is decreased, becoming intolerable if the treatment interval is reduced significantly below 5 days, but not decreasing with particular rapidity as the span of treatment is increased above 20 days.

With this information, and in consideration of the practical military problems involved, it was decided, for the patient with early syphilis, to give clinical trial to the following scheme of treatment: One mg. of Mapharsen per kilogram of body weight (but not to exceed a single dose of 75 mg.) was to be given by syringe daily for 20 days. The choice of a 20-day treatment scheme was not only convenient, as it allowed doses of 1 mg. per kilogram per day to total 20 mg. per kilogram in 20 days, but was also determined by sound theoretical consideration.31 The treatment was carried on in hospital; the patient was carefully observed both clinically and by laboratory tests. In addition to the Mapharsen, he was given at regular intervals 8 doses each of 0.2 gm. of bismuth subsalicylate suspended in oil; that is, approximately a dose of bismuth every other day.

Over 4,000 patients were treated by this method in the European theater, with no deaths. The treatment was completed in 96.3 percent of the first 775 patients and in a somewhat higher percentage of the remainder. In one series of 1,343 consecutive cases of early syphilis treated by the 20-day form of intensive arsenotherapy, results of serological tests for syphilis were reported after 6 or more months in 982. In 258, followup reports were received more than a year after completion of therapy. Ninety-five percent of both groups had a negative serological test and a normal cerebrospinal fluid at the time of last examination. The time relations of the observed serological relapses were such, however, that approximately twice as many definitely un-

30Moore, Joseph Earle: The Modern Treatment of Syphilis. 2d edition. Springfield, Ill: Charles C. Thomas, 1943.
31See footnote 26, p. 420.


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satisfactory results were noted at the end of 12 months as at the end of 6 months after treatment.

The authors who reviewed this material concluded32 that the 20-day scheme for intensive arsenotherapy will yield very satisfactory 1-year results in the treatment of early syphilis but that when compared to penicillin or penicillin plus chemotherapy given on a less toxic schedule it carries an unjustifiable risk. This is illustrated33 by an analysis of 500 consecutive patients who were treated by this method. Four hundred and seventy-six of these eventually completed the treatment, sometimes with delays necessitated by minor reactions, but in 24, or 4.8 percent, the procedure had to be abandoned because of severe reactions. Seven of these patients had definite signs of cerebral irritation, and two more presented the classical picture of hemorrhagic encephalitis. Jaundice occurred in six, toxemia and agranulocytosis in three each, while severe fever occurred in two and severe albuminuria in one.

Penicillin-In June of 1943, Mahoney and his collaborators treated four sailors with early syphilis with penicillin in a dose of 1.2 million units which they had calculated as being the theoretical optimum34 from observations on experimental animals. The results were so dramatic that the experiment was immediately extended within the limits imposed by the short supply of penicillin at that time.

This information spread rapidly, largely by word of mouth (all the data concerning penicillin were then classified information). At the 20th meeting of the Subcommittee for Venereal Diseases on 29 September 1943, "It was agreed that the clinical and experimental evidence so far available justified an extensive trial of penicillin in human beings * * *," and recommendations were passed for the formation of a penicillin panel, under the National Research Council, to coordinate experimental and clinical trials of penicillin in humans with syphilis which were to be conducted by appropriate facilities of the Army, the Navy, the U.S. Public Health Service and eight35 participating civilian clinics. At the first meeting of the penicillin panel a month later, six treatment schedules for investigation were agreed upon. Five of these were to be undertaken immediately, one was deferred because of the shortage of penicillin, and the Army agreed to contribute observations upon

32Pillsbury, D. M., and Loveman, A. B.: Six- to Twelve-Month Follow-Up Results in Early Syphilis Treated by a Twenty-Day Intensive Arsenobismuth System. Am. J. Syph., Gonor. & Ven. Dis. 31: 115-123, March 1947.
33Cormia, F. E., and Blauner, S. G.: Reactions to Twenty-Day Intensive Therapy With Mapharsen and Bismuth for Syphilis With a Note on the Use of BAL in Their Management. Am. J. Syph., Gonor. & Ven. Dis. 31: 135-149, March 1947.
34Mahoney, J. F., Arnold, R. C., and Harris, A.: Penicillin Treatment of Early Syphilis; A Preliminary Report. Ven. Dis. Inform. 24: 355-357, Dec. 1943; also Am. J. Pub. Health 33: 1387-1391, December 1943.
35The number was greatly increased later, so that at one time there were nearly 40 clinics participating.


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120 patients treated by two of these schedules within the first 3 months of the experiment.36

From this point (October 1943), the development of the use of penicillin in the treatment of syphilis was, essentially a civilian activity, the history of which has been summarized in detail by Moore. The Army continued to participate in the clinical investigations on a small scale, but it was quite properly much more concerned with the application of this new, safe, and simple therapeutic method on a mass treatment scale than in attempting clinical investigative work.

On 5 April 1944, Brig. Gen. James S. Simmons, Chief, Preventive Medicine Service, Office of the Surgeon General, addressed the following letter to Dr. Moore, Chairman, Subcommittee on Venereal Diseases, National Research Council:

It is desired that the Subcommittee on Venereal Diseases, National Research Council, consider at its April 20th [1944] meeting the present state of knowledge of the penicillin treatment of syphilis in relationship to its suitability for application to Army practice. The present prolonged treatment schedules place a great chore on the Medical Department and interfere seriously with training and combat. Furthermore, in active Theaters of Operation it is impossible to maintain any degree of regularity in administering treatment.

For these reasons The Surgeon General would appreciate an expression of opinion of the Subcommittee on Venereal Diseases as to the earliest possible time penicillin treatment of syphilis may be applied to Army practice.

This was a staggering request. Arsphenamine and its derivatives had been employed in the treatment of syphilis for nearly 35 years without reaching satisfactory agreement on the details of its utilization, yet here was a request for advice regarding the large-scale application of an entirely new therapeutic agent which had first been used in the treatment of syphilis only 9 months before and with which experience on any statistically significant scale was only 6 months old. Well aware of the magnitude of the responsibility being assumed, but equally aware of the problems confronting the Army, the minutes of the 22d meeting of the Subcommittee on Venereal Diseases, 20 April 1944, merely say:

The purpose of the request and its relationship to campaign conditions was further amplified in general discussion. This led to the following recommendation: It is recommended that in active theaters of operation the penicillin treatment of early syphilis (i.e., infections of less than one year's duration, whether or not partially treated with arsenical chemotherapy) be adopted immediately. The minimum total dosage of penicillin should be 2.5 million units, given over an eight-day period, administered in 64 intramuscular injections every three hours day and night. It is further desirable that such penicillin treated patients be followed without subsequent antisyphilitic treatment (unless in the event of clinical or serologic relapse) as frequently as is practicable and that all such cases be thoroughly resurveyed as to syphilis prior to separation from the service.

36Minutes, Conference on Penicillin in the Treatment of Syphilis in Human Beings by a Panel Composed of Members of the Subcommittee on Venereal Diseases and the Committee on Chemotherapeutics and Other Agents, National Research Council, 29 Oct. 1943.


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A subsequent letter from The Surgeon General to the commanding generals of the oversea theaters for the attention of the chief surgeon summarized current knowledge of the use of penicillin in the treatment of syphilis and directed (1) that all new cases of primary and secondary syphilis be treated with penicillin, (2) that the schedule of treatment be 40,000 units intramuscularly every 3 hours for a total of 60 doses or 2.4 million units for each case, and (3) that followup examinations should be obtained at monthly intervals for a minimum period of 1 year.37

The receipt of this directive in the European theater coincided almost exactly with the date of the invasion of continental Europe. It was, therefore, particularly welcome in the attempt to provide facilities for proper diagnosis and treatment of the venereal diseases, especially syphilis, within the Army areas. Evacuation and the loss of a trained soldier to his organization was to be avoided, but at the same time it was important not to increase the patient load which must be carried by field or evacuation hospitals. Accordingly, venereal disease treatment centers were planned within the Army areas staffed by at least one medical officer with experience and ability in the diagnosis and treatment of the venereal diseases, and equipped with adequate laboratory facilities and technicians detached from the Army medical laboratory. The plan proved efficient and was greatly expedited by the availability of penicillin for the treatment of syphilis. This made is possible to return all patients treated for syphilis to their organizations within 10 days or less.

The necessary followup was operated by a central syphilis register set up in the Office of the Chief Surgeon, European theater, where the soldier's syphilis register was filed as soon as treatment was completed. The followup was accomplished by letters to the commanding officer of the patient's organization requesting the desired observations at the appropriate time.

The Subcommittee on Venereal Diseases made further recommendations at its 23d meeting on 29 June 1944 for the use of penicillin in the treatment of syphilis by the Army. These provided for the treatment of all soldiers with early and latent syphilis with 2.4 million units of penicillin according to the scheme advised to the oversea theaters. The necessity for frequent followup of patients who were treated for early syphilis was emphasized, and it was pointed out that knowledge concerning the action of penicillin in neurosyphilis was so imperfect as to prevent any advice on its use in such cases. TB MED 106, 11 October 1944, developed in detail the general principles contained in the committee's recommendations.

As the war ended, TB MED 198, 20 August 1945, defined the criteria for the diagnosis of syphilis, restated the advice to treat early and latent

37Letter, Maj. Gen. Norman T. Kirk, The Surgeon General, to Commanding Generals, all Theaters of Operations, attention of Chief Surgeon, 24 May 1944, subject: Penicillin Treatment of Primary and Secondary Syphilis.


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syphilis with 2.4 million units of penicillin in 7.5 days, defined the details of the necessary posttreatment followup, and advised that all patients with any manifestation of late syphilis, including, of course, neurosyphilis, be transferred to the appropriate neurosyphilis center. Like its companion TB MED 196 on gonorrhea, dated 20 August 1945, this bulletin on the management of syphilis represented the best information available at the time for the proper management of early and latent syphilis among Army personnel, but events which could not be foreseen at the time of its preparation necessitated important changes in the dosage schedules recommended.

At its 24th meeting on 23 February 1945, the Subcommittee on Venereal Diseases recognized that there were several fractions of the substance known as penicillin, that none of these fractions was available commercially, and that the constitution of commercially available penicillin was not known. It made recommendations for extending the assay supervision of commercial penicillin and most importantly made provision for investigation of the chemical and biological properties of the several known fractions. By the following spring, a great deal of information had been assembled and published by Moore, the highlights of which were (1) that the substance known as penicillin was made up of at least four chemically individual fractions which in the American nomenclature were known as G, F, X, and K, (2) that originally the commercially supplied penicillin was largely made up of penicillin G, (3) that with the substitution of Penicillium chrysogenum Q-176 for Penicillium notatum in the manufacture of penicillin the commercially available preparations contained an unknown, certainly large (the average was estimated at about 50 percent) amount of fraction K, and (4) that fraction K while exceedingly active in vitro was apparently in some way denatured by the animal or human body to become comparatively inert and therapeutically ineffective when injected. As these facts were brought out, the manufacturers of penicillin immediately took steps to convert to the production of a crude penicillin consisting largely of fraction G and eventually to the production of crystalline penicillin G on a commercial scale. This took time, however, since so large and complicated an industry cannot convert itself overnight. For the protection of the soldier patient, Change 1 to TB MED 198 was published on 21 November 1946. This change directed (1) that patients with seronegative primary syphilis be given 6 million units of penicillin in 60 doses of 100,000 units each at 3-hour intervals for 7 days, (2) that those with seropositive primary, secondary, and latent syphilis be given 8 million units in 80 consecutive intramuscular injections of 100,000 units at 3-hour intervals for 10 days, and (3) that the re-treatment of failures be by the 8-million-unit schedule with the addition of 10 doses each of 60 mg. of Mapharsen given twice weekly and five weekly intramuscular injections each of 0.2 gm. of bismuth subsalicylate suspension in oil. Failures after this combined penicillin, Mapharsen, and bismuth schedule were to be treated


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by the 26-week Mapharsen and bismuth system outlined in Circular Letter No. 74, 25 July 1942.

Comparison between Circular Letter No. 18, 10 March 1941, and TB MED 198, 20 August 1945, affords a number of interesting contrasts. To the criteria for diagnosis has been added the concept of the biological false-positive serological test for syphilis which was first introduced to the Army in Circular Letter No. 93, Office of the Surgeon General, 30 April 1943; methods of treatment are totally different, but the most interesting change is in the concept of proper posttreatment followup. Under the scheme of treatment recommended by Circular Letter No. 18, the patient who came under treatment with early syphilis and pursued the treatment faithfully should have reached and maintained a negative serological test for some time before the treatment was ended. With rapid treatment with penicillin, this is not the case, and TB MED 198 goes to some pains to explain the interpretation of the titered serological test in the posttreatment followup.

Neurosyphilis-Prior to 1944, the Army had made no special provision for the care of patients with neurosyphilis and the various forms of late syphilis. Patients suffering from these maladies, unless by chance they fell into the hands of someone professionally qualified to individualize their management, were treated, if at all, by whatever scheme was in vogue at the time for the treatment of early syphilis. While cardiovascular syphilis and the other forms of late syphilis, other than of the central nervous system, were numerically unimportant, examination, by increasing numbers of medical officers, of the cerebrospinal fluid of every patient with syphilis was revealing a substantial number with asymptomatic neurosyphilis. As this situation became recognized, a special committee met in Washington at the request of The Surgeon General on 8 March 1944 to consider the problem of the professional management of neurosyphilis in the U.S. Army.38 In due time, TB MED 48, 31 May 1944, was published creating a number of neurosyphilis centers in named general hospitals in the continental United States and setting forth standards for diagnosis and treatment. The plan was to staff each of the hospitals with one or more medical officers with special training in the management of neurosyphilis and other forms of late syphilis, and although these hospitals were designated as neurosyphilis centers it was tacitly understood at the time, and later formally stated in TB MED 198, that all problem cases of syphilis would be referred to them.

The provisions of TB MED 198 were largely administrative but the basic principles leading to uniformity of diagnosis in the various centers

38Present at the meeting were Drs. Moore and Stokes from the Subcommittee on Venereal Diseases; General Morgan, Lt. Col. Thomas H. Sternberg, MC, Maj. (later Lt. Col.) Charles R. Rein, MC, Maj. (later Lt. Col.) William H. Everts, MC, Major Dyar, and Maj. (later Lt. Col.) Paul G. Reque, MC, from the U.S. Army; Comdr. W. H. Schwartz, MC, and Lt. H. P. Rowe, MC, from the U.S. Navy; Drs. Lewis H. Weed, E. Cowles Andrus, T. R. Forbes, Philip S. Owen, and Maj. Gen. James C. Magee, USA (Ret.), from the National Research Council; Maj. Georges Leclerc, MC, and Surgeon Lieut.-Comdr. R. G. Struthers, MC, Canadian Liaison Officers; and the following invited conferees: Drs. Harry C. Solomon, Paul A. O'Leary, Evan W. Thomas, and Arthur G. Schoch.


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were defined and general recommendations for classification and treatment were made. These were extended by a series of three articles39 which were published in the Bulletin of the U.S. Army Medical Department where they served as authoritative but unofficial guides.

The specific recommendations of TB MED 48 for treatment were:

1. A trial of routine metal chemotherapy on a duty status for 6 months for all patients with early syphilis or syphilis of unknown duration and Groups I (minimal) and II (intermediate) changes in the cerebrospinal fluid.

2. The same scheme for patients with late syphilis and Group I changes. 

3. The immediate induction of fever (preferably by tertian malaria for whites and Northern Negroes, and by quartan malaria for Southern Negroes) in those in the first two groups in whom 6 months of metal chemotherapy had occasioned no improvement in the cerebrospinal fluid, and in all patients with Group III (maximal) changes in the cerebrospinal fluid, those with late asymptomatic neurosyphilis and Group II changes, and all patients with symptomatic neurosyphilis except those with acute syphilitic meningitis or predominantly vascular lesions.

Great stress was laid upon the necessity for both frequent and long continued followup examinations of all patients treated for neurosyphilis, and detailed directions for accomplishing this were laid down regardless of whether the man stayed in the Army or was separated.

On 13 November 1945, Change 3 to TB MED 48 advised that all patients with neurosyphilis should be treated with penicillin. The recommended dose was 3.6 million units given in 120 injections of 30,000 units each in the usual manner.

The patients who qualified for a trial of metal chemotherapy alone under the previous regimen were to be returned to duty after completion of the treatment with penicillin, followed with clinical examination and retest of the cerebrospinal fluid at 3 and 6 months after treatment, and returned for reevaluation if either examination gave abnormal results 6 months after treatment was completed.

The same group of patients as previously were considered candidates for fever therapy, and the suggestion was made that the first doses of the prescribed 3.6 million units of penicillin be given at the time of the first febrile paroxysm.

Records-The old practice of recording treatment of syphilis, as outlined in Circulars Nos. 2 and 3, 13 December 1910 and 3 June 1911, respectively, Office of the Surgeon General, was continued in more or less its orig-

39(1) O'Leary, P. A., Moore, J. E., Solomon, H. C., Stokes, J. H., and Thomas, E.: Asymptomatic Neurosyphilis. Bull. U.S. Army M. Dept. 80: 46-51, September 1944. (2) Solomon, H. C., Moore, J. E., O'Leary, P. A., Stokes, J. H., and Thomas, E.: Symptomatic Neurosyphilis; A Clinical Survey. Bull. U.S. Army  M. Dept. 81: 55-64, October 1944. (3) Solomon, H. C., Moore, J. E., O'Leary, P. A., Stokes, J. H., and Thomas, E. W.: The Treatment of Neurosyphilis. Bull. U.S. Army M. Dept. 82: 66-76, November 1944.


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inal form until after World War I, during which it had proved to be unnecessarily laborious and to serve no useful purpose. By this time numerous individual medical officers had created their own record systems and their ideas were consolidated, eventually to produce WD MD Form 78, The Syphilis Register. This was authorized by War Department General Orders No. 6, 13 February 1923, and incorporated in AR 40-235 on 30 December 1924.

This form with relatively minor changes (the last was necessitated by the introduction of penicillin) has been employed since its first introduction. The form is opened at the time of the original diagnosis of syphilis, contains all of the relevant information concerning both the infection and the general physical condition of the patient, provides space for recording treatment, reactions, the results of laboratory tests, and progress notes and is closed at the completion of treatment and a specified period of observation. Upon completion, the record was transmitted to the Venereal Disease Control Division, Preventive Medicine Service, Office of the Surgeon General, where it was reviewed and, if found acceptable, filed for future record.40

During the period in which the treatment for syphilis was prolonged, this record facilitated continuity of treatment of the patient which might all be carried out in the same place or by the same medical officers. During the first part of World War II, however, because of the rapid and secret troop movements, it frequently became impossible for the syphilis register to keep up with the patient. Several different methods of accomplishing this were explored, including a brief trial of having the syphilis register transmitted with the service record of the soldier concerned, but none proved to be entirely satisfactory.

In an effort to obviate this difficulty, there was inaugurated at Fort Bragg, in 1941,41 an individual record of treatment patterned after the similar form supplied to seamen under the auspices of the then functioning Health Organization of the League of Nations. This served to give the patient a pocket record of treatment which provided adequate information for any medical officer into whose hands he might fall. The proper functioning of this accessory form, of course, depended on the willingness of the patient to report for treatment before his syphilis register caught up with him, but experience showed that on the average the form substantially reduced the number and duration of lapses from treatment. Similar forms were introduced in the European theater in 1942 and in the Mediterranean Theater of Operations, U.S. Army, in 1943. Still another but again similar form (WD MD Form 78a) which had been authorized by The Surgeon General in October 1943 was made available by TB MED 3, 11 January 1944.

40By an agreement between The Surgeons General of the Army and the Public Health Service and the Chief Medical Officer of the Veterans' Administration, the syphilis registers from World War II were filed with the Veterans' Administration to arrange for men in certain categories, especially those treated for neurosyphilis, to be followed through the Public Health Service.
There were also other exceptions to this standard procedure; for example, the Central Syphilis Registry used in the European theater.
41Annual Report, Office of the Surgeon, Fort Bragg, N.C., 1941.


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After the introduction of rapid treatment methods, all done under the continuing control of one small group, a form of this type was no longer required for assisting in continuity of treatment, but it may continue to serve a useful purpose in facilitating posttreatment followup.

THE MINOR VENEREAL DISEASES

Aside from chancroid, which became troublesome in certain areas, the lesser venereal diseases (lymphogranuloma venereum and granuloma inguinale) were of little numerical importance during World War II. Although these three types of venereal diseases were less common than gonorrhea or syphilis, the period of disability often produced by each of them was potentially great enough to vest them with a certain degree of military importance. The earlier deliberations of the Subcommittee on Venereal Diseases which had led to the suggestions upon which Circular Letters Nos. 18 and 74 were based, included considerations of the lesser venereal diseases, and these circulars laid down methods of diagnosis and treatment of these conditions. Later, TB MED 157, dated April 1945, with Change 1, dated 17 December 1946, brought up to date the accepted practices in the diagnosis and treatment of the minor venereal diseases.42

Chancroid-Up to the end of World War II, the diagnosis of chancroid was one of exclusion and therefore essentially unsatisfactory. Circular Letters Nos. 18 and 74 and TB MED 157 emphasized the necessity of excluding syphilis, both by dark-field examination and by serological followup, and that this must be done even if the diagnosis of chancroid can be proved bacteriologically in order to exclude a mixed infection. At the time of the first directive, the bacteriology of Hemophilus ducreyi was so unsatisfactory that Circular Letter No. 18 reads, as follows: "Laboratory tests for the absolute diagnosis of chancroid (Ito-Reenstierna skin test or the staining or cultural isolation of the Ducrey bacillus) are not recommended." In TB MED 157, considerable advance in the bacteriology of the causative organism is illustrated in the following statement: "The diagnosis of chancroid may be aided by the laboratory examination of stained smears from the lesion, or by culture of pus from the lesion or the bubo." This reflects a growing interest in the bacteriology of chancroid and the fact that the experts have developed methods for more accurately staining and for culturing the Ducrey bacillus which are satisfactory in their hands. The complete omission of the

42TB MED 157 was based on the recommendations of a special committee which convened on 25 January 1945 at the request of The Surgeon General. Present at the meeting were Dr. Moore, Subcommittee on Venereal Diseases; Lt. Col. (later Col.) Harrison J. Shull, MC, Colonel Sternberg, and Major Rein, representatives of The Surgeon General; Dr. Paul D. Rosahn, Technical Aide to the Committee on Medical Research, Office of Scientific Research and Development; and the following conferees: Dr. Arthur W. Grace, Long Island College of Medicine, Brooklyn, N.Y.; Dr. Geoffrey W. Rake, Squibb Institute for Medical Research, New Brunswick, N.J.; Dr. Katherine H. Anderson, Vanderbilt University School of Medicine, Nashville, Tenn.; Dr. Franco Mortara, New York University College of Medicine, New York, N.Y.; and Dr. Robert B. Greenblatt, U.S. Public Health Service.


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Ito-Reenstierna or other similar skin test from this latest directive is apparently a reflection of the growing doubt of the value of skin tests of this type in general.

In contrast to the unsatisfactory state surrounding the diagnosis of chancroid, treatment with the sulfonamide drugs was eminently satisfactory. Circular Letter No. 18 recommended sulfanilamide in the dose of 33 gm. given over a period of 14 days and local treatment with powdered sulfanilamide after primary syphilis had been excluded by a series of at least three darkfield examinations of material from the lesions. Surgical procedures, such as circumcision or dorsal slit, "* * * should be resorted to only on the basis of sound clinical judgment." Incision of the fluctuant bubo was allowed but not advised.

The changes between the recommendations just cited and those contained in TB MED 157 are worth comment. The more recent recommendations were to treat systemically with sulfadiazine in a dose of 1 gm., four times daily, for 5 to 7 days; no local treatment except soap and water; aspiration of the fluctuant bubo with a 16-gage needle if necessary but, "the bubo should never be incised," and regarding other surgical procedures "circumcision or dorsal slit is undesirable and is rarely necessary."

As indicated earlier, chancroid became exceedingly prevalent and consequently troublesome in certain areas. This was especially true in the Philippines,43 at the end of the war, and earlier in North Africa44 and the China-Burma-India theater.45 Recommendation by special investigators of the problem in the Philippines, however, dealt largely with control and preventive measures. In no theaters in which chancroid was troublesome was there advance in therapy greater than that reported in TB MED 157.

Lymphogranuloma venereum-Fortunately, this disease was of low incidence both in the continental United States and in the theaters of operations. In the latter, the disease occurred almost entirely in small sporadic outbreaks clearly suggesting a single focus of infection. The same three directives (p. 430) deal with diagnosis and treatment.

Between the first and the last, there was essentially no change in the diagnostic criteria laid down. TB MED 157 explains that the diagnosis is based upon collateral consideration of the results of the Frei test, the clinical picture, epidemiological information, and the exclusion of other causes of inguinal adenopathy. It is emphasized that a positive Frei test is not in itself adequate reason for making the diagnosis of lymphogranuloma vener-

43Letter, Dr. Joseph Earle Moore, Consultant to The Surgeon General, U.S. Army, and Lt. Col. Thomas H. Sternberg, MC, Director, Venereal Disease Control Division, Office of the Surgeon General, U.S. Army, to The Adjutant General, U.S. Army, 6 June 1945, subject: Venereal Disease in the U.S. Army in the Philippine Islands, and Recommendations for Their Control.
44Annual Report, Preventive Medicine Division, Office of the Surgeon, North African Theater of Operations, 1943.
45Letter, 1st Lt. M. A. Bouton, MC, VD Control Officer, Office of the Theater Surgeon, Rear Echelon, Headquarters, U.S. Army Forces, China, Burma, and India, to Commanding General, Rear Echelon, Headquarters, U.S. Army Forces, China, Burma, and India, 8 Apr. 1943, subject: Venereal Disease Situation in the C.B.I. Theater.


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eum in the absence of the typical clinical picture, but it is suggested that a negative Frei test in the presence of a suggestive clinical picture is of some value in excluding the diagnosis.

In the treatment of lymphogranuloma venereum, conservatism is advised. TB MED 157 recommends aspiration of fluctuant nodes where necessary but avoidance of radical surgical procedures; chemotherapy with sulfadiazine in doses of 3 gm. daily for 21 days; and the utmost conservatism in management of rectal stricture when it occurs. Perirectal abscess and fistulo-in-ano may be dealt with radically in the hope of gaining surgical cure. The use of Frei antigen intravenously, which was previously touched upon lightly in Circular Letter No. 18, was not even mentioned.

Granuloma inguinale-This disease was completely unimportant from the military standpoint but was included in the various directives (p. 430) for the sake of completeness. TB MED 157 suggests that the diagnosis of the condition can be made by a competent observer on the basis of morphology alone but points out the obvious desirability of demonstrating Donovan's bodies in smears from the lesions.

Fuadin (stibophen) was recommended as the drug of choice. This is given intramuscularly by a rather complicated dosage schedule, is commonly well tolerated, and is therapeutically effective in the majority of instances. Where there was no response to Fuadin, tartar emetic was recommended. This is given intravenously also on a rather complicated dosage schedule. It was further recommended that if secondary infection was present, penicillin be used in doses of 10,000 units intramuscularly every 3 hours for a total of 400,000 units. With the exception of this addition of penicillin for secondary infection, there were no other advances in the treatment of this condition during World War II.

Miscellaneous-The more strictly urologic conditions which are sometimes grouped with the venereal diseases (venereal warts, gangrenous balanitis, and so on) need not be considered here, but the role of scabies as a venereal disease must be mentioned.

In the early winter of 1942, the Senior Consultant in Dermatology, Office of the Chief Surgeon, European theater, had noted that the incidence of scabies severe enough to require hospitalization in the European theater was greatly in excess of the frequency of the disease among troops in the United States. A determined campaign was instituted to educate unit medical officers in the early diagnosis and proper treatment of the disease and to provide them with benzyl benzoate for its treatment.

The incidence of the disease continued to increase and the following simple facts led to an inference that the disease was venereal in origin. Troops arriving from the Zone of Interior were free from the disease; the disease was exceedingly common among the British, especially the civilians; and the pattern of distribution of the individual cases made soldier-to-soldier spread most unlikely. From this obvious inference, a comprehensive study


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of the matter was initiated based on the same type of interview by the same interviewers used in the contact investigation of gonorrhea and syphilis, and the study resulted in the conclusion that at least 90 percent of scabies among U.S. soldiers in the European theater was venereal in origin.46 This thesis, incidentally, was amply verified in the experiences of our troops in Germany after V-E Day. There the incidence of scabies made a meteoric rise, exactly paralleling the increase in the incidence of the venereal diseases.47

INDUCTION OF INDIVIDUALS WITH VENEREAL DISEASE

In the early period of mobilization, persons known to have venereal disease were rejected for military service. This policy resulted in the accumulation of a large backlog consisting mainly of men rejected because they had syphilis. It was the practice, at the time, to defer men with gonorrhea and chancroid only until they became asymptomatic and then to refer them for induction. By 1942, this reservoir of manpower had grown to tremendous proportions, the manpower shortage was becoming acute, and the Army felt that its medical facilities and training program were sufficiently advanced to undertake the additional burden of inducting men with syphilis. In the fall of that year, plans were initiated to provide in certain selected posts, camps, and stations additional treatment facilities with a total capacity of 6,510 beds for the management of inductees with syphilis and to a much lesser extent the other venereal diseases. The plan was placed in operation in December 1942 by directives from The Adjutant General48 and was functioning smoothly by March 1943.

The inductees with syphilis were hospitalized in specially provided barrack-type hospitals which were staffed by officers especially trained in the diagnosis and treatment of the venereal diseases. Some of these medical officers had been recruited from civilian life but most had been given a short intensive course at the Institute for the Control of Syphilis at the University of Pennsylvania, Philadelphia, Pa., under the auspices of the U.S. Army.

As a result of this program, 200,000 individuals with venereal disease were inducted into the Army through December 1945. Of these, nearly 170,000 were syphilitics.49 The treatment which they received followed the current directives for the management of the venereal diseases occurring after induction and require no special comment.

One administrative problem was greatly expedited by a directive, in June 1943,50 authorizing preinduction hospitalization for the examination of the cerebrospinal fluid of all those found to have a positive serological test for

46See footnotes 26, p. 420.
47Quarterly Report, Preventive Medicine Division, Office of the Chief Surgeon, U.S. Forces in the European Theater, 1 Apr. to 30 June 1946.
48Radiograms, The Adjutant General, to all Service Commands, 7 and 10 Dec. 1942. 
49Karpinos, B. D.: Venereal Disease Among Inductees. Bull. U.S. Army M. Dept. 8: 806-820, October 1948.
50Letter, The Adjutant General, to all Service Commands, 9 June 1943, subject: Induction of Individuals With Positive Serology for Syphilis.


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syphilis. This made possible the preinduction rejection of registrants with neurosyphilis, thereby avoiding the laborious process of boarding for a certificate of disability for discharge of the 15 to 20 percent of the men with syphilis who would be found to have an abnormal cerebrospinal fluid at the first examination.

THE RESULTS

The extremely energetic venereal disease control program which was sponsored by the Army throughout the war was effective in minimizing the number of venereal infections. In spite of these preventive activities, however, gonorrhea and syphilis continued to be among the important disease

CHART 22.-A comparison of computed and actual rates1 reflecting savings attributed to improved treatment of venereal disease, Army in the United States, June 1942 to August 1945 

problems.51 The yeoman's task of reducing to the minimum the number of days lost from duty because of these infections remained for the therapist who may well be proud of the accomplishment which he can report.

The reduction in the noneffective rate and changes in therapy, incidence, and duration of treatment of venereal disease in the U.S. Army in the con-

51Medical Department, United States Army. Preventive Medicine in World War II. Volume V. Communicable Diseases Transmitted Through Contact or By Unknown Means. Washington: U.S. Government Printing Office, 1960.


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CHART 23.-Changes in therapy, incidence, and duration of treatment of venereal disease, Army in the United States, June 1942 to August 1945

tinental United States are shown in charts 22 and 23. If the length of treatment required in June 1942 had been maintained without change, the venereal disease noneffective rate for the continental United States would have been 2.0 per 1,000 per day in December 1944 and 2.5 per 1,000 per day by August 1945. As it was, in spite of the mounting venereal disease rate which skyrocketed after V-E Day, in December 1944 the noneffective rate was less than 1 per 1,000 per day and was only 0.66 per 1,000 per day in August 1945.

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