|OFFICE OF MEDICAL HISTORY AMEDD REGIMENT AMEDD MUSEUM|
HISTORY OF THE OFFICE OF MEDICAL HISTORY
The Typhus Fevers
Chris J. D. Zarafonetis, M.D.
Part I. Epidemic Typhus
Epidemic typhus fever is an acute febrile disease caused by infection with Rickettsia prowazeki. It is a louseborne infection and is characterized clinically by sustained high fever, headache, malaise, and later an exanthem. It has been known under many names including exanthematous typhus, jail fever, ship fever, war fever, camp fever, Old World typhus, Fleckfieber (German), typhus exanthematiqué (French), el tabardillo (Spanish), and hassin chifusu (Japanese).
For centuries, epidemics of typhus fever have been associated with war, revolution, and famine, and have indeed, in the past, been a factor affecting the outcome of wars. The death toll exacted in some epidemics has been estimated in millions of lives. An account of the historical role of typhus fever has been written by Zinsser,l and Strong and his associates2 have documented the great Serbian epidemic of 1915.
Clinically, no differentiation was made between typhoid fever and louse-borne typhus fever until 1837. In that year, Gerhard, in Philadelphia, noted differences between the two, and was the first to call attention to the presence of typhus in the New World. That typhus is transmitted by Pediculus humanus var. corporis was discovered by Nicolle, Comte, and Conseil in 1909. The causative agent, R. prowazeki, was first described in 1916 by Da Rocha-Lima. For many years, it was believed that there was only one form of typhus fever, but it is now known that the epidemic louseborne form and the endemic fleaborne typhus are caused by different micro-organisms. It has been further shown that epidemic typhus fever may be recrudescent in a patient years after the original illness, in the disorder known as Brill's disease.
Typhus fever exists in many parts of the world, with important foci in the Balkans, North Africa, China, and Mexico, and it presumably occurs in Poland, the U.S.S.R., and elsewhere. Man is the reservoir of epidemic typhus (p. 201). It is transmitted from man to man by body lice which become infected by feeding upon typhus patients during the febrile period. The rickettsiae multiply in the cells lining the intestinal tract of the louse. A week
1Zinsser, Hans: Rats, Lice and History. New York:
Little, Brown and Co., 1934.
or 10 days after the vector has become infected, the parasitized cells rupture and large numbers of rickettsiae begin to appear in its feces. Lice prefer the normal temperature of the body and usually remain close to their human host. If the temperature is raised by fever or lowered by death, however, they will migrate to a new host. Here, lice suck blood and defecate as they feed, and when the site of the bite is scratched, the infected feces are rubbed into the skin. This appears to be the principal means by which the infection is passed from man to man. It is also possible to acquire it by crushing an infected louse upon the skin, or by having dried infected feces come into contact with the conjunctivae or the mucous membranes of the respiratory tract. Infection with typhus rickettsiae is eventually fatal to the louse.
Conditions that predispose to louse infestation naturally predispose to epidemics of typhus fever. The scene is set by crowding, inadequate housing, lack of bathing facilities, lack of fuel, and such continued cold weather that people wear their garments for long periods of time. Once louse infestation is prevalent, introduction of the infection, either from a patient with typhus or from one with the recrudescent (Brill's) disease, may set off an epidemic. The chaotic effects of war and famine, shifting populations, and the breakdown of orderly processes of government contribute conditions that favor spread of the infection.
At the beginning of World War II, it was evident that American troops would be exposed to typhus fever in most oversea theaters of operations. It was recognized that few physicians in the Armed Forces would have had experience with a disease conspicuous by its absence from the continental United States. Against this background, the United States of America Typhus Commission was created by the Secretary of War on 22 October 1942 in response to a staff-approved recommendation of The Surgeon General, initiated by Col. (later Brig. Gen.) James S. Simmons, MC, and established by Executive order of President Roosevelt on 24 December 1942.3 The order provided for a joint attack upon the problems of the disease by the Army, the Navy, and the U.S. Public Health Service. As a result of the comprehensive mandates and authorizations of this broadly conceived Executive order, and of the impetus given to the work by the director, field director, and members of the Commission, typhus investigation was intensified, leading to the development of specific diagnostic procedures, improved methods of treatment, the large-scale production of a potent vaccine, and excellent louse-control measures. For detailed information regarding epidemiology and preventive measures, and a history of the Typhus Commission, the reader is referred to the brilliant account by Stanhope Bayne-Jones in another volume in the history of the Medical Department in World War II.4
3Bayne-Jones, S.: The United States of America
Typhus Commission. Army M. Bull. No. 68, pp. 4-15, July 1943.
Although epidemic typhus fever posed a constant threat to soldiers in several oversea theaters (table 13), the remarkable fact remains, however, that there were only 104 cases in U.S. forces and not a single death (table 14). Bayne-Jones has described the extraordinarily effective measures that were implemented for the protection of U.S. troops in areas where epidemics of louseborne typhus were prevalent among civilian populations. As one result of this splendid record, there was no opportunity for medical officers in various station and general hospitals to accumulate extensive experience with epidemic typhus in our troops. The clinical studies to be recorded here are, therefore, largely those performed by members of the Typhus Commission, and are generally concerned with the disease as observed in civilian populations. This is in contrast to the observations on scrub typhus in the several excellent studies made by other medical officers and units in addition to the contributions of the U.S.A. Typhus Commission (pp. 116-138).
1Data pertain to cities only.
Source: (1) Stowman, K.: Typhus During the War. Epidemiol. Inform. Bull. 1 (7): 289-310, 30 Apr. 1945. (2) Current Reports on the Prevalence of Certain Diseases. Epidemiol. Inform. Bull. 1 (7): 311-326, 30 Apr. 1945.
The Disease in Nonvaccinated Individuals
The Typhus Commission established special study facilities at the Cairo Fever Hospital, Egypt, in March 1943.5 The Ministry of Health of the
5Minutes, Conference on Typhus, National Research Council, 22 June 1944.
Egyptian Government provided the study ward and space for laboratories. During the 1943 and 1944 seasons, 159 patients with typhus fever were admitted to this ward, and numerous other cases were observed in other wards of the hospital. With three exceptions, all of the patients studied on the Commission ward were males. Their ages ranged from 10 to 70 years, the great majority falling in the 21- to 35-year age group. In general, the patients were selected as early in the disease as possible. The majority were admitted between the 5th and 10th day of illness. A few were admitted on the first day of disease, while in four instances, patients were actually under observation before the onset of illness.
[Rate expressed as number of cases per annum per 1,000 average strength]
1Includes North Africa.
This section of the chapter will be restricted to a consideration of the unvaccinated subjects who received no special therapy beyond supportive measures. There were 64 such "untreated" cases studied on the Commission ward. The severity of the clinical course of the disease was estimated for each patient after discharge from the hospital. The principal factors which influenced the estimation of severity were the intensity of subjective symptoms (headache, generalized bodily aches and pains, tinnitus, deafness), the degree of prostration, the extent of neurological involvement (mental dullness, stupor, coma, incontinence of urine and feces, signs referable to the central nervous system), the severity of cardiovascular involvement (hypotension, tachycardia, peripheral vascular failure, myocardial damage), and, finally, occurrence of urinary retention, oliguria, nitrogen retention, bronchopneu-
monia, otitis media, parotitis, furunculosis, and gangrene.6 On the basis of these criteria, these cases were grouped as follows:
B. Cases with minimal signs and symptoms, yet definitely diagnosed as typhus on clinical evidence.
C. Cases of moderate severity, showing slight prostration, involvement of the central nervous system, cardiovascular changes, or mild complications.
D. Severe typhus cases with pronounced prostration, involvement of the central nervous system, cardiovascular changes, or serious complications.
E. Cases of such severe illness that at some point in the clinical course a fatal outcome was expected.
F. Fatal cases.
Of the 64 cases of "untreated" typhus fever, there were 2 in the B group, 14 in C, 26 in D, 7 in E, and 15 in F, the fatal cases, a mortality of 23 percent. It was of particular interest that 33 (52 percent) of the patients developed nitrogen retention (nonprotein nitrogen over 45 mg. percent) during the disease. All 15 fatal cases were in this group, and no patient died who throughout his illness had normal concentration of nonprotein nitrogen in the blood.
The following case histories, taken from a Commission publication,7 will serve to illustrate typhus fever classified as severe (E or F):
Case 1 (classified as E; severe, with neurological involvement)-The patient, male, aged 25, was admitted on the sixth day of disease with headache as his chief complaint. Temperature 40.7° C. p.r. Pulse 108. Respirations 36. Blood pressure 126 mm. Hg systolic and 66 mm. diastolic. Weight 121 pounds. The patient was moderately well developed and nourished. He appeared mentally clear and not acutely ill. There was no tinnitus or deafness. The skin was dark; no evidence of a typhus rash was seen. The conjunctivae were negative. The tongue was white coated and moist. The chest was clear to percussion and auscultation. Examination of the heart showed nothing remarkable.
Laboratory data on admission-Hemoglobin 83 percent (CuSO4); erythrocytes 4,500,000; leukocytes 7,550, with 81 percent polymorphonuclear cells. Urine was amber in color, cloudy, reaction acid, and specific gravity 1.028. A few squamous epithelial cells, 1-2 granular casts per low-power field, 1-3 leukocytes per high-power field were seen in the centrifugated sediment. The concentration of nonprotein nitrogen was 46 mg. per 100 cc. of blood. The plasma proteins were 6.8 gm. per 100 cc.
Hospital course (chart 4).-Throughout the first week of hospitalization the patient's fever remained high and the rash appeared, with intense conjunctival injection and the development of petechiae in the left conjunctival sac. The patient, actively delirious, became very talkative and attempted to get out of bed. Intake by mouth continued satisfactorily until the 12th day of disease when subcutaneous injections of 5 percent dextrose in saline and normal saline became necessary for the next 12 days.
On the 13th day he became more stuporous and then semicomatose. He lay with half-opened eyes, breathing quietly. Facial grimaces and grinding of the teeth were noted. Fluid intake by mouth practically ceased. He was put on constant bladder drainage on this day because of urinary retention. His condition remained much the same to the
6Yeomans, A., Snyder, J. C., Murray, E. S.,
Zarafonetis, C. J. D., and Ecke, R. S.: The Therapeutic Effect of Para-Aminobenzoic
Acid in Louse Borne Typhus Fever. J.A.M.A. 126: 349-356, 7 Oct. 1944.
17th day of disease. The rash gradually faded out during this period and the conjunctival suffusion disappeared.
On the 17th day slight improvement was noted in his mental state. He stared about the ward, his mouth open in a wide grimace. When spoken to he replied in a series of unintelligible whining sounds. There was no indication that he recognized people. The rash was no longer visible.
In the next 2 days he was able to obey simple commands. It was evident that he was almost totally deaf. On the 20th day his temperature reached normal levels. Examination showed hyperactive knee jerks and ankle jerks but normal plantar response. An area of skin necrosis appeared over the coccyx.
On the 22d day the catheter was removed. When he was spoken to it was obvious that he was attempting to reply, but he could not articulate and the facial expressions were similar to those of a crying baby.
The area of necrosis over the lower back continued to enlarge. The patient was placed in a chair on the 24th day. A low-grade fever continued. He was by that time able to eat solid food and the oral fluid intake gradually increased.
On the 27th day the patient was found to have not only hyperactive knee and ankle jerks but a bilateral positive Babinski reaction. Voluntary motion of the extremities was uncoordinated.
From this time onward improvement in his general condition was steady but slow. The ability to stand and walk unassisted returned before the ability to form words. At the time of discharge 68 days after the onset of the disease, the lesion over the coccyx was healed. Speech was slow, expressionless, and labored. Hyperactive reflexes were still present in the lower extremities, but the positive Babinski phenomenon had disappeared.
On followup examinations during the next 4 months the patient showed progressive improvement. Mentally he appeared alert. There was no residual deafness. The reflexes in the lower extremities remained hyperactive, however, and speech was still slow, labored, and monotonous in tone. Examination of the urine showed normal concentrating power, no albumin, and a negative urine sediment. The anemia that had developed during the disease was no longer present.
Case 2 (classified as F; fatal, with post mortem)-The patient, male, aged 30, was admitted on the fourth day of disease complaining chiefly of headache. Temperature 40.0° C. p.r. Pulse 88. Respirations 36. Blood pressure 118 mm. Hg systolic and 64 mm. diastolic. Weight 116 pounds. The patient appeared moderately ill, mentally clear, with rapid respirations, and no cough. A few poorly defined maculopapular lesions were noted over the chest, abdomen, and arms. The conjunctivae appeared moderately injected. The tongue was moist. A few crepitant rales were heard in the right midlung field posteriorly. Examination of the heart showed nothing remarkable. The spleen was enlarged, but not tender; its tip was felt 7 cm. below the costal margin. The liver was not palpable, but was found enlarged 3 cm. below the costal margin by percussion.
Laboratory data on admission-Hemoglobin 72 percent (CuSO4); red cells 4,110,000; white cells 4,300, with 76 percent polymorphonuclear cells. Urine was amber in color, reaction acid, specific gravity 1.023, albumin 2+, 8-10 white cells per high-power field, and an occasional granular cast was seen in the centrifugated sediment. The concentration of nonprotein nitrogen was 30 mg. per 100 cc. of blood. The plasma proteins were 6.5 gm. per 100 cc.
Hospital course (chart 5).-In spite of frequent sponging, the patient continued to run a high fever from the fourth to the ninth day of disease. On the fifth day, the maculopapular rash increased, but the macules were still scanty and poorly defined. On the sixth day, the patient became disoriented. On the eighth day he was quite drowsy and vomited twice. His general condition, however, appeared satisfactory. On the ninth day he became semicomatose. The pulse rate had increased to between 130-140 beats per
minute. The blood pressure fell. The respirations were rapid. The neck was resistant to passive flexion. Examination of the heart and lungs was negative. Spinal puncture revealed an initial pressure of 90 mm., and the dynamics were normal. Seven cubic centimeters of spinal fluid was withdrawn. The final pressure was 60 mm. The cell count of the spinal fluid was 5 per cu. mm. The Pandy test was negative. An electrocardiogram showed low voltage of the QRS complexes. The patient was given 1,000 cc. of 5 percent dextrose in saline subcutaneously.
On the morning of the 10th day, his general condition had become critical. There was oliguria; the blood pressure was low; the heart rate still rapid. He was given 100 cc. of concentrated human albumin intravenously. Subcutaneous injections of 0.5 gm. of caffeine with sodium benzoate were given every 2 hours. Slight improvement in his general condition was noted throughout the day, with a decrease in heart rate and a rise in blood pressure. The state of oliguria continued, however. There was no increase in the rash from the fifth day.
On the morning of the 11th day the patient had a generalized convulsive seizure and died.
At post mortem examination 1 hour after death, the interesting findings were as follows: The rash, which had been scanty throughout his illness, was not discernible. No gross areas of pneumonitis were noted in the right lung; the left lung was crepitant throughout; the bronchi appeared normal. The heart weighed 330 gm.; no gross abnormalities were seen on the epicardial or endocardial surfaces; the ventricular walls were
of normal thickness; the coronary arteries were patent. The liver weighed 2,430 gm.; its was grayish in color, firm and rubbery in consistency; the surface was lobulated, with numerous white fibrotic areas in the depressions between the lobules. On section the cut surface was gray. Areas of dense fibrosis were present throughout the organ. Numerous adult schistosomes were obtained from the blood in the portal vein. The spleen weighed 770 gm.; the surface was mottled with numerous white, bluish, and reddish areas, some of which were firm in consistency. On section the pulp was firm and deep red in color. The surface patches extended a few millimeters into the spleen substance and appeared to be demarcated by a narrow zone of hemorrhage.
The right kidney weighed 210 gm.; there were a few pinpoint hemorrhagic spots on its surface. On section the cortex appeared to be slightly pale. The kidney pelvis appeared normal. The left kidney weighed 190 gm., with findings similar to those seen in the right kidney. The ureters appeared normal and patent. The mucosa of the bladder was of light yellowish tint and was thickened. Small areas of hemorrhage were present in the region of the trigone.
The mucosa of the large intestine and rectum showed mottled areas of bluish and brownish discoloration. There were numerous elevated nodules of 0.5 to 0.7 cm. in diameter with smooth surfaces. These were not pedunculated and were pale green to blue black in color. The findings in the liver, bladder, and large bowel were secondary to an extensive Schistosoma infection.
Pathological physiology-The observation that there was a high incidence of nitrogen retention in their typhus cases led Yeomans and his associates to analyze the factors that might contribute to its development. They reasoned that-
* * * a fundamental consideration * * * [is] that the caloric and protein intake of nearly all typhus patients is grossly insufficient. There is good reason to believe that the destruction of the body tissues must be considerable * * *. In order to prevent the accumulation of nitrogenous metabolites in the blood, the excretion of an adequate [amount] of urine * * * is necessary. In the presence of a greatly increased protein catabolism it is apparent that dehydration with a diminished output of urine will have considerable effect upon the degree of azotemia observed.
Another factor * * * in the more critically ill patients * * * is the onset of renal insufficiency, most often associated with a rapid fall in blood pressure. [This] * * * is of serious prognostic import. In our experience * * * the majority of these patients died with evidences of overwhelming rickettsial infection or complicating conditions, such as pneumonia, [but] a rapid diminution in kidney function was almost without exception the first indication that the patient would probably succumb to the disease. The * * * renal insufficiency itself was of more significance than a fall in blood pressure, since at times such a fall was not observed or occurred in the absence of renal failure. At present we have no evidence to indicate that the loss of renal function observed in these critically ill patients was due to other than extrarenal factors.
In French Morocco, Maj. Theodore E. Woodward, MC, of the U.S.A. Typhus Commission collaborated with Maj. (later Lt. Col.) Edward F. Bland, MC, 6th General Hospital, in a study of 30 native patients with typhus fever.8 They draw a composite picture of the pathological physiology of severe typhus as follows:
The patient is acutely ill and very toxic, with a significantly low arterial tension and a labile pulse. Usually, unless actively supported, the patient becomes dehydrated, the
8Woodward, T. E., and Bland, E. F.: Clinical Observations in Typhus Fever, With Special Reference to the Cardiovascular System. J.A.M.A. 126: 287-293, 30 Sept. 1944.
red cells decrease and plasma proteins fall with a considerable loss of the albumin fraction, indicating a reduced colloidal osmotic pressure. All factors indicate a drop of blood volume with the pattern of hypoproteinemia, hypochloremia, and hemodilution without blood destruction. The unstable circulation results in lowered glomerular filtration pressure, and hence oliguria and anuria occur. The kidney, partially damaged by the specific pathologic condition and called on to eliminate an increased amount of nitrogenous waste, is unable to function normally unless adequately supported by fluids. Lowered blood volume means less adequate filling of the heart during diastole and hence lowered cardiac output. Each beat of the heart is less efficient. The use of cardiac stimulants under these conditions is ineffectual, but when the volume of the blood is restored the organ can operate more efficiently.
Woodward and Bland note that the typhus lesion had been demonstrated by Wolback and his associates in heart muscle, in the kidney, and in almost every other organ. However, the degree of both cardiac and renal changes they observed was not disproportionate to the pathological changes occurring elsewhere, and from their clinical studies it appears "unlikely that cardiac failure as such is often a significant factor in the outcome of the fatal case." In treatment, they advocate "general supportive measures to increase the circulating blood volume."
Metabolic studies-These observations focused attention on the azotemia and hypochloremia associated with a high proportion of typhus fever cases. Since a better understanding of electrolytes and protein metabolism was deemed essential for appropriate supportive treatment, Tierney and Yeomans9 undertook metabolic studies in cases of typhus fever on the Commission ward in Cairo.
Tierney and Yeomans determined the carbon dioxide content and the chlorides of the serum in 34 cases. They found the serum chlorides to be low in 62 percent of the patients during the first 2 weeks of disease, but the serum carbon dioxide content was appreciably reduced in only four cases. Explanation was sought for the low serum chlorides in the early stages of typhus. The diets of these patients were probably poor in salt prior to hospitalization, but this was not an important factor since there was no conspicuous chloride deficit in patients admitted to the Commission ward with relapsing fever and typhoid fever. Perspiration was not a factor, as it was rarely observed; indeed, failure to perspire was noted in typhus patients not only in the dry climate of Egypt but also in moist climates. The salt was not lost in the urine, for urinary excretion was in relation to the concentration of chlorides in the serum; when serum chlorides fell below normal levels, the urinary chlorides diminished markedly. The fact that the serum chlorides returned to normal spontaneously in spite of a poor salt intake was taken as evidence that the salt was not lost by the body and that the lowered chloride concentration was therefore due to expansion of the extracellular fluid volume. During the early stage of typhus, the patients frequently have nonpitting
9Tierney, N. A., and Yeomans, A.: Metabolic Studies in Louse-Borne Typhus; Observations on Serum Electrolyte Pattern, Serum Protein Partition, and Nitrogen Balance. J. Clin. Investigation 25: 822-837, November 1946.
edema; in the later stage, shortly before defervescence there is often a fairly marked diuresis. These observations are in keeping with the suggestion that early in the disease there is an increase in extracellular fluids, which would lower the serum chlorides, and later in the disease there is a loss of extracellular fluid by diuresis with a resultant increase in serum chlorides. The pH was normal in all of the patients except one who had renal failure and acidosis. The total base was also normal in all but one of the subjects studied. In all instances, the quantity of undetermined acid anions was increased in the majority of cases equaling that found in severe metabolic acidosis.
The total serum proteins were normal in approximately 75 percent of the patients, but the majority showed a depression of the albumin fraction and a very striking elevation of the globulin fraction to over 40 percent in the average case. An electrophoretic analysis10 of sera obtained from a severely ill patient on the ward of the Cairo Unit of the Typhus Commission showed that the relative proportion of albumin and the albumin to globulin ratio was markedly reduced on the fourth day of fever and through convalescence. The alpha and beta globulins were practically unaffected, but the gamma globulin was strikingly increased on the fourth day and was even higher in convalescence.
Nitrogen balance studies were performed on 21 subjects. Eight of the patients were given high-protein, high-caloric diets; ten, low-protein, low-caloric diets; and three were given a combination of these. It was found that there was no relationship between nitrogen output and intake or between protein destruction and azotemia. A high-protein, high-caloric diet decreased nitrogen wastage and loss of body weight during the acute phase of typhus. Indeed, positive nitrogen balance was achieved in five of the patients studied.
Dietary management-From these and other observations on the Commission ward, the following recommendations were made with regard to management of diet, electrolytes, and fluids in the typhus patient:
1. A liquid diet high in protein and calories should be given. With diligent nursing, the average patient will ingest at least 90 gm. of protein and 2,500 calories a day. If the patient is too ill to take the diet, Amigen may be given intravenously.
2. The routine administration of large amounts of sodium chloride without determining the serum chlorides should be avoided. By including in the diet or in the parenteral fluids 4 to 6 gm. of sodium chloride a day, the serum chlorides should be kept within normal limits and good state of hydration achieved. Usually, the fluid intake should be maintained between 3 and 4 liters daily.
3. The urine output should be at least 1 liter a day, and preferably 1.5 liters. As a marked drop in the urine output is an ominous sign, particularly
10Dole, V. P., Yeomans, A., and Tierney, N. A.: Electrophoretic Changes in the Serum Protein Pattern of a Patient With Typhus Fever. J. Clin. Investigation 26: 298-300, March 1947.
if associated with a fall in the arterial blood pressure, plasma or blood transfusions in such cases are urgently required.
4. In cases of shock or impending shock, plasma or blood transfusions are indicated. The effect of plasma or blood transfusions on hypoalbuminemia is transient. In order to produce any significant change, very large amounts of plasma over a period of days would be required.
5. Acid salts, such as ammonium chloride, are obviously contraindicated because of the increase in undetermined acids in the blood.
Epidemic in Italy-The clinical observations that have been described were carried out under relatively ideal conditions. However, members of the Typhus Commission and other physicians of the U.S. Army Medical Service saw thousands of additional cases under epidemic, and often chaotic, conditions throughout Europe and the Far East. In a few instances, efforts were made to glean clinical data even under the most adverse of circumstances. These reports will be mentioned briefly.
The epidemic at Naples, Italy, during 1943 and 1944 involved some 1,407 cases within the city itself and 492 cases outside Naples. Vigorous application of delousing measures quickly brought this epidemic under control. This historic accomplishment has been detailed by Bayne-Jones.11 Here, it will suffice to note that the case fatality rate was about 22.6 percent. Woodward,12 in his report of the activities of the flying squadron group for typhus control outside Naples, recorded brief observations on 257 cases diagnosed on the basis of clinical findings, along with serological tests. Of interest was the relatively high incidence in children, many of whom showed a characteristic rash and were moderately ill.
Observations in concentration camps-Maj. William A. Davis, MC, while serving as liaison officer from the U.S.A. Typhus Commission to the 21st Army Group, recorded the typhus fever epidemic that occurred at the Belsen Concentration Camp, Belsen, Germany.13 This camp was taken by the British Second Army on 15 April 1945. Among the 61,000 inhabitants, there was widespread suffering from starvation, typhus, dysentery, tuberculosis, and other diseases. Typhus had been prevalent in the camp for 4 months, and there were approximately 3,500 cases at the time of liberation. Practically all of the internees were heavily infested with lice.
Davis stated that the appraisal and diagnosis of cases was peculiarly difficult in this group. Prostration, semistupor, dehydration, loss of weight, weakness, tremors, and a petechial rash, which are considered characteristic of typhus, were so common in the starving, louse-infected people that he
11Bayne-Jones, Stanhope: Epidemic Typhus in the
Mediterranean Area During World II. In Rickettsial Diseases of Man. Washington:
American Association for the Advancement of Science, 1948, pp. 1-15.
found these signs of little value. The rash was mild; very few had ecchymoses, and the usual finding was a scattered petechial exanthem best seen after the patient had been washed. Gangrene was common, particularly dry gangrene of the toes. Pleuritic pain was a frequent complaint in the post-typhus period. About 30 cases of parotitis were observed that required incision. Several patients had polyneuritic leg pains, which may have reflected vitamin B deficiency exacerbated by the increased metabolic demands of fever. No statistics were available on the death rate from typhus fever at Belsen.
Epidemic typhus fever was also prevalent at the Dachau Concentration Camp, Dachau, Germany, when it was liberated by the Seventh U.S. Army on 29 April 1945. Measures were taken to control the disease, and special clinical facilities were made available to the Typhus Commission14 at the 116th Evacuation Hospital. On 16 May 1945, six nurses from the 59th Evacuation Hospital arrived and began their duties on the Typhus Commission Service, a special ward of 64 beds which admitted patients, 83 in all, until 30 May 1945. The ward was closed 9 June 1945. Most of these patients were treated with PABA (para-aminobenzoic acid) or serum therapy as discussed in the section on treatment (p. 192). Here, the data on 121 untreated controls are of interest. These were male patients of various nationalities in the wards of the 116th Evacuation Hospital, ranging in age from 17 to 58 years, with an average age of 28 years. The duration of fever averaged 16.2 days in this group.
Of particular interest is the observation that the typhus fever encountered at Dachau was clinically a mild disease. Fewer patients were seen with full-blown rashes than in other epidemics. There appeared to be less prostration and delirium, and a shorter convalescence. To be sure, there were some severe cases, but not so many as had been expected. The comparative mildness of the disease was surprising to Commission observers who had seen patients in Cairo, Naples, and elsewhere, and had anticipated that the general debility of the Dachau patients would predispose them to a considerable mortality. The fatality rate from typhus for all Dachau hospitals during 9 May to 9 June 1945, was, however, 9.1 percent.
Additional serious outbreaks of typhus fever were encountered among civilian populations in other areas of the European Theater of Operations, U.S. Army,15 and in Japan and Korea,16 but circumstances prevented the undertaking of special clinical studies during these epidemics.
14A Report on the Activities of the U.S.A. Typhus Commission at the Dachau
Concentration Camp, Dachau, Germany, 10 May 1945-10 June 1945, prepared by Lt.
Comdr. A. Yeomans, MC; Maj. C. J. D. Zarafonetis, MC; Capt. D. H. Clement, MC; Lt.
Comdr. R. A. Phillips, MC, USNR; and Lt. Col. J. C. Snyder, MC.
The Disease in Vaccinated Individuals
The remarkable record of low morbidity with no fatalities from epidemic typhus fever in the U.S. Army during the war years, 1942-45, was achieved by taking adequate protective measures against the disease. One of the most important was the compulsory immunization of all soldiers going to areas where epidemic typhus was present or suspected. Accordingly, those few cases that did occur in troops, along with those encountered in certain special studies, offer an unusual opportunity to analyze the modifications of clinical course resulting from vaccination. The value of serological tests in the diagnosis of typhus in vaccinated individuals is implicit in the clinical material to be summarized, although particular consideration of these tests will be left for the section on laboratory methods (p. 179).
The Cox (U.S. Army) vaccine-Early work by Da Rocha-Lima (1918) and Weigl (1920) suggested that killed suspensions of typhus-infected lice or infected louse feces could endow some immunity as vaccines. However, these and other methods advanced for vaccine preparation up to 1938 were not practical for large-scale production. It was a highly significant discovery, therefore, when Cox17 demonstrated in 1938 that rickettsiae could be grown in the yolk sac of the developing chick embryo. Cox and Bell18 soon prepared an epidemic typhus vaccine which consisted of a killed suspension of micro-organisms grown in yolk sacs and purified by centrifugation. Subsequent modifications included an ether-extraction technique devised by Craigie19 and the incorporation of soluble antigen in the vaccine.20 The resultant product was not only satisfactory from the standpoint of potency but was also feasible for commercial production. The final product used by the U.S. Army consisted of a 10-percent yolk-sac suspension of the Breinl strain of R. prowazeki, extracted with ether; it contained both killed microorganisms and soluble substances. Up through 1943, the initial vaccination for U.S. Army personnel consisted of three injections of the vaccine, 1.0 cc. each, administered subcutaneously at intervals of 7 to 10 days, with stimulating doses given every 6 months in endemic areas. As the vaccine was improved in potency through improvement in production, the initial immunization series was reduced in mid-1944 to two doses of vaccine, with
17Cox, H. R.: Use of Yolk Sac of Developing Chick Embryo as Medium for
Growing Rickettsiae of Rocky Mountain Spotted Fever and Typhus Groups. Pub.
Health Rep. 53: 2241-2247, 23 Dec. 1938.
stimulating doses at the beginning and in the middle of the typhus season (1 November and 1 February in the Northern Hemisphere).21
As might be expected, a satisfactory field trial of vaccine of the Cox type was one of the principal objectives of the Typhus Commission when it was formed in 1942.22 In January 1943, the field group of the Commission, with the cooperation of the Egyptian Ministry of Public Health, began a study on the effect of the vaccine in a large number of persons intimately exposed by their occupations to naturally acquired typhus fever. This study was continued through the epidemics of 1943 and 1944. The subjects were employees of the Cairo Fever Hospital at Abassia and the Embaba Hospital. Because of the exceptionally large numbers of patients with typhus being admitted to these hospitals, the hospital staff was unusually exposed to the infection, and in addition many of the employees lived in areas of the city where attack rates were high. Before 1943, these workers had not been vaccinated against typhus. During 1943 and 1944, vaccine of the Cox type was, accordingly, administered to all employees who desired it. Careful records were kept on more than 800 employees at Abassia and over 500 at Embaba. Most of those who contracted febrile illnesses, whether vaccinated or not, were seen by one or more of the Commission members. During the course of these two typhus seasons, a group of 61 postvaccination cases were observed.
Despite the mild course that distinguished many of these cases, Ecke and his associates23 usually found it possible to recognize the disease on clinical grounds alone, and laboratory tests confirmed the diagnosis in almost every case. In some patients, however, the diagnosis of typhus was made only by a rise in titer in the Weil-Felix and complement fixation tests during illness or in early convalescence. The diagnostic significance of these laboratory aids had been worked out by Zarafonetis in studies of 100 known febrile illnesses other than typhus and 16 definite cases of postvaccination typhus. In brief, he found that, on the one hand, nontyphus febrile illnesses do not evoke high complement fixation titers in the sera of patients who have had multiple doses of vaccine of the Cox type. On the other hand, typhus infections regularly do stimulate high complement fixation titers in the sera of vaccinated patients. Similar results were usually obtained with the Weil-Felix test. So interpreted, these laboratory aids could be relied upon in those cases where the clinical evidence alone was inadequate for diagnosis, either because of inconspicuous symptoms or insufficient observation (p. 179).
21Sadusk, J. F., Jr.: Typhus Fever in the United States Army
Following Immunization: Incidence, Severity of the Disease, Modification of the
Clinical Course, and Serologic Diagnosis. J.A.M.A. 133: 1192-1199, 19 Apr. 1947.
These postvaccination cases were arbitrarily classified in the categories devised for typhus in nonvaccinated persons (p. 145) with, in addition to B, C, D, E, and F groups, an A group for cases "so mild that a definite diagnosis of typhus on clinical evidence alone was not possible, the final diagnosis being made only with the aid of laboratory data." The cases were further grouped according to the amount of vaccine received and the interval between the last inoculation and the onset of illness.
The course of typhus fever in vaccinated Egyptians was recorded by the Typhus Commission observers, as follows:
Group 1 (three doses of vaccine at least 21 days prior to onset).-Clinical notes from the records of five patients who were thoroughly studied on the Commission ward illustrate some of the features of postvaccination typhus.
Case 1.-Three doses of vaccine, the last dose 39 days before onset. Male, aged 45 years. This patient had a severe chill the first day combined with frontal headache and, later, joint pains. Rash was moderate. His mild course was marked latterly by the development of bilateral costovertebral pain and microscopic hematuria. After 12 days of moderate elevation of temperature he continued to maintain a low-grade fever until the 21st day. (The importance of his hematuria in relation to typhus is not clear: Bilharzia infection is widespread in Egypt.) Clinical classification of severity: B.
Case 2-Five doses of vaccine, the last dose 117 days before onset. Male, aged 26 years, Typhus Commission field worker. He had rather severe headache and malaise. The rash was fleeting but definite. With the history and the rash no difficulty was experienced in making the diagnosis, though the course was mild. Fever lasted 9 days. Clinical classification of severity: B.
Case 3-Three doses of vaccine, the last dose 87 days before onset. The patient, male, aged 45 years, appeared to be at least 55. He was never especially ill during his course. He developed a tremor of his limbs, almost parkinsonian in character. This disappeared during convalescence. Fever lasted 12 days. Clinical classification of severity: B.
Case 4-Three doses of vaccine, the last dose 103 days before onset. Male, aged 18 years. This case was a problem in diagnosis. Moderately ill; said he felt "weak," but had no specific complaint. There was nothing to be found but a very few fleeting macules requiring careful search. There was no conjunctival injection. Fever lasted 10 days. Clinical classification of severity: B.
Case 5-Five doses of vaccine, the last dose 79 days before onset. An obese male, aged 33 years. He complained of generalized body pains, especially in the knees, and said he felt "feverish." He had severe headache. There was some tinnitus and slight deafness. His course was mild. Fever lasted 8 days. Clinical classification of severity: B.
The average duration of fever for all the patients in group 1 was 10½ days. The cases were classed as follows: 1 in A, 20 in B, 5 in C, none in D, E, or F. Fifteen of the patients were females, average age 22.7 years; 11 patients were males, average age 31.8 years.
Group 2 (two doses of vaccine at least 21 days prior to onset).-The seven patients in group 2 had an average duration of fever of 12 days. The cases were classed as follows: 4 in B, 3 in C. Four patients were females, average age 19 years. Three patients were males, average age 28 years.
Group 3 (one dose of vaccine at least 21 days prior to onset).-The 11 patients in group 3 had an average duration of fever of 12.7 days. The cases
were classed as follows: 2 in B, 8 in C, and 1 in D. Five patients were females, average age 21 years. Six patients were males, average age 34 years.
Group 4 (onset of typhus less than 12 days after first dose of vaccine).-There were 17 patients in group 4. The average duration of fever in the nonfatal cases was 15 days. The cases were classed as follows: 4 in B, 8 in C, 4 in D, and 1 in F. There were 12 females, average age 23.6, and 5 males, average age 27.8 years.
In discussing these results, Ecke and his coworkers pointed out that, before the vaccination program was undertaken, typhus fever among the employees of the Cairo Fever Hospital was characteristically severe. The relatively few employees who remained unvaccinated and contracted typhus during the study period were likewise severely stricken. By contrast, among those who had received two or more doses of Cox vaccine 21 days or more before the onset of illness (groups 1 and 2), there were no severely ill patients, that is, D, E, or F cases, whereas two-thirds of the unvaccinated patients in the same age groups fell into the severe groups, D, E, or F. (Compare with the 64 nonvaccinated cases summarized on p. 147.) On the basis of these observations, and insofar as attenuation of clinical course is concerned, it was postulated that adequate vaccination against typhus could be defined as two or more doses of Cox-type vaccine of standard potency administered more than 21 days before the onset of typhus.
On the basis of their observations during this study, Ecke and his coworkers recommended that vaccination be included in epidemic control programs.
Sadusk24 consolidated much of the information regarding epidemic typhus fever that occurred in U.S. Army personnel subsequently to immunization. His report contains details of five cases, three in members of the Typhus Commission. These case histories will illustrate the course of typhus fever in vaccinated Americans and, at the same time, will serve as a reminder of the added health hazards to which medical officers are at times exposed in line of duty.
Case 1-A 41-year-old male officer, member of the U.S.A. Typhus Commission, for almost a month before the onset of illness was engaged in typhus research work in Cairo, Egypt, together with the officer described in case 2. They were both daily exposed to infection with typhus by examining patients, picking infected lice off rabbits and patients, and handling and grinding infected louse feces for injecting into experimental animals. During the preceding 2 years, this officer had received a total of 22.0 cc. of vaccine in single 1.0 cc. doses. Five cubic centimeters of this vaccine was of an experimental lot and contained both epidemic and murine virus. The last dose of vaccine was given on 1 March 1944.
On 21 May 1944, the patient had a mild headache, general malaise, and felt feverish. Although the headache became more severe and the temperature ranged between 100.0° and 101.0° F. during the next 3 days, he continued his work. On the sixth day, 26 May,
24See footnote 21, p. 157.
he took to his bed because of headache, fatigue, and malaise. Backache was marked. The next day he reported to a medical dispensary where physical examination revealed a few pink papules on the left palm and wrist, a temperature of 99.2° F., and a pulse rate of 100. The rash had disappeared by the following morning and except for a mild headache, anorexia, and sense of fatigue, the patient did well on bed rest in his quarters, reporting daily to the dispensary. He was afebrile by 27 May (7th day) and was permitted to remain out of bed on 31 May (11th day).
Prior to the onset of typhus, on 21 March and 4 April 1944, the Weil-Felix reaction was negative with both Proteus OX-19 and OX-2 antigens and the complement fixation titer was 1:8 with epidemic antigen and 1:4 with murine antigen. By the end of the first week of disease the Proteus OX-19 titer rose to 1: 20, and in the second week it rose to 1: 80. It reverted to negative in the fourth week. The complement fixation titer rose rapidly to a high of 1: 1,024 in the second week. More than 2 years later, the complement fixation (with epidemic antigen) was still positive with a titer of 1: 10.
Case 2-A 35-year-old male officer, member of the U.S.A. Typhus Commission, was engaged in typhus research work in Cairo with the patient described in case 1, for a month prior to onset of illness. Although exposed daily, he recalled that he was dangerously exposed on 11 June 1944 when he assisted with the handling and grinding of infected louse feces in large amounts. During the period from 23 December 1941 to 10 October 1943, he received a total of 12.0 cc. of typhus vaccine in 1.0 cc. increments. On 22 November 1943 he received 1.0 cc. epidemic typhus vaccine and on 10 April an additional and final dose of 1.0 cc. of vaccine. Although the Weil-Felix reaction was negative with both Proteus OX-19 and Proteus OX-2 antigen, the complement fixation titer with epidemic antigen was 1: 8, 3 days before and 11 days after the last dose of vaccine.
On 23 June 1944, the patient awakened in the morning with a mild but troublesome frontal headache which persisted through most of the day, and the following day recurred together with malaise and easy fatigability. His temperature was 101.0° F. As these symptoms persisted with an increase in both severity and extent of the headache, he was admitted to the hospital late in the afternoon of the next day, 25 June. The following day his temperature was 100.4° F., pulse rate was 80, respiratory rate 20, blood pressure was 106 systolic and 60 diastolic. Although he did not appear acutely ill, he complained of headache, chilly sensations, and nausea. Physical examination revealed only a marked injection of the scleral conjunctivae. Later in the afternoon his temperature rose to 102.0° F. and a diffuse macular eruption appeared over the anterior chest, arms, shoulders, and flanks with an erythematous blush that disappeared upon pressure. He continued that afternoon and night to have slight chills. By the next morning the rash had definitely faded but his headache, which was now generalized, became exceptionally severe. Chills continued, and he appeared quite ill. There were intermittent, drenching sweats, and he complained of severe backache and general malaise. The temperature rose to 103.2° F. that night with a pulse rate of only 90. The respiratory rate was normal. Although the temperature fell to 99.2° F. the following morning (28 June) and remained below 100.6° F. throughout the course of the day, severe headache, malaise, sweating, and occasional chills persisted. He vomited several times and on one occasion there was a transient amnesia. During the course of the next 2 days, these symptoms persisted but the temperature remained relatively low and the rash became increasingly less evident, and disappeared completely by 1 July. On 29 June the physician reported that the patient appeared to be disoriented for a brief period but this was not confirmed and was later denied by the patient. From 30 June on, there was rapid and progressive improvement, as illustrated in chart 6, with rapid fall in temperature by lysis, subsidence of headache, malaise, nausea, and vomiting, and rapid increase in serological titers for typhus fever. On 30 June, there was a left earache which disappeared within 48 hours without specific
therapy. Temperature was normal by 3 July. On 5 July he was permitted out of bed and was discharged on the following day as an ambulatory patient.
During the course of the patient's stay in the hospital, there was no marked hypotension. On 25 June, the day of admission, the red cell count was 4,600,000, the hemoglobin was 95 percent, and the leukocyte count was said to be 6,300 with 45 percent stab cells, 33 percent polymorphonuclear neutrophils, 20 percent lymphocytes, and 2 percent monocytes. On 3 July the blood count was as follows: red cells 4,650,000, hemoglobin 95 percent, leukocytes 5,600 with 15 percent stab cells, 53 percent polymorphonuclear neutrophils, 18 percent lymphocytes, and 14 percent monocytes. Urine examination on 26 June was negative. It was clear amber and specific gravity was 1.010. Tests for albumin and sugar were negative.
Serological tests were performed daily during the acute phase of the disease. The Weil-Felix reaction with Proteus OX-19 antigen remained negative until the eighth day when it became positive in a titer of 1:20. It then rose rapidly reaching a top figure of 1:1,280 on the 19th day. It was still positive at 1:80 on the 124th day but when next checked, almost 2 years after the onset of the disease, it was found to be negative. Complement fixing antibodies began to rise by the end of the first week of disease, reaching a peak with epidemic antigen of 1: 512 by the 19th day. The titer began to fall after the
31st day and when last checked almost 2 years later, the titer was still positive at 1: 20. Specific rickettsial agglutinations were negative at that time. The temperature and pulse record, along with other pertinent findings during the acute phase of this patient's disease, are shown in chart 6.
Case 3-A 36-year-old male officer, member of the U.S.A. Typhus Commission, was engaged in typhus control work in Hokkaido, Japan. On 10 November 1945, he was heavily exposed in the room of a Japanese hospital to dust containing suspended louse feces from the clothing of a patient with active typhus. From 17 February to 28 July 1944 he had received a total of 4.0 cc. of typhus vaccine in 1.0 cc. doses. On 9 May and 1 October 1945, he received additional 1.0 cc. doses of the vaccine. On 6 June and 4 August 1945, serology was as follows: Weil-Felix negative, complement fixation 1: 10 with epidemic antigen and negative with murine antigen, and rickettsial agglutination 1: 40 with epidemic antigen and negative with murine antigen.
On 22 November 1945, the patient experienced chilly sensations and generalized malaise. The following day headache, apathy, anorexia, and irritability appeared. These persisted during the next 2 days with chilliness, and although he felt feverish he did not take his temperature. On the fifth day, his temperature was 101.8° F., pulse rate was 88, and respiratory rate was 20. Headache became more severe and was predominately bitemporal. A persistent dry hacking cough set in and he vomited once. The next day, sixth day of disease, he refused hospital admission but finally took to bed in his quarters. Headache became excruciating in severity, temperature rose to 102.2° F., and nausea and cough persisted. Although the temperature rose to 103.8° F. the night of the seventh day and he became drowsy, there was suddenly a feeling of relative well being the following day with sudden resolution of fever by crisis and profuse sweats. He was afebrile by the 9th day, and was out of bed on the 10th day, and back to work on the 13th day, although he tired easily on exertion. The blood pressure remained normal throughout and there was no rash. The lungs were clear.
The leukocyte count on the seventh day was 5,000. On the 13th day complete blood count at an outpatient clinic showed 4,620,000 red cells, 90 percent hemoglobin, and 6,600 leukocytes with a differential of 64 percent segmented neutrophils, and 36 percent lymphocytes. On the 12th day, urine was negative except for a faint trace of albumin with a few leukocytes in the microscopic examination. These findings had disappeared by the following day. On the 21st day, electrocardiographic tracing was normal in all four leads. The heart rate was 84, the PR interval was 0.16 second, sinus rhythm was present, QRS complexes were 0.06 second, T waves were upright in all leads, and there were no ST changes.
The serological changes are given in detail in table 15. Briefly, Weil-Felix reaction became positive on the 7th day with a titer of 1: 40 and reached as high as 1: 80 by the 14th day. The complement fixation with epidemic antigen began to rise by the end of the first week, reached its peak at 1: 1,280 at the end of the third week, and was still positive by the ninth month. Rickettsial agglutination did not rise until the second week but reached its peak at that time with a titer of 1: 640 with epidemic antigen. It was still positive by the ninth month.
The pertinent serological data on the three cases just mentioned are given in table 15, and the essential clinical features of these and two other vaccinated cases are summarized in table 16. Of particular interest is the method of infection. In each instance, there was evidence to indicate inhalation or conjunctival absorption of infected louse feces.
Sadusk's report was in keeping with other observations that the clinical course of epidemic typhus is greatly modified when infection occurs subsequently to vaccination (chart 7). Fever is much lower and of shorter duration than in nonvaccinated cases, the extent and duration of rash are diminished, circulatory and nervous symptoms are lessened, and the incidence of complications is minimal. If hospitalization is necessary, the length of it is reduced. The only symptom that is regularly present in vaccinated cases is severe headache.
Following is the only case known to have occurred in our troops in Sicily.25 The patient, a private with the 77th Field Artillery, was admitted to the 59th Evacuation Hospital, Palermo, Sicily, in the summer of 1943. His history and clinical course were recorded by Lt. Col. (later Col.) William A. Reilly, MC, Chief of Medical Service, as follows:
A private claimed he was immunized against typhus in June 1941, and a recall dose was given in June 1943. No record was obtainable. He left Africa on 13 July, after a
25(1) Dr. Stanhope Bayne-Jones kindly brought this case report to the attention of the author and made the records available for inclusion here. (2) Letter, Lt. Col. William A. Reilly, MC, Chief of Medical Service, 59th Evacuation Hospital, to Commanding Officer, 59th Evacuation Hospital, North African Theater of Operations, U.S. Army, 21 Sept. 1943, subject: Resume of Typhus Patient's History, Photo, and Chart.
long stay, and arrived in Sicily on 14 July 1943. He does not know of having been bitten by ticks, lice, or fleas.
He was taken ill on 23 August with headache, injected eyes, and fever. Fever disappeared by lysis on 2 September (chart 8). On the third day of disease, 26 August, a maculopapular rash appeared on the trunk, thighs, and arms, gradually increasing in amount, intensity and distribution for the next 5 days and being heaviest on the limbs (fig. 11). In spots it was petechial and hemorrhagic and did not fade on pressure. No tache noir or regional lymphadenitis was detected. There was a macular rash on buccal mucosa. The pharynx was slightly reddened. Between the fourth and eighth day, the enlarged spleen was palpable. On the third and seventh day, he had 5,100 and 7,500 WBC normally differentiated and urine specimens were negative except for low specific gravity. The boy was very ill, lost weight and strength. There were a few loose bowel movements between the seventh and ninth days. A blood culture on the fifth day was negative. Weil-Felix tests with the three Proteus types were entirely negative on the ninth day in an Italian laboratory. On the 11th day, the Proteus OX-19 was positive 1: 40, Proteus OX-2 was positive 1: 160, and Proteus OX-K was negative. A third Weil-Felix test, on the 18th day of disease (10 September) showed a rising titer: OX-19 was positive 1: 640, OX-2 was positive 1: 1,280, and OX-K was negative. A guinea pig inoculated on the 11th day, when temperature was normal for the first time, did not develop scrotal reaction. After fever subsided, the patient gradually recovered strength, weight, and appetite. No complications or sequelae were present 1 month after onset.
Only three confirmed cases of typhus occurred among U.S. troops serving in the European theater, despite its prevalence among the civilian populations.26 Two infections were contracted in the Rhineland and one in the Inner Reich. All three patients had mild attacks of the disease, as indicated by the following brief case summaries:27
Case 4.-A captain of the Medical Corps investigated a typhus outbreak at Fischbach, Germany, on 23 March 1945. He was intimately exposed to the disease while examining and disinfecting patients but does not recall ever having found lice on his person. On 9 April, he developed a macular rash. He was never delirious, stuporous, or disoriented. His convalescence was rapid and uneventful. A Weil-Felix test on 17 April was positive in a serum dilution of 1: 640. The patient had not received a stimulating dose of typhus vaccine since the original course in April 1944.
Case 5-A lieutenant colonel, Medical Corps, accompanied the officer noted in case 4 (above) and both became ill on the same day. This patient's illness was even less severe, with no rash at any time. He remained on quarters status, and returned to duty 15 April. A stimulating dose of typhus vaccine had been administered on 23 March 1945, the day previous to his exposure to the disease. The stimulation antedating that was in September 1944.
Case 6-A sergeant of the 15th Infantry became ill 4 April 1945 complaining of pains in the legs, headache, and fever of 102° F. He was admitted to hospital and observed for several days. On 22 April he was transferred to a general hospital with the diagnosis still undetermined. The patient had daily chills with fever up to 104° F. for 11 days and at one time developed a slight rash on the wrists, ankles, and abdomen. A Weil-Felix test performed 5 May was positive in dilution of 1: 320. No likely source of infection could be determined and there was clinical difference of opinion as to the identity of the disease.
26See footnote 15, p. 155.
The Craigie (British Army) vaccine.-The cases of typhus fever acquired after vaccination that have thus far been described occurred in soldiers who had received vaccine of the Cox type employed in all U.S. Armed Forces, containing, as has been noted, soluble antigen and killed rickettsial micro-organisms of epidemic typhus (R. prowazeki). British troops, on the other hand, were inoculated with the Craigie vaccine, which consisted of two parts of epidemic (R. prowazeki) and one part of murine typhus (Rickettsia mooseri) antigens. Soluble substances as well as killed micro-organisms were included in the Craigie vaccine. In Germany, observing the typhus epidemic at Belsen, Davis28 also had an opportunity to estimate the value of this vaccine under epidemic conditions, collecting data on 14 cases of typhus in British personnel who had been vaccinated more than 24 days before the onset of their fever. Their clinical courses were milder and shorter than is seen in typical epidemic typhus in nonvaccinated persons, with no deaths and no serious complications. He noted as significant "the absence of serious complications * * *. Parotitis, gangrene, conjunctivitis, deafness due to typhus, epistaxis, pulmonary consolidation, and pleuritic pains were never observed in the British, although all were to be seen in the typhus patients from the concentration camp. Their rash was never extensive, rarely developed into true petechiae which would not blanche on pressure, and never formed ecchymoses. Delirium was observed in only 2 cases, and in these it was brief. Roentgenograms of the chest were reported as normal or 'marked increase in bronchovascular markings throughout both lungs.'" Determinations of blood nonprotein nitrogen were made on 10 patients about a week after the onset of fever. Values ranged from 21 to 42 mg. percent in these cases.
Davis also made observations on 16 cases of typhus in Hungarian soldiers who had only one or two doses of Craigie vaccine after exposure to typhus at Belsen and 41 cases of typhus in well-nourished Germans who had no vaccine. From a comparison of the three groups as shown in table 17, and other data, it was concluded that Craigie vaccine was of definite value in shortening the course and reducing the severity of epidemic typhus fever when given in two or more doses from 24 to 100 days before the onset of the disease.
The course of epidemic typhus fever was thus shown to be modified favorably by prior vaccination with vaccine of either the Cox or the Craigie type. The observations regarding the effectiveness of these two vaccines, however, were not made under controlled or even similar conditions, and it is not possible to draw conclusions as to their relative effectiveness from these data.
28Davis, W. A.: Typhus at Belsen. II. Clinical Course of Epidemic Typhus in Persons Who Had Received Craigie Typhus Vaccine. Ann. Int. Med. 34: 448-465, February 1951.
Source: Modified from Davis, W. A.: Typhus at Belsen. II. Clinical Course of Epidemic Typhus in Persons Who Had Received Craigie Typhus Vaccine. Ann. Int. Med. 34: 448-465, February 1951.
Two important studies of the pathology of epidemic typhus fever were undertaken during World War II. The first of these,29 by Maj. Arthur C. Allen, MC, and Dr. Sophie Spitz, at the Army Institute of Pathology (now Armed Forces Institute of Pathology), Washington, D.C., entailed a comparison of the histological preparations and protocols of 78 cases of scrub typhus (tsutsugamushi disease), 24 cases of epidemic (louseborne) typhus, 12 cases of Rocky Mountain spotted fever, and lung sections of 2 cases of American Q fever. Since the principal emphasis of this study was placed on the changes induced by scrub typhus, the main findings of the authors are given in the chapter dealing with that infection (p. 132). However, a number of other observations were made which are relevant here. The histology of the cutaneous lesion is described, as follows:
The macule of epidemic typhus histologically was essentially similar to that of scrub typhus, although several differences were found. In the first place, although capillary thrombi were present in all of the available sections of macules of scrub typhus as against only 15, or 65 percent, of the macules in epidemic typhus, the thrombi were considerably more conspicuous in the latter disease. They were more prominent not only because more thrombi occurred in a single section, but because they were larger and were associated with more pronounced endothelial changes. In epidemic typhus, the affected endothelial cells tended to be larger, more hyperchromatic, and more often disintegrated into chromatin dust, the last being a feature observed also in the capillaries of other organs, including the glomerular capillaries. Secondly, there was a tendency to the occurrence in epidemic typhus of a necrotizing arteritis and thrombo-arteritis, not found in scrub typhus. The necrosis might extend through the entire wall of the artery, unlike the lesser degree of involvement that is stated to occur in the experimental animal infected with
29Allen, A. C., and Spitz, S.: A Comparative Study of the Pathology of Scrub Typhus (Tsutsugamushi Disease) and Other Rickettsial Diseases. Am. J. Path. 21: 603-681, July 1945.
the rickettsiae of epidemic typhus. Indeed, in the human skin of cases of epidemic typhus there may be infarct-like hemorrhagic suppurative necrosis of the portions of corium in association with severe arteritis. Thirdly, whereas no significant changes were noted in the epidermis of the macule of scrub typhus, minor changes consisting of focal spongiosis, patchy parakeratosis and focal "liquefaction degeneration" of the basal layers were infrequently observed in the skin of patients with louse-borne typhus.
The interstitial myocarditis and interstitial pneumonitis of epidemic typhus were intermediate in intensity between that produced by scrub typhus and by spotted fever.
Changes in the adrenal glands of patients with epidemic typhus were similar to those of scrub typhus, except that there was a more conspicuous focal mononuclear reaction. In addition, a few cases of epidemic typhus exhibited inflammatory and degenerative changes of capillaries and arterioles of both parenchymal and adventitial tissues.
Similarly, lesions in the kidneys from patients with epidemic typhus qualitatively resembled those of scrub typhus but were considerably more pronounced. "Acute diffuse glomerulonephritis was found in 18, or 78 percent, of the cases; acute focal glomerulitis in 3, or 13 percent, and essentially normal glomeruli in 2, or 9 percent. The glomerular alterations were basically those of scrub typhus, differing in more marked swelling and hyperchromasia of the endothelial cells, more frequent occurrence of thrombosis of the glomerular capillaries and fragmentation of the endothelial cells. Similarly, focal interstitial infiltrations, calcific bodies, hemoglobin casts of the distal convolutions, and phlebitis, arteritis, and arteriolitis were more conspicuous in epidemic typhus."
A comparison was made between reactions in the brain and meninges in epidemic and scrub typhus. It was found that-
1. Although the meningitis of scrub typhus is slightly more frequent and extensive than the qualitatively similar reaction in epidemic typhus, the involvement of the substance of the brain is considerably greater in the latter disease.
2. The distribution of lesions in the gray and white matter in the two diseases is the same: in both the white matter is spared, in contrast with Rocky Mountain spotted fever.
3. In the current series the case incidence of involvement of the cortex in epidemic typhus is much greater than in scrub typhus. The actual concentration of nodules in the pons, medulla, and basal ganglia in epidemic typhus is more pronounced than in the cortex. The pons and medulla are sites of predilection also in scrub typhus.
Several distinct histologic differences between scrub typhus and epidemic typhus are noted:
4. The nodules tend to be larger in epidemic typhus, averaging 55 to 75 cells as against 15 to 40 cells, and about 120 to 180 μ as against 60 to 120 μ.
5. There is somewhat greater cellular pleomorphism in the nodules of epidemic typhus, especially in the larger. Karyorrhexis is common in the cells of the nodule of epidemic typhus and rare in that of scrub typhus.
6. In epidemic typhus, the capillaries of the nodules show much more obvious evidence of damage in the form of markedly enlarged endothelial cells, karyorrhexis of endothelial cells, and thrombosis of capillaries. Similar changes are found in arterioles without associated nodules.
The character of the tissue reaction in these cases, such as fibrinoid degeneration of collagen, necrosis of lymph nodes and spleen, the predominance of plasma cells and basophilic macrophages, and the acute glomerulo-nephritis, led these observers to postulate that rickettsiae may exert hyperergic effects in addition to the better known diffuse vascular phenomena caused by them.
The second important investigation of the pathology of epidemic typhus was initiated by the collection of material from 23 fatal cases studied by the U.S.A. Typhus Commission in Cairo, Egypt, during 1943-45, which was reviewed by Spitz and Allen. This, along with material from additional cases, was subsequently studied by members of the Committee on Pathology, Division of Medical Sciences, National Research Council, in collaboration with the Armed Forces Institute of Pathology. The splendid report30 of this group was not issued until 1953 but because of its broad scope and pertinence to other work discussed in this chapter, the summary statement of this study is quoted, as follows:
This paper describes the lesions encountered in an epidemic of typhus which occurred in Cairo during 1943-1945. The findings have been compared to those observed by Wolbach, Todd, and Palfrey in the Warsaw epidemic of 1918 and by others since that time in order to bring together in one report all the known facts abort the pathology of epidemic typhus.
The patients studied in the Cairo epidemic were Egyptians between the ages of 10 and 70 years. Some of them were undernourished, but there was no clinical or pathological evidence of avitaminosis, and some had clinically inactive schistosomiasis. The patients were admitted to the hospital during the first 2 weeks of their disease, and the clinical diagnosis of louse-borne typhus was confirmed in many cases by the Weil-Felix and complement fixation tests. In same instances rickettsiae were recovered from blood or from normal lice fed on the patients, and each strain isolated showed the characteristics of louse-borne typhus. Two patients were given para-aminobenzoic acid, without clinical or pathological effects. The other patients received no specific antityphus treatment, and none had been vaccinated against typhus. In 14 patients special efforts were made to reduce secondary bacterial infection by using sulfonamides and penicillin when necessary. This paper and the reports of the United States of America Typhus Commission on the clinical and laboratory features constitute one of the few comprehensive accounts of an epidemic of typhus in Egypt or, indeed, in any tropical country. It seems likely, in view of the discovery of antibiotics that may be effective in the treatment of the disease and of the development of satisfactory vaccines, that there may never again be a similar opportunity to study an epidemic of typhus which has not been significantly modified either by treatment or by complicating infection.
The lesions discovered in the Cairo patients were essentially the same as those described in other epidemics in different parts of the world and in experimental animals. The wide dissemination of vascular and other lesions in the skeletal muscles, which was well illustrated by the frequent involvement of the muscles of the tongue, was more apparent in Cairo cases than in others, probably because abundant material was available for microscopic examination. Evidence was obtained by the demonstration of rickettsia-
30Pathology of Epidemic Typhus; Report of Fatal Cases Studied by the United States of America Typhus Commission in Cairo, Egypt, During 1943-1945. Prepared by the Committee on Pathology, Division of Medical Sciences, National Research Council With Collaboration of the Armed Forces Institute of Pathology. Arch. Path. 56: 397-435, October; 512-553, November 1953.
like bodies in sections of the lungs, which suggests, but does not prove, that a true rickettsial pneumonia may exist. Interstitial orchitis and prostatitis of a type not ordinarily seen in other infectious diseases was also observed.
New information has been obtained concerning the topography of lesions in the central nervous system and the effect of the duration of the illness on the intensity of the reaction. So-called microinfarcts have been demonstrated for the first time in the brains of patients who died from epidemic typhus.
Glomerulonephritis did not occur in the Cairo patients, and a review of published articles has led to the conclusion that its occurrence has not been proved. The bulk of the evidence supports the idea that renal failure in epidemic typhus is probably due to extrarenal factors, such as increased protein catabolism, dehydration, and reduction of arterial blood pressure, rather than to primary renal damage brought about by direct action of the rickettsiae. We have not been able to convince ourselves that lower nephron nephrosis occurs.
The pathological observations that have been briefly described here are well illustrated in the Committee's report; selected prints are reproduced as figures 12 through 32, through the courtesy of the Archives of Pathology.
FIGURE 16.-(Lower left) Same case as shown in figure 15. Occlusion of capillary in tongue by swelling and necrosis of endothelium. Pronounced exudation of mononuclear cells in the surrounding tissues. (X 875)
FIGURE 26.-(Top) Mononuclear infiltrate in corticomedullary junction of kidney. Numerous cells have abundant basophilic cytoplasm and an eccentrically placed nucleus similar in chromatin pattern to that of plasma cells. Some of these are within the lumen of the small vessel, and the remainder are interstitial between the renal tubules. Numerous red blood cells are visible in the neighboring loops of Henle. The patient was a 30-year-old male, the duration of whose illness was not known. (X 400)
DEVELOPMENT AND USE OF LABORATORY AIDS IN DIAGNOSIS
Along with the advances in louse-control measures and immunization, and extension of fundamental knowledge of the clinical and pathological aspects of the disease, progress was also made during World War II in the development of diagnostic laboratory procedures for epidemic typhus fever. The most active work in this connection was performed at the Division of Virus and Rickettsial Diseases, Medical Department Professional Service Schools, Army Medical Center, Washington, D.C., at the Cairo Unit of the U.S.A. Typhus Commission, and at the National Institutes of Health in Bethesda, Md.
Weil-Felix test-In 1916, Felix31 demonstrated that sera from patients with epidemic typhus fever would agglutinate suspensions of Proteus microorganisms. Although it was soon recognized that these bacteria were not etiologically related to typhus fever, the agglutination of Proteus organisms was quickly developed into a diagnostic test for typhus. Further study revealed that Proteus vulgaris organisms could be dissociated into a motile flagellated "H" type and a nonmotile unflagellated "O" type. The diagnostic agglutinin that appears in the blood of typhus fever patients is the somatic "O" type. Additional experience prior to World War II indicated that suspensions of the Proteus OX-19 strain were agglutinated by sera from typhus fever cases; that OX-19 and another strain, Proteus OX-2, were often agglutinated by Rocky Mountain spotted fever sera; and that suspensions of still another variant, Proteus OX-K, were agglutinated by scrub typhus sera (p. 133). There remained, however, conflicting statements as to the time of appearance of the agglutinins during the course of illness, and concerning what constituted a significant or diagnostic titer. Accordingly, early in 1943, Plotz sought to determine the rise and fall of the various types of demonstrable antibodies in cases of epidemic typhus fever. Serial serum specimens were obtained from 32 untreated and unvaccinated typhus fever cases studied by members of the Typhus Commission in Cairo. Blood specimens were obtained early in the disease, during the course of illness, and as long after convalescence as possible. It was thus possible to establish patterns of antibody dynamics in cases confirmed, in 21 instances, as epidemic typhus by isolation of the strain. The results of the various serological tests performed on these sera were summarized in an important series of papers from the Army Medical School.32
31Felix, A.: Die Serodiagnostik des Fleckfiebers.
Wien. klin. Wchnschr. 29: 873-877, 13 July 1916.
In these cases, there was usually a high Proteus OX-19 agglutination titer, a low OX-2, and a negative OX-K reaction. A rise in titer was found in all cases when early and late specimens were compared. A test was regarded as having diagnostic significance when the titer rose fourfold, occurring, in this group of cases, by the 5th to the 13th day of disease. Tests on followup sera showed that the titer had fallen to insignificant levels within about 3 months after the onset of illness. Table 18 shows the characteristic pattern as observed in one of these patients.
Source: Wertman, Kenneth: The Weil-Felix Reaction. In Rickettsial Diseases of Man. Washington: American Association for the Advancement of Science, 1948, pp. 184-189.
Using the identical macroscopic agglutination technique as employed in the Division of Virus and Rickettsial Diseases, Zarafonetis33 performed Weil-Felix tests on 1,002 sera from 203 cases of epidemic typhus fever. Two or more serum samples were tested from each of the patients who had been studied clinically in Egypt, Greece, Yugoslavia, and the Dachau Concentration Camp in Germany. All of these patients had survived their disease, and sufficient time had elapsed for the development of antibodies if they were to appear in amounts detectable by these tests. A summary of the
(4) Plotz, H., and Snyder, J. M.: The
Serological Pattern in Epidemic Typhus Fever. IV. Rickettsial Agglutination.
Division of Virus and Rickettsial Diseases, Army Medical School, Army Medical
Center, Washington, D.C., 1944. [Official record.]
Proteus OX-19 agglutination results is given in table 19. An agglutination titer of 1: 160 or more developed in 191 (or 94 percent) of these subjects. Sera in five cases were entirely negative, sera in four others gave complete agglutination only to a dilution of 1: 40, and in three more, to 1: 80. Of interest was the finding that the complement fixation tests yielded diagnostic titer changes in all of these patients. Thus were the Weil-Felix and complement fixation reactions found to be dissociated phenomena. A similar dissociation was also demonstrated for the Weil-Felix and rickettsial agglutination responses. (See p. 185.) This significant observation is illustrated in table 20.
1Complete agglutination in dilution given.
Wertman34 summarized the wartime experience with the Weil-Felix reaction and constructed the following table to indicate the usual findings in the various rickettsial diseases of man (table 21). He pointed out that, despite the introduction of specific diagnostic reagents, the Weil-Felix reaction remained a valuable laboratory aid, as follows:
* * * The value of the Proteus agglutination test is that these antibodies appear somewhat earlier than the specific ones. The antigen is easy to prepare and the technic can be performed in any diagnostic laboratory. It should be emphasized, however, that a significant test is one in which a rise in antibody titer can be demonstrated and no single titer should be regarded as significant. Since one rickettsial disease cannot be differentiated from another by means of this test, it must be regarded as only a diagnostic aid. The demonstration of the presence of specific antibodies, either complement fixing or rickettsial agglutinating, is necessary to establish a final serologic diagnosis.
34Wertman, Kenneth: The Weil-Felix Reaction. In Rickettsial Diseases of Man. Washington: American Association for the Advancement of Science, 1948, pp. 184-189.
1End point titer was not reached.
Source: Wertman, Kenneth: The Weil-Felix Reaction. In Rickettsial Diseases of Man. Washington: American Association for the Advancement of Science, 1948, pp. 184-189.
Wertman further describes the limitations of the Weil-Felix reaction:
In the first instance, it is impossible to differentiate epidemic typhus, murine typhus, and Rocky Mountain spotted fever by this technic. * * * Secondly, positive reactions have been reported with sera from cases other than those of rickettsial origin. * * * Lastly, the Proteus agglutinins in rickettsial infections disappear in late convalescence: therefore, the test cannot be employed as a survey tool to determine the qualitative or quantitative degree of past infection in a given area.
The next step was to determine what serological changes were induced by vaccination as carried out in U.S. troops with vaccine of the Cox type. In a series of serological studies at the Cairo laboratory of the Typhus Commission,35 it was demonstrated, first, that a 1.0 ml. stimulating dose of typhus vaccine in 100 multivaccinated individuals resulted in no significant change in Weil-Felix agglutination titers in tests with suspensions of Proteus OX-19, OX-2, and OX-K on sera taken before and 2 weeks after the injection. Secondly, no anamnestic reactions were detected when these tests were performed on sera from 104 febrile patients who had previously been vaccinated. Finally, serological tests were performed on serial serum specimens from 29 cases of suspected epidemic typhus developing subsequently to vaccination. Here, it was found that the titer changes in Proteus OX-19 agglutination tests were greater than those in the first and second groups and were, furthermore, of sufficient magnitude to have diagnostic significance. Examples of results in typhus cases occurring after vaccination are given in table 15.
Complement fixation tests with rickettsial antigens-Numerous investigators were aware of the limitations of the Weil-Felix tests and strove to develop specific rickettsial antigens for use in complement fixation and agglutination tests. The preparation of pure suspensions of rickettsiae in sufficient quantity was an obstacle until, in 1938, Cox introduced the yolk-sac culture method. Using this method of rickettsial cultivation, Bengtson36 prepared antigens and successfully performed complement fixation tests upon sera from murine typhus cases. In 1942, Craigie37 demonstrated that rickettsiae could be separated from yolk-sac suspensions by ether extraction, thereby eliminating most of the embryonic egg materials. This made available essentially pure suspensions of rickettsiae for use as antigens in serological tests and vaccines. Indeed, Wertman38 later showed that this method actually increased the specificity of the rickettsial suspensions by removing about half of the syphilitic antigens normally present in tissues of the embryonic chick. Plotz and his associates39 soon noted that sera from both epidemic and murine typhus patients gave complement fixation titers with both epidemic and murine antigens. These investigators found that by repeated washing and centrifugation of the rickettsial suspensions a "soluble substance" present in the supernatant fluid could be removed. This process
35(1) Zarafonetis, C. J. D.:
Serologic Studies in Typhus-Vaccinated Individuals. I. The Effect of a
Stimulating Dose of Typhus Vaccine on the Weil-Felix and Complement-Fixing
Antibodies. J. Immunol. 51: 365-374, November 1945. (2) Zarafonetis, C. J. D.:
Serologic Studies in Typhus-Vaccinated Individuals. II. The Effect of
Non-Typhus Fevers on the Weil-Felix and Complement-Fixing Antibodies. J.
Immunol. 51: 375-388, December 1945. (3) Zarafonetis, C. J. D., Ecke, R. S.,
Yeomans, A., Murray, E. S., and Snyder, J. C.: Serologic Studies in
Typhus-Vaccinated Individuals. III. Weil-Felix and Complement-Fixation
Findings in Epidemic Typhus Fever Occurring in the Vaccinated. J. Immunol. 53:
15-30, May 1946.
also served to eliminate the remainder of the syphilitic antigen. The resuspended rickettsial suspensions were then shown to be essentially specific for homologous sera. Thus was made possible the serological differentiation between epidemic and endemic typhus, with obvious epidemiological as well as clinical significance.
This specific complement fixation test was used in several laboratories, but comprehensive data for nonvaccinated cases were recorded primarily at the Army Medical School and by the Cairo Unit of the Typhus Commission. At the Army Medical School, Plotz and his coworkers performed systematic complement fixation tests on the sera from the Cairo series of 32 unvaccinated patients with typhus fever (p. 179). All of these patients showed a rise in titer in tests with epidemic antigen; 56 percent gave positive complement fixation by the 10th day, 78 percent by the 12th day, and 100 percent by the 16th day of illness. Most of them gave fixation with epidemic antigen and no fixation with murine antigen (table 22). Where cross-fixation did occur, the titer with homologous (epidemic) antigen was always higher than with murine antigen. All cases showed persistence of complement fixing antibodies, even when specimens taken many months after onset of the disease were examined.
Source: Plotz, H., Wertman, K., and Bennett, B. L.: The Serological Pattern in Epidemic Typhus Fever. I. The Development of Complement Fixing Antibodies. Division of Virus and Rickettsial Diseases, Army Medical School, Army Medical Center, Washington, D.C., 1944. [Official record.]
Employing the same technique and antigens prepared by the Division of Virus and Rickettsial Diseases, Zarafonetis40 performed complement fixation tests on 1,002 sera from 203 cases of typhus fever, with results sum-
40See footnote 33, p. 180.
marized in table 23. Almost all of the cases were epidemic typhus fever, confirmed in many instances by isolation of the strain. In only two patients did the complement fixation titer with murine antigen equal or exceed that obtained with epidemic antigen. Sera from two of the cases failed to develop titers in complement fixation tests with either epidemic or murine typhus antigens, while both showed good responses in Weil-Felix OX-19 and rickettsial agglutination tests. From the serological findings in these two cases (table 24), it appears that the rickettsial agglutination response is dissociated from the antibody that gives rise to complement fixation. From this and from similar observations with the Weil-Felix test (p. 181), it is seen that all three of the serological reactions occur independently of one another, and one test may be negative while the other two give a positive finding for typhus fever.
Source: Zarafonetis, C. J. D.: The Serological Reactions in the Rickettsial Diseases of Man. In Rickettsial Diseases of Man. Washington: American Association for the Advancement of Science, 1948, pp. 179-183.
It now remained to determine the effect of vaccination per se on the complement fixing antibodies. Tests were made on sera taken before and 2 weeks after a 1.0 ml. stimulating dose of typhus vaccine in 100 multivaccinated subjects (p. 183). Sera from 21 of these individuals gave epidemic complement fixation titers ranging from 1:4 to 1:32 before the stimulating dose, while 2 weeks later sera from 70 of the subjects were positive in dilutions ranging from 1:4 to 1:128. Where there was an increase in complement fixation titer as a result of booster vaccination, there was a tendency to return to the previous level within 8 weeks after the booster injection.
The question of anamnestic reactions was studied in 104 persons who had been immunized with vaccine of the Cox type at some time before the
1End point titer was not reached.
febrile illness that led to their hospitalization (p. 183). No significant increase in complement fixing antibodies occurred in them as a result of the nontyphus fevers.
With these studies as background, Zarafonetis and his coworkers,41 studying 29 vaccinated patients with probable epidemic typhus fever, found that the diagnosis could be made serologically provided the possible effects of vaccination per se were evaluated as well. A higher degree of cross-fixation was encountered in these tests than had been found in nonvaccinated patients with epidemic or murine typhus fever. An example is shown in table 25. This patient was proved to have epidemic typhus fever by isolation of the strain. The high degree of cross-fixation present in the sera was not due to a peculiarity of the strain itself, since sera from guinea pigs infected with it gave high titers in complement fixation tests with epidemic antigen but were negative in tests with murine antigen. Because of the observed cross-fixation, it was deemed unjustifiable to attempt differentiation between epidemic and murine typhus in vaccinated persons on the basis of the complement fixation test alone.
In seeking an explanation for the cross-fixation, it was noted that the same lots of antigen were used in both the vaccinated and the unvaccinated groups and in the latter revealed no lack of specificity. Again, tests on sera from guinea pigs infected with two strains isolated from the vaccinated patients gave clear-cut identification of epidemic typhus fever. Accordingly,
41See footnote 35 (3), p. 183.
1Verified by strain isolation.
with the antigens known to be specific and the possibility of "intermediate" strains ruled out, it appeared that the increased amount of cross-fixation was the result of the vaccination itself. Furthermore, in vaccinated subjects without typhus there was a higher amount of cross-fixation than one would expect. It appeared, therefore, that vaccination introduces some factor that gives rise to cross-fixation and that this is simply exaggerated by subsequent infection. The following hypothesis was advanced:
Several workers have noted the presence of a soluble substance in epidemic and murine rickettsial suspensions derived from infected yolk sacs. This soluble substance is common to both strains and if present in antigens used in complement fixation tests is responsible for cross-fixation with heterologous sera. Plotz and his coworkers removed this soluble antigen from rickettsial suspensions and these purified rickettsial antigens gave little or no heterologous fixation. The antigens used in this laboratory are similarly purified rickettsial suspensions and have demonstrated their specificity in nonvaccinated typhus cases.
While this soluble material is responsible for cross-fixation in complement fixation tests, it also has immunogenic properties. Topping and his associates have found that this material produced positive Weil-Felix reactions in rabbits, and that guinea pigs were immunized as judged by the stimulation of immunity to challenge with guinea pig passage material. They also found that it produced complement fixing antibodies when injected into guinea pigs. These findings were considered sufficient to warrant the retention of the soluble material in vaccine preparations such as are in use today.
Thus, antigens for complement fixation tests are purified by removing the soluble substance, while vaccines retain it for its immunogenic properties. Therefore, an individual vaccinated with Cox-type epidemic typhus vaccine receives both epidemic rickettsiae and soluble substance. It seems reasonable to assume that an immunogenic response will be elicited by both of these components of the vaccine, though this may not necessarily be detected in serologic tests. Subsequent infection with typhus rickettsiae stimulates a further antibody response, including a soluble substance component which fixes complement in the presence of both epidemic and marine antigens. In other words, a complement fixing antibody against both epidemic and murine rickettsiae results from inocula-
tion with vaccine containing a soluble substance. This antibody gives rise to cross-fixation, thus tending to counteract the specificity of antigens purified by removing the soluble substance.
Rickettsial agglutination-Limited agglutination studies with rickettsial suspensions had been performed by a number of investigators prior to World War II. In most of the early tests, a microscopic technique was used, but with the development of methods for producing larger yields of rickettsiae, macroscopic tests offered promise of practical application. Stuart-Harris and his associates,42 using epidemic and murine suspensions prepared from the lungs of mice infected by the intranasal route, detected agglutinins in guinea pig and human convalescent sera. They concluded that differences between epidemic and murine typhus could be demonstrated by rickettsial agglutination. Van Rooyen and Bearcroft43 were the first to employ suspensions of epidemic and murine typhus micro-organisms prepared from yolk-sac cultures and purified by the Craigie extraction technique. They used a macroscopic agglutination technique with sera from patients with typhus fever and concluded that a differential diagnosis between epidemic and murine typhus was possible with this test.
Plotz and Synder44 undertook an evaluation of rickettsial agglutination with purified antigens similar to those employed in the complement fixation studies that have been described (p. 183). Again, the specimens tested consisted of the sera obtained from the 32 unvaccinated patients in Cairo. Agglutinins occurred in rising titer in all cases during the course of the disease. Table 26 summarizes the results in one of the patients. It may be seen that the titer obtained with epidemic typhus antigen exceeds that found with the murine typhus antigen, but there is more cross-reaction here than was noted in the complement fixation tests on the same specimens (table 22). In extending the test to sera from patients with other diseases, it was found that titers were obtained at times. These workers concluded, therefore: "Since epidemic and murine agglutinins may occur in convalescent specimens from cases of Rocky Mountain spotted fever, occasionally in high titer, caution should be observed in evaluation of this test when used as a diagnostic procedure."
Regrettably, routine rickettsial agglutination tests were not performed in the Cairo laboratory of the Typhus Commission partly because the procedure utilizes about 10 times the amount of antigen employed in complement fixation. In the vaccinated patients with epidemic typhus fever, the serological tests did not, therefore, include rickettsial agglutination. Data obtained in tests on sera from one such patient, however, are given in table 15 (case 3). In the section (p. 204) dealing with murine typhus, it
42Stuart-Harris, C. H., Rettie, G. K. C., and
Oliver, J. O.: Rickettsial Agglutination Studies in Typhus Fever. Lancet 2:
537-538, 30 Oct. 1943.
Source: Plotz, H., and Snyder, J. M.: The Serological Pattern in Epidemic Typhus Fever. IV. Rickettsial Agglutination. Division of Virus and Rickettsial Diseases, Army Medical School, Army Medical Center, Washington, D.C., 1944. [Official record.]
has been suggested that the rickettsial agglutination test may be more specific in vaccinated individuals than is the complement fixation test.45 Further information on the antibody responses of patients acquiring epidemic typhus fever after vaccination would be required to establish this point.
Neutralizing antibody test-In 1940, Gildemeister and Haagen46 described the association of a toxin with living marine typhus rickettsiae grown in yolk sacs of developing chick embryos. These workers were interested in producing a vaccine and, among other questions to be answered, wished to establish whether rickettsiae grown by this technique had kept their pathogenicity for white mice. Accordingly, they injected a suspension of yolk sac infected with R. mooseri intraperitoneally into white mice in 0.5 and 1.0 ml. amounts. To their surprise, all the mice died within 4 to 20 hours, some in convulsions. Further study of this finding revealed that this effect was due to the presence of a rickettsial toxin and that the toxin was destroyed by heating to 60° C., or by treating with formalin; that is, it was destroyed by procedures used to kill the rickettsiae. Finally, they demonstrated that convalescent serum from either epidemic or murine typhus would neutralize the toxin.
45Plotz, H., and Wertman, K.:
Modification of Serological Response to Infection With Murine Typhus by
Previous Immunization With Epidemic Typhus Vaccine. Proc. Soc. Exper. Biol.
& Med. 59: 248-251, June 1945.
Following the report of Gildemeister and Haagen, Bengtson and her coworkers47 found that a toxic substance was present in yolk-sac cultures defected with epidemic typhus rickettsiae. Henderson and Topping48 then showed that this toxic substance could be neutralized by convalescent epidemic typhus serum, and devised a neutralization test in mice which was adopted by the National Institutes of Health as the standard potency test for typhus vaccines. At about the same time, Hamilton49 demonstrated that the toxins associated with suspensions of living epidemic and murine typhus rickettsiae were immunologically separable as were the antibodies that neutralized them.
Plotz and Bennett50 undertook an evaluation of the mouse neutralization test as a possible laboratory tool for use in the diagnosis of typhus fever. Employing some 13,000 mice, they carried out neutralization tests on the serial serum specimens obtained from the 32 Cairo cases of epidemic typhus fever. In recording the results of this study, complete protection indicated that all mice tested at a given serum dilution survived; partial protection, that one or more but not all of the animals survived; and no protection, that all the mice in a group died. For uniformity in recording, the 50 percent end point of each titration was determined by the method of Reed and Muench. Table 27 illustrates the neutralization titers obtained in tests on sera from one of the Cairo cases. Actually, neutralizing antibody appeared during the course of illness in all of the cases studied; 28 percent developed neutralizing antibodies by the 6th day, 75 percent by the 8th day, and 100 percent by the 11th day. The curve of neutralizing antibody response was quite similar to that obtained in Weil-Felix Proteus OX-19 agglutination tests on the same sera.
Of additional interest were the results obtained by the same authors when epidemic typhus neutralization tests were performed with specimens of serum from cases of Rocky Mountain spotted fever. The patients from whom the specimens were obtained had not been given any typhus vaccine, nor did they have a history of typhus fever. Neutralizing antibodies for epidemic toxin were found, however, in 11 cases of Rocky Mountain spotted fever studied. This finding indicated that the epidemic neutralizing antibody was not restricted to epidemic typhus fever, and hence, these workers concluded that the mouse neutralization test is not reliable as an indication of a past infection with typhus.
Isolation and identification of R. prowazeki strains-Isolation of the causative agent and identification of it through appropriate means is classically the only absolute method of diagnosis of an infectious disease. Strain
47U.S. Public Health Service,
Federal Security Agency: National Institute of Health Bulletin No. 183,
Studies of Typhus Fever. Washington: U.S. Government Printing Office, 1945,
Source: Plotz, H., and Bennett, B. L.: The Serological Pattern in Epidemic Typhus Fever. III. The Neutralizing Antibody. Division of Virus and Rickettsial Diseases, Army Medical School, Army Medical Center, Washington, D.C., 1944. [Official record.]
isolation of R. prowazeki was, therefore, often performed in the field laboratories of the U.S.A. Typhus Commission in order to establish a firm basis for the observations made in their various investigations. In addition to the obvious importance of strain isolation for diagnostic purposes, it was also desirable for laboratory comparison of immunity relationships between strains that were isolated during epidemiological surveys in various parts of the world. Strains of R. prowazeki were also available for special vaccine production if differences in immunogenic properties from the Breinl strain (employed in the U.S. Army vaccine) had become manifest. Strains were used further in the laboratory evaluation of chemotherapeutic agents and in the preparation of antigens for serological tests.
Guinea pigs were, of course, invaluable in the initial isolation of typhus fever organisms, either from the ground clot of blood drawn from the patient early in the course of illness or from ground infected lice. The Cairo Unit of the Typhus Commission maintained a colony of noninfected lice for use in such studies.51 Pill boxes containing approximately 200 lice each, and prepared with a fine-mesh cloth screen through which the lice could feed, were often carried by members of the Typhus Commission to distant points of survey. The lice were fed on their persons until such time as an appropriate case of suspected typhus fever was found. The pill box would then be attached with adhesive tape to the patient's leg for about 10 days, At the end of this feeding period, the louse box was carefully removed and sealed in an envelope, not to be opened again until the worker had returned to the laboratory, often hundreds of miles distant from the patient. At the laboratory, the material was carefully ground and injected into guinea pigs for the conventional isolation-of-strain procedure. In this manner, for
51Snyder, J. C., and Wheeler, C. M.: The Experimental Infection of the Human Body Louse, Pediculus humanus corporis, With Murine and Epidemic Louse-Borne Typhus Strains. J. Exper. Med. 82: 1-20, July 1945.
example, one officer52 was able to isolate in Cairo 10 strains of R. prowazeki from partisan soldiers ill with typhus in Yugoslavia during March 1945.
Supplies of guinea pigs were limited so that field studies were often hampered. For this reason, the observation of Snyder and his coworkers53 that two desert rodents, namely, Gerbillus gerbillus and Gerbillus pyramidum, were susceptible to experimental typhus infection proved to be valuable for the studies of the Typhus Commission in Cairo.
The developing chick embryo was employed for cultivation of R. prowazeki in large quantities for vaccine production and for antigens, as has been noted. However, the embryonated egg was not widely used for direct isolation of rickettsiae from the blood of patients ill with typhus fever, and the degree of successful strain isolation that might be achieved through this technique remains to be determined.
The treatment of epidemic typhus fever may be considered in two broad categories. First are the general supportive measures including good nursing, particular attention to diet, fluids and electrolytes, and appropriate management of complications as they arise. These measures have been outlined (p. 153) with the observations and reasoning on which they were based, and need little exposition here.
Supportive therapy-Diligent nursing care is required throughout the febrile period and also during convalescence. The position of semistuporous patients should be changed often to prevent both skin and pulmonary complications. The oral cavity should be cleansed frequently in an effort to prevent parotitis. Careful attention must be given to fluid intake and output. As much as 4,000 cc. of fluids may be required daily, preferably administered orally. Supplemental intravenous fluids should be given whenever necessary to maintain fluid balance. With respect to diet, high protein and caloric intake is associated with less loss of weight and a shorter period of convalescence. In severe cases, nourishing protein and carbohydrate mixtures may be given via an indwelling stomach tube. Delirium and extreme restlessness may be controlled by chloral hydrate or paraldehyde, but barbiturates act unpredictably.
The present discussion is chiefly concerned with specific treatment, including serotherapy, the use of antibiotics, and chemotherapy, and some consideration is given to prophylaxis.
Serotherapy-Immune serum had been used by a number of workers in the treatment of louseborne typhus prior to World War II. Human con-
52Memorandum, Maj. Chris J. D. Zarafonetis, MC,
to Brig. Gen. S. Bayne-Jones, Director, U.S.A. Typhus Commission, 27 Apr.
1945, subject: Typhus Strains from Yugoslavia.
valescent serum generally showed no noticeable effect on the course of the disease, while there were conflicting reports regarding the efficacy of sera obtained from animals that had recovered from experimentally induced typhus. With improved techniques for the growth of large quantities of rickettsiae, however, the hyperimmunization of animals was facilitated. Refined, concentrated antityphus serum was prepared from rabbits hyperimmunized with suspensions of infected yolk sacs of developing chick embryos.54 Serum prepared in this manner was shown to have a strikingly protective effect in experimental typhus.55
Knowledge of this laboratory experience prompted Yeomans, Snyder, and Gilliam56 to undertake a clinical trial of hyperimmune rabbit serum in patients admitted to the ward of the Typhus Commission at the Cairo Fever Hospital. This study was begun in April 1943; 25 patients with typhus were treated. All were skin tested for sensitivity to the serum, and, if negative, serum therapy was administered. The total amount of serum given to each varied from 51 to 512 cc., with an average dose of 186 cc. for this group of patients.
Therapeutic effectiveness of hyperimmune rabbit serum was found to be related to the duration of illness at the time treatment was instituted. The results in 10 patients treated on the second and third day of the disease were almost uniformly good. The 15 patients who had been sick for 4, 5, or 6 days before serum was given did not show a striking difference in clinical severity from the "untreated" controls, except that there were no fatal cases. Of the 25 patients who received hyperimmune rabbit serum, 7 developed mild serum sickness.
Another opportunity to test the efficacy of serum therapy presented itself to the U.S.A. Typhus Commission group working at the Dachau Concentration Camp in May and June 1945.57 Ten patients admitted to the Commission ward were given hyperimmune antityphus rabbit serum on the following dosage schedule: In the first 24 hours after admission, 0.5 cc. per pound of body weight; on the second and third days, 0.25 cc. per pound of body weight. All of the serum was injected intramuscularly in the buttocks after appropriate skin testing. Owing to limited supply, the average amount administered to these subjects was less than was given to the patients in the Cairo series. This may be the explanation for results less impressive than those obtained in the Cairo study. The illness in four patients was mild; four were moderately ill, and one was severely ill. The 10th patient treated died of widely disseminated tuberculosis 4 weeks after the
54Kurotchkin, T. J., van der Scheer, J., and
Wyckoff, R. W. G.: Refined Hyperimmune Rickettsial Sera. Proc. Soc. Exper.
Biol. & Med. 45: 323, October-December 1940.
onset of typhus fever. The average duration of fever in the treated cases was 15.2 days as opposed to 16.2 days in 121 "untreated" control cases. Serum sickness appeared in 5 of the 10 patients treated.
It is of interest to observe that the hyperimmune serum did not have a rickettsiocidal effect, for Plotz and his coworkers58 isolated rickettsiae from 11 of the Cairo patients after the serum had been given. From the prolonged incubation periods noted in isolating these micro-organisms in guinea pigs, it was postulated that the serum may have exerted a rickettsiostatic effect. Finally, these workers suggested that the beneficial clinical effect attributed to hyperimmune rabbit serum was due to its ability to neutralize the toxic substance elaborated by typhus rickettsiae.
Antibiotics-In 1944, crude commercial penicillin was shown to inhibit the growth of typhus rickettsiae in the yolk sac59 and markedly to reduce, or even completely prevent, mortality from murine typhus infection in mice.60 Clinical trials of penicillin, however, were limited in both the number of cases treated and the dosages administered. For example, Col. William S. Stone, MC, Chief, Preventive Medicine, Medical Section, North African Theater of Operations, U.S. Army, and Captain Woodward of the Typhus Commission made available to British workers in Italy61 4 million Oxford units of penicillin for trial in the treatment of epidemic typhus fever. Four patients were treated, none before the sixth day of disease. The total amount of penicillin dosage ranged from 509,000 units to 800,000 units. Two of the four patients died.
Penicillin was given to four additional cases of epidemic typhus fever on the Typhus Commission ward in Cairo.62 Yeomans and his coworkers could not determine on the basis of this limited experience whether penicillin given early, and in what were then considered "large amounts," did or did not affect the course of typhus. The potential usefulness of penicillin for the treatment of secondary bacterial infections superimposed on typhus fever, however, was recognized by them soon after this antibiotic became available.
Postwar studies by Greiff and Pinkerton63 with pure crystalline penicillin fractions revealed important differences in the rickettsiostatic activity of the different fractions. Penicillin X was about four times as effective on a unit basis as penicillin G, and there were differences in the potency of other fractions. From this, it would appear that the irregular results reported
58Plotz, H., Bennett, B. L., and Tabet, F.:
Effect of Concentrated Hyperimmune Rabbit Serum on Circulating Agent in Louse
Borne Typhus. Proc. Soc. Exper. Biol. & Med. 63: 176-178, October 1946.
could have been due to varying proportions of the penicillin fractions in the preparations used. These workers concluded that the clinical trials referred to above were invalidated by the use of low doses, started late in the course of the disease, by the small number of cases, and by the fact that fractions of proved potency against R. prowazeki were not employed. The effectiveness of penicillin in human rickettsial infection, therefore, remained undetermined.
The newer broad-spectrum antibiotics were not discovered until after the period under review and so are not included here, but their importance will be indicated at the end of the discussion of therapy.
Chemotherapy-A new chapter in the treatment of epidemic typhus fever and other rickettsial diseases was begun during World War II with the observation that PABA exhibited antirickettsial activity in vivo. This was discovered independently by Snyder, Maier, and Anderson in 194264 and by Greiff, Pinkerton, and Moragues in 1944.65 Its use was suggested to the former group by the apparently deleterious effect of sulfonamides on the course of experimental typhus infection and the knowledge that PABA and sulfonamides are metabolic antagonists. The second group of workers first tried PABA in in effort to enhance the action of penicillin. Still a third discovery of the inhibitory effect of PABA on the growth of typhus rickettsiae was made in 1944 by Takemori, working at the Hygienic Institute in Dairen, Manchuria .66
The letter report of Snyder and his associates was circulated in laboratories known to be concerned with rickettsial diseases. At the Army Medical School, Hamilton, Plotz, and Smadel67 undertook a systematic study of the effect of PABA and related substances on the growth of rickettsiae. Inoculating the test compound directly into the yolk sacs of infected chick embryos, which were allowed to develop until death resulted from rickettsial infection, they found a marked difference in survival time of the treated eggs as compared with the controls (chart 9). In addition, it was shown by direct count of rickettsiae in eggs, opened after an arbitrary period of time, that their numbers had been greatly reduced in those treated with PABA in comparison with the relatively rich growth in the controls.
The percentage of embryos protected with 2 mg. of PABA was, in general, higher than when 4 mg. (approximately 70 mcg/ml.) was used,
64Letter, J. C. Snyder, John
Maier, and C. R. Anderson, International Health Division, The Rockefeller
Foundation, to Division of Medical Sciences, National Research Council, 26
Dec. 1942, subject: [Report on Chemotherapy of Typhus Fever].
suggesting a toxic effect of excessive PABA. Even so, the necessity for using quantities of PABA up to 2 mg. to inhibit rickettsial growth in an egg suggested the possibility that a nonspecific effect might be involved. Accordingly, two isomers, ortho- and meta-aminobenzoic acid, as well as acetyl-p-aminobenzoic acid (both sterilized by heat and sterilized by Seitz filtration), sulfanilamide, sodium benzoate, and benzoic acid were tested in concentrations equivalent to the maximal dose of PABA (4 mg. per egg). With the exception of the heat-sterilized acetyl derivative, none of these substances had any apparent effect on either the time of death or the number
of rickettsiae. Heating hydrolyzes a certain portion of acetyl-PABA into PABA, which is the probable explanation for the above observation. These studies clearly indicate that the inhibition of growth by PABA is due to a specific action of the drug.
An outstanding series of investigations by Greiff68 and his colleagues shed further light on the mechanism of action of PABA in rickettsial infections, as shown by Greiff in the discussion which follows.
The rickettsiostatic action of para-aminobenzoic acid, first observed by Snyder and his co-workers in mice, later confirmed in the yolk sac by Hamilton and others and still later (because of war-time secrecy) observed independently in our laboratory, is a rather
68(1) See footnote 65, p. 195. (2) Greiff, Donald: Biology of the Rickettsiae. In Rickettsial Diseases of Man. Washington: American Association for the Advancement of Science, 1948, pp. 51-63.
striking example of the inhibition of an intracellular parasite by a compound usually regarded as a vitamin. Pinkerton and Bessey showed that in riboflavin-deficient rats, practically moribund from typhus, riboflavin had a striking "chemotherapeutic" action, causing rapid recovery from what appeared to be overwhelming and certain fatal infection. With the sudden resumption of cellular respiration when the missing link is furnished, the normal resistance of the rat is restored. With this fact in mind we have been interested in learning the mechanism of action of PABA, and particularly in determining whether or not this compound like other compounds and conditions found to discourage rickettsial growth, causes an increase in the cellular metabolic rate.
In conjunction with our earlier work, we proved conclusively that cyanide had no effect on the rickettsiostatic action of PABA. From this fact we concluded that PABA either acted directly on the rickettsiae, in a manner similar to the action of sulfadrugs on bacteria, or that PABA, like toluidine blue, increased cell respiration by short-circuiting the cyanide sensitive system of respiratory enzymes.
Recently we have developed a reliable method for measuring the oxygen consumption and carbon dioxide output of fertile eggs. In 3 separate experiments, we have found that the injection of PABA into the yolk sac markedly increases the oxygen consumption. The effect is noted after a delay of about 5 days, which is perhaps caused by slow absorption of the precipitated compound from the yolk sac. From the 5th to the 10th days after injection (almost exactly the period of active rickettsial multiplication) the oxygen consumption continues to be 25-50 percent above that of the uninjected control eggs. This of course does not prove that the rickettsiostatic action of PABA is due solely to its indirect action in increasing cellular respiration, but in view of the facts previously brought out, this seems to be a reasonable assumption.69
Greiff commented further in summarizing the work of his group:
Conditions such as low temperature and riboflavin deficiency, which decrease the rate of cellular metabolism, favor the growth of rickettsiae. Higher temperatures and certain dyes and other agents which increase cellular metabolism are unfavorable to rickettsial growth. Our experiments indicate that the activity of the cyanide sensitive respiratory enzyme (cytochrome oxidase) is one essential factor in the protection of cells against rickettsial multiplication. In the case of toluidine blue and para-aminobenzoic acid, however, rickettsiostatic activity is correlated with increased cellular respiration brought about by mechanisms which are cyanide-insensitive.
Clinical studies designed to determine the therapeutic effect of PABA in epidemic typhus fever were begun on the ward of the Cairo Unit of the Typhus Commission in 1943. Yeomans, Snyder, Murray, Zarafonetis, and Ecke70 were able to report in 1944 that the drug had a favorable influence on the clinical course of patients whose treatment was begun in the first week of the disease. These studies were continued through 1945, both in Cairo and at the Dachau Concentration Camp,71 and a summary of the results of treatment of a cumulative total of 95 patients suffering from typhus fever was later issued.72
69Recent observations indicate that PABA enhances
monamine oxidase activity. This may represent the pathway through which
increased oxygen uptake is mediated by PABA.
The most carefully controlled observations were made in Cairo. Here, patients were placed alternately in control and PABA-treated groups. The study groups were composed of 39 male Egyptian patients, ages 18 to 48, suffering from epidemic typhus fever. The diagnosis was based on the clinical course, serological findings, and, in 19 instances, isolation of R. prowazeki from the blood or from normal lice fed on the patients during the febrile period. None of the patients had been vaccinated against typhus fever or gave a history of a previous attack of the disease. Most were somewhat underweight but appeared to be in good physical condition otherwise. A few of the patients were subsequently found to have subclinical schistosomiasis, but none was excluded because of this finding. One PABA-treated patient developed an exacerbation of amebic dysentry during convalescence from typhus, but his case was included in the results. The patients were in the first week of illness when they were placed in the control and PABA-treated groups in automatic rotation.
In the 19 control subjects, mean values were as follows: Age, 27.9 years; duration of illness when admitted to the group, 4.4 days; duration of fever,
17.9 days (chart 10). The incidence of complications was higher in this group, and there were six fatal cases.
In the 20 patients treated with PABA, mean values were as follows: Age, 28.5 years; duration of illness when treatment was started, 4.4 days; duration of fever, 12.8 days. The incidence of complications was less than in the control group, and there was one death in this series.
The treatment regimen to be followed with PABA was evolved only after considerable experimentation. Yeomans and his coworkers73 outlined the plan of therapy, as follows:
In all instances, PABA was administered by mouth. The initial dose varied from 4 to 8 gm. In the majority of cases, the initial dose was followed by 2 gm. every 2 hours unless the concentration in the blood attained excessive values. Adjustments in dosage were made in relation to fluid intake and urinary output. The fluid intake in nearly all instances was adequate to maintain the output of urine between 1,500 and 3,000 cc. in 24 hours.
The effort was made to keep the concentration of PABA in the blood between 10 and 20 mg. per 100 cc. PABA is absorbed and excreted very rapidly, so that a 2-hourly schedule of administration was decided on as that most likely to produce a relatively constant blood level. Determinations made at various times during treatment indicated that the 2-hourly schedule was effective in maintaining a satisfactory concentration of PABA throughout the period of therapy.
PABA was continued for varying lengths of time in the first cases. Subsequently, it was decided that treatment should be continued until the patient's rectal temperature was 37.5° C. (99.5° F.) or less for 24 hours. The average amount of PABA for each case was approximately 127 gm. The patients who are the subject of discussion in this study received PABA for at least 3 days.
Nausea and vomiting attributable to PABA occurred in the first few cases. Thereafter, in order to lessen gastric irritation, sufficient sodium bicarbonate was given to neutralize the PABA. The acidity of the urine was determined at least once daily during therapy. The amount of sodium bicarbonate was varied as required to keep the urine approximately neutral in reaction. After this plan was adopted, vomiting was encountered very infrequently.
PABA was available in tablets of 0.5 gm. each and in capsules of 0.3 gm. each. Neither form was suitable for administration to typhus patients, who could not be persuaded to swallow the large numbers of tablets or capsules required for each dose, but they took powdered PABA readily if it was suspended in water or partially dissolved in a sufficient volume of 5 percent sodium bicarbonate solution to render the mixture slightly alkaline. The usual amount was 2 gm. of powdered PABA with 25 cc. of sodium bicarbonate solution.74 After swallowing the mixture, the patient was quickly given water to take away the slightly unpleasant taste of the drug. This method of administration was entirely satisfactory in most instances.
Premature withdrawal of PABA therapy was followed by a mild febrile period which probably represented a mild recrudescence of the disease. For
73See footnote 6, p. 147.
this reason, it was found advisable to continue the initial course of PABA for 48 hours after the patient's temperature had returned to normal.
At no time were crystals of PABA ever noted in the urine of the patients treated. There was detected, however, a slight tendency to leukopenia during this form of therapy. Snyder and his coworkers75 found the mean of the lowest counts was 5,200 per cubic millimeter for 19 control patients, while the mean for the 20 patients treated with PABA was 4,100 per cubic millimeter, but the difference was not statistically significant. Analysis of the differential leukocyte counts did, however, reveal a slight but statistically significant reduction in the percentage of segmented neutrophils (69.9 percent was the mean for the controls, and 55.1 percent was the mean for the treated group) and an increase of a similar percentage in the lymphocytes. The differences in percentages of monocytes, eosinophils, and basophils were not significant. Although slight depression of the neutrophils was attributable to the administration of PABA, no instance of true agranulocytosis was encountered in these studies.
PABA was thus discovered to have important antirickettsial activity and, through studies as just described, was brought to the position of a safe and promising drug for clinical use during World War II. Its importance in the management of epidemic typhus fever and other rickettsial diseases was short lived as a result of the postwar development of broad-spectrum antibiotics.76 The wartime studies with PABA may yet be shown, however, to have great significance both from the standpoint of rickettsial growth factors and as a clue to certain intracellular metabolic processes.
75See footnote 72, p. 197.
Prophylaxis.-Prevention of epidemic typhus fever was made practicable during World War II with the production of adequate quantities of a potent vaccine and by improved methods of louse control.
Personnel in the Armed Forces of the United States were vaccinated with antityphus vaccine of the Cox type. Although 104 cases of epidemic typhus were detected in U.S. troops, there was not a single death. Typhus contracted after vaccination is, therefore, relatively mild and rarely if ever causes death. Furthermore, lice fed on patients who were vaccinated before acquiring typhus develop very few rickettsiae in comparison to lice fed on unvaccinated patients. Thus, vaccination not only alters the susceptibility of the individual but, when used on a broad scale, also serves to reduce the epidemic potential of the disease.
In the complementary effort to prevent the disease by destroying the vector, a number of agents were developed, the most effective being DDT (dichlorodiphenyltrichloroethane). A 10 percent DDT powder dusted into the clothing was found to provide almost complete protection against lice for 3 weeks or more.77 DDT or other insecticide powders are of greatest importance when conditions prevail which are favorable for an epidemic. During World War II, the vigorous application of delousing measures in the prevention or prompt control of typhus epidemics was an historic accomplishment in the annals of preventive medicine.78
Part II. Brill's Disease
It is now recognized that Brill's disease is clinical recrudescence of a previous epidemic typhus infection. The causative micro-organism, R. prowazeki, may remain latent in an individual for years following the original infection. As immunity wanes, and possibly influenced by still undetermined factors, the rickettsiae are activated and give rise to illness which often resembles that associated with the primary infection.
Nathan Brill first described the disorder in 1898 and again in 1910 as an acute infectious disease of unknown origin. His reports were based on the study of 221 cases occurring sporadically in New York City during more than a decade of observation. Brill's clinical description is classic. He also noted that Widal tests and blood cultures were negative and called attention to the similarity of the disease to typhus fever.
Additional cases were soon reported by others, and in 1912, Anderson and Goldberger showed by cross-immunity tests that Brill's disease was
77Some strains of lice
encountered during the recent Korean conflict, however, were DDT resistant (Hurlbut,
H. S., Altman, R.M., and Nibley, C., Jr.: DDT Resistance in Korean Body Lice.
Science 115 : 11-12, 4 Jan. 1952).
related to Mexican typhus. At that time, it was believed that there was only one form of typhus fever, but during the next 30 years, it was clearly established that there were two distinct varieties; namely, louseborne epidemic typhus and fleaborne murine typhus. In the absence of epidemiological evidence incriminating either lice or fleas, however, the position of Brill's disease remained uncertain until Zinsser offered an explanation in 1934. On epidemiological grounds, Zinsser postulated that Brill's disease resulted from recrudescence of an old typhus infection which had been acquired in Europe. This theory was further supported by the fact that three strains of rickettsiae which he and Castaneda had recovered from patients with Brill's disease gave biological reactions similar to those induced by R. prowazeki.
Brill's disease occurs sporadically and infrequently among individuals who have previously had epidemic typhus fever. The original infection may have been acquired from a few years to as long as 50 years or more in the past. Subjects who continue to live in typhus zones may serve as the interepidemic reservoir of epidemic typhus fever.79 On the other hand, Brill's disease in individuals who have migrated to nontyphus areas presents no epidemic problem. The incidence of Brill's disease is not known, but it is very small in proportion to the total number of cases of epidemic typhus fever.
The typical case resembles a mild to moderately severe attack of epidemic typhus fever as described in the preceding section. All of Brill's original cases exhibited a rash, as it was a required feature for diagnosis. It is now recognized, however, that many mild cases occur without all eruption at any time during the course of illness.
The febrile course varies from a few days in mild cases to 2 weeks or more in severe attacks. If an eruption is present, it may be sparse and evanescent or it may be moderately extensive. Headache and malaise persist until the fever subsides. The mortality is low, possibly 1 or 2 percent. The great majority of patients have a prompt convalescence and complications are rare.
The clinical diagnosis of Brill's disease may be made in a patient who has lived at some previous time in an epidemic typhus area and whose illness is characterized by fever, intense headache, and a maculopapular rash ap-
79In this connection, it has been shown that lice fed upon patients during the first week of Brill's disease become readily infected with R. prowazeki and, therefore, could initiate an epidemic under suitable conditions (Murray, E. S., and Snyder, J. C.: Brill's Disease. II. Etiology. Am. J. Hyg. 53: 22-32, January 1951).
pearing on the fourth to sixth day of disease. In cases without a rash, the remaining criteria should lead to the consideration of Brill's disease in the differential diagnosis.
From the foregoing, it is evident that the specific diagnosis of Brill's disease must rest on other than clinical findings alone. In this area, Col. Harry Plotz, MC, made a highly significant contribution during World War II,80 demonstrating that complement fixation tests with purified rickettsial antigens could be applied to the specific diagnosis of epidemic typhus and murine typhus. The following serological evidence substantiates this point of view:
In 23 cases of Brill's disease examined all showed a positive complement fixation with an epidemic rickettsial antigen. In 10 cases there was fixation with an epidemic rickettsial antigen and no fixation with an endemic rickettsial antigen. In 13 cases there was some cross-fixation but in all instances where this occurred the titer obtained was higher with epidemic antigen. The pattern of fixation in this disease resembles that obtained in epidemic typhus fever.
Absorption tests were performed on specimens of serum from Brill's disease where cross-fixation had occurred. An endemic rickettsial antigen removed all the endemic antibody with slight effect upon the titer of epidemic antibody. On the other hand, a similar treatment of the serum with an epidemic rickettsial antigen resulted in the removal of both the epidemic and endemic antibody; no selectivity of absorption was observed. These results would indicate that the endemic rickettsial antigen pattern was different from that of the antigenic pattern of the epidemic strain. The removal unselectively of both endemic and epidemic antibodies by the epidemic antigen suggests that the latter may be a more complete or complex antigen than the endemic antigen.
The results obtained in Brill's disease are highly significant for the epidemiology of typhus fever. They would indicate that mild cases of epidemic typhus actually exist in the United States. The disease is not transmitted from person to person in this country simply because the louse vector is not present. Furthermore, these results indicate that one attack of typhus does not confer a lifelong immunity as is generally believed. The virus is probably harbored in the body and when the resistance is lowered the virus multiplies and induces a mild attack. If these cases should occur in a louse-infested community the disease might readily spread from person to person. The observations on Brill's disease strongly suggest that man serves as the reservoir for epidemic typhus between outbreaks just as the rat does in endemic typhus.
Plotz further stated: "The complement fixation test now provides a tool with which surveys of the prevailing types of typhus in a region can be determined."81
Thus, recrudescence of rickettsial activity occurs unpredictably in a small percentage of persons who have had epidemic typhus fever. The factors which give rise to this phenomenon are not known, so that the specific
80Plotz, H.: Complement Fixation in
Rickettsial Diseases. Science 97: 20-21, 1 Jan. 1943.
prevention of Brill's disease is not feasible at this time. Fortunately, other measures kept the incidence of epidemic typhus fever in our troops to a minimal level and, thereby, reduced the likelihood of Brill's disease in them to zero. The importance of Brill's disease to the U.S. Army Medical Service, therefore, lies in its epidemiological implications among civilians in oversea areas where our forces may be stationed.
Part III. Endemic (Murine) Typhus
Endemic or murine typhus is an acute febrile illness caused by infection with R. mooseri (syn. Rickettsia typhi) transmitted to man by rat fleas. Many of the terms applied to louseborne typhus have also been used in the past in referring to cases of endemic typhus. Clinically, the disease is similar to epidemic typhus, but it usually runs a milder course.
Probably the first clinical description was written in 1913 by Paullin who recognized a mild form of typhus fever occurring in Atlanta, Ga. The recognition of murine or endemic typhus as a separate entity from epidemic typhus fever and Brill's disease, however, was not made until some years later. An important advance was made by Neill in 1917. He noted that scrotal swelling was produced in male guinea pigs by the intraperitoneal injection of blood obtained from cases of typhus fever in Texas. Mooser extended observations along this line in 1928 and emphasized that this biological reaction was characteristic for a Mexican strain of typhus.82 In contrast, scrotal swelling was not a feature in guinea pigs infected with strains of classical or louseborne typhus rickettsiae. Meanwhile, Maxcy and Havens conducted extensive epidemiological studies on the typhus cases which occurred in the Southern and Southeastern United States. On the basis of these investigations, Maxcy, in 1926, postulated a rodent reservoir for this form of typhus, and suggested that transmission of the disease to man was accomplished by fleas.83 This theory was confirmed in 1931 by Dyer and his associates who isolated the causative micro-organism from rat fleas obtained at a typhus focus in Baltimore, Md.84
Murine typhus occurs as a natural infection of rats and certain other rodents in many parts of the world. The infection appears to be transmitted
82Mooser, H.: Experiments
Relating to Pathology and Etiology of Mexican Typhus (Tabardillo). I. Clinical
Course and Pathologic Anatomy of Tabardillo in Guinea Pigs. J. Infect. Dis.
43: 241-260, September 1928.
among rodents by fleas, lice, and mites. The rat flea, Xenopsylla cheopis, is the principal vector involved in human infections. The causative microorganism, R. mooseri, may persist for long periods of time in the brain tissues of reservoir hosts. Similarly, it has been shown that once fleas have become infected, their feces may contain rickettsiae for at least 52 days and presumably for the remainder of their lives. Rickettsiae present in dry flea feces may remain infectious for long periods of time.
Human infections are acquired through the rubbing of infected feces into the fleabite wound or into an abrasion from scratching. Infection may also result from ingestion of food contaminated by infected flea feces or rat urine and from contamination of the oral or nasal mucosa with these excreta.
Cases of murine typhus occur sporadically throughout the world. In the United States, about 97 percent of the cases have been reported from Alabama, Georgia, Florida, Louisiana, Mississippi, North Carolina, South Carolina, Tennessee, and Texas (fig. 33).85 Other foci of importance are the New York City area, N.Y., Los Angeles County, Calif., Norfolk area, Va., and Pulaski County, Ark. Murine typhus is encountered in port cities and in rural areas south of 33° N. latitude. Below this line, the long warm season and field storage of crops permit rats to live and multiply outdoors throughout most of the year, thereby enhancing the epidemiological potential for this disease. Although approximately 300 cases were reported in the United States in 1931, the number later increased greatly and reached a peak of 5,353 in 1944 (chart 11).
Murine or endemic typhus was not an item of diagnosis in the U.S. Army medical statistics until 1940; all forms of typhus were included in a single figure prior to that time. From a practical standpoint, therefore, the experience of the U.S. Army Medical Department with murine typhus did not become meaningful until 1940 and thereafter.
During World War II, there were 787 cases of murine typhus in the U.S. Army (table 28). Fifteen fatalities were attributed to this infection. It is surprising that U.S. Army troops experienced a much greater incidence of fleaborne typhus than of the louseborne disease. Bayne-Jones has discussed in detail the basis for the less effective control measures of murine typhus during the period under review.86
85Bradley, George H., and Wiley,
John S.: The Control of Murine Typhus in the United States. In.
Rickettsial Diseases of Man. Washington: American Association for the
Advancement of Science. 1948, pp. 229-240.
[Preliminary data based on sample tabulations
of individual medical records]
1Includes North Africa.
Despite the relatively high incidence of endemic typhus, the sporadic and unpredictable occurrence of cases generally prevented clinical studies by Medical Department personnel. A few observations were made, however, which merit record. One of these was an investigation in Jamaica, B.W.I., carried out by Plotz, Woodward, Philip, Bennett, and Evans.87 Since Jamaica had become a military base for U.S. forces as a result of the lend-lease agreement of 1940, the presence on this island of typhus in any form was a matter of concern to the Medical Department of the Army. The first case of typhus to be recorded in Jamaica was observed by Captain Woodward in December 1941. The patient was a native laborer who complained of fever, headache, and generalized pains on admission to the Army hospital. He was moderately toxic and, aside from conjunctival injection and a few rales at the base of the lungs, there were no other findings. The temperature ranged from 100° to 105° F. for 14 days and fell by lysis. In spite of careful search, no rash was observed. His skin was café au lait in color, and a slight rash may have been missed. The Weil-Felix OX-19 agglutination titer was 1: 500 on the 8th day of illness, 1: 1,000 on the 9th day, and 1: 2,500 on the 12th day. Complement fixation tests indicated that this patient had murine typhus. This case directed attention to the likely presence of murine typhus on the island and led to the investigation. Although 68 cases of the disease were diagnosed, only 33 of these were seen in the hospitals at Kingston. The clinical and laboratory findings in this group were summarized as follows:
The onset is usually sudden with severe headache, generalized pains, and temperature which is maintained for about 14 days when it falls by rapid lysis. Rash was only seen in 7 cases. In these cases the rash was maculopapular in character. No rash was observed in 26 cases but may have been masked in some instances by the dark skin of the natives. However, some patients, who were carefully observed, showed no rash, and hence the possibility of typhus occurring without an eruption must be considered.
All of the cases had a Weil-Felix (OX-19) agglutination, ranging from 1: 500 to 1: 5,000; in most of them a rising agglutination titer was observed. Specimens of serum examined for complement fixing antibodies were positive at least late in all cases. In the sera of most patients, complement fixing antibodies were present which reacted with an endemic rickettsial antigen but not with an epidemic rickettsial antigen. In a few cases, convalescent sera had relatively large amounts of complement fixing antibody against an endemic antigen and small amounts against an epidemic antigen.
This study was particularly important in that it proved that endemic typhus was indigenous to Jamaica and had not been introduced by U.S. Army engineer troops in 1941, as had been rumored in some quarters.
A number of workers had voiced suspicion that murine typhus was present in the Philippine Islands. It remained for Woodward, Philip, and
87Plotz, H., Woodward, T. E., Philip, C. B., Bennett, B. L., and Evans, K. L.: Endemic Typhus Fever in Jamaica, B.W.I. Am. J. Pub. Health 33: 812-814, July 1943.
Loranger to establish its endemicity there during the latter part of World War II. The following case was recorded in their report:88
On 23 April 1945, an American soldier became suddenly ill with a headache and chill soon followed by fever, general malaise, nausea, and vomiting. At this time and for the 3 previous weeks he was billeted in a large warehouse in San Juan del Monte, a township bordering the outskirts of Manila, Philippine Islands. Rats (Rattus norvegicus) had been seen and subsequently trapped in this structure which is situated in close proximity to native dwellings. Social contact in the latter was not denied.
Until 26 April when the patient was admitted to the 5th Field Hospital, the fever, headache, and general malaise continued. These were the presenting symptoms with the physical examination at this time essentially negative. The subsequent 2 weeks' febrile course was of a remittent nature ranging from 99.4° to 104.4° F. On the 15th day the temperature was normal and remained so except for minimal sporadic elevations to 99.4° F. Chills, headache, pains in the chest, abdomen, and lower back were the predominant symptoms during the first week of illness until the sixth day, when irregular, brownish-pink macular lesions appeared on the chest, shoulders, and abdomen. These lesions became more intense and within 24 hours had spread to include the lower extremities and feet at which time the individual macule was fixed on digital pressure. Remnants of the petechial-like lesions were observed until the 15th day of illness when a biopsy of one of the fading macules was performed. Other than faint pigmented spots, there was no evidence of the skin manifestations after the 20th day.
During the early phases of the second week the temperature was high, the patient was moderately toxic with moderate weakness and prostration. The severest phase lasted 4 days until the ninth day when he was symptomatically much improved. Moderate lymphatic glandular enlargement was observed. There were no lesions whatever suggestive of a primary eschar. A slight cough with fleeting pulmonary rales was not remarkable. Delirium and severe central nervous system findings were not observed. By the 13th to 15th day all outward signs of weakness and prostration had disappeared and the patient became steadily stronger.
The treatment, entirely symptomatic, included parenteral physiological saline and glucose solutions, small blood transfusions, supplemental iron, calcium, and vitamins.
Laboratory findings.-Repeated examinations of blood smears for malaria parasites were negative. Urinalyses were within normal limits. Numerous blood counts on 27, 28, and 29 April, 3, 4, 6, and 19 May were normal with the white count ranging from 5,500 to 7,900, and normal differential counts. Red blood cells ranged from 3.8 to 4.5 millions. Stool examinations were noncontributory. Agglutination with the O and H antigens of typhoid and the A and B antigens of paratyphoid fever were negative and two spaced blood cultures showed no growth. Diagnosis was established by the serial examinations of repeated blood specimens as shown in table 29.
Comment.-The clinical features of continued pyrexia for 2 weeks with headaches, absence of marked central nervous system manifestations, and the appearance of a macular body rash on the sixth febrile day (without primary eschar) are strongly suggestive findings of murine typhus fever. A biopsy of one of the late skin lesions demonstrates the capillary changes and perivascular accumulation of cells so frequently observed in rickettsial diseases collectively. The serological findings are unquestionably significant. The patient developed increasing titers of Proteus OX-19 agglutinins, as shown by tests performed employing suitable control serums. Agglutinins for Proteus OX-K did not appear. More significantly, complement fixation on serial specimens of serums using
88Woodward, T. E., Philip, C. B., and Loranger, G. L.: Endemic Typhus in Manila, Philippine Islands; Report of Cases and the Identification of Murine Rickettsial Agent in Domestic Rats by Complement Fixation. J. Infect. Dis. 78: 167-172, March-April 1946.
purified murine (yolk-sac culture) rickettsiae as antigen clearly demonstrated antibodies of sufficient diagnostic titer (table 29). The low titer of 1: 6 using an epidemic typhus antigen is within the normal range of cross fixation frequently observed when these two closely related antigens are employed to detect antibodies in the serum of the typhus patient. Studies by Plotz and his collaborators, based on the use of purified antigens, have clarified the serological patterns in epidemic and murine typhus fevers.
Source: Woodward, T. E., Philip, C. B., and Loranger, G. L.: Endemic Typhus in Manila, Philippine Islands; Report of Cases and Identification of the Murine Rickettsial Agent in Domestic Rats by Complement Fixation. J. Infect. Dis. 78: 167-172, March-April 1946.
Woodward and his coworkers noted two other cases which occurred in Manila, and another which originated on Mindanao. In addition, they found that 18 percent of rats trapped in Manila gave evidence of endemic typhus infection as detected by complement fixation tests with purified rickettsial antigens.
Woodward also observed murine typhus in Morocco.89 There, Dr. Georges Blanc of the Pasteur Institute undertook to determine the efficacy of a living murine typhus vaccine in human volunteers. This study gave Woodward an opportunity to follow closely the incubation period and clinical course of endemic typhus. Although no clinical report was issued, the pertinent observations made at that time were incorporated in his later description of the disease.90
Murine typhus was encountered by other U.S. Army medical officers, but no series of cases was reported as a clinical study. Scoville, Bennett, Wertman, and Gauld,91 for example, obtained data on 15 cases which occurred in Nashville, Tenn., during September 1944, focusing upon serological aspects of the disease. Similarly, Plotz and Wertman92 described 12 cases
89Letter, Capt. Theodore E. Woodward, MC, to
Director, U.S.A. Typhus Commission, 14 Dec. 1943, subject: Report of Human
Typhus Fever Vaccine Experiment.
of murine typhus contracted after immunization with epidemic typhus vaccine (table 30), again with the emphasis on the serological findings, which are to be discussed.
Zarafonetis93 reported the epidemiological, clinical, and laboratory findings in two U.S. Army enlisted men who were stationed in Dakar, French
93Letter, Capt. Chris Zarafonetis, MC, U.S.A. Typhus Commission, to Chief Surgeon, U.S. Army Forces in the Middle East, through Brig. Gen. Leon A. Fox, Field Director, U.S.A. Typhus Commission, 10 Aug. 1944, subject: Report of Typhus Situation in Dakar.
West Africa, at the time of their illness. Brief summaries of their case histories follow.
A 27-year-old private (case 1) was admitted on 5 July 1944 with the diagnosis of acute tonsillitis. He had a 1-day history of sore throat and difficulty in swallowing, and there were associated complaints of joint pains and aching. Physical examination was essentially negative except for evidence of tonsillar involvement. Temperature at that time was 99.6° F. On the following day, the patient complained of a headache which was not relieved by aspirin and other analgesics and which persisted for several days thereafter. On 9 July the patient experienced a chill and complained of generalized aching. His temperature reached 102.4° F., which was the maximum attained during his hospitalization. From 9 July until 24 July, he continued to run a low-grade fever. At no time was there a rash evident. Serum taken on 12 July was tested at the Pasteur Institute at Dakar and found to agglutinate Proteus OX-19 in dilution of 1: 200. Serum was tested again on 18 July and this time agglutinated OX-19 to a titer of 1: 1,000. On the basis of the laboratory findings a diagnosis of typhus was made.
The second case was that of a 23-year-old T/5 (case 2) who was admitted on 18 July with complaint of severe headache and pain in the chest for 24 hours prior to admission. His physical examination at that time was essentially negative except for an admission temperature of 101.6° F. On 25 July, the 10th day of disease, a fine macular rash appeared over the chest and arms.
The rash had practically disappeared by 27 July. Fever had been present continuously for 15 days but was falling toward normal on 29 July. His course had been relatively mild for typhus.
These two patients were believed to have had murine typhus principally on the basis of epidemiological evidence. Durieux and other French workers had concluded from extensive studies of typhus in French West Africa that the louseborne form of this disease did not exist there. However, some 200 cases of relatively mild typhus had been diagnosed during the preceding decade, with only 1 death recorded. The strains of rickettsiae that had been isolated from some of these cases were all identified as R. mooseri. At the time the American soldiers contracted their illness, two other cases, both unrelated, occurred in the native population. Because of an outbreak of plague in Dakar, both soldiers had remained within their military establishments for over a month prior to the onset of their illness. An intensive antirat campaign was underway, and many rats were known to have been present in the areas where these soldiers contracted their typhus. Both patients were aware of frequent fleabites prior to their illness but recalled no contact with lice.
On this evidence, Zarafonetis concluded that both patients had murine typhus and were of particular interest as instances in which epidemic typhus vaccination had been followed by murine typhus infection.94 The results of serological studies in these two cases are presented in table 31.
The foregoing reports, some of which were fragmentary, contained the principal clinical references made by U.S. Army personnel to murine typhus during World War II. To be sure, many individual cases were observed in
94See footnote 35 (3), p. 183.
Hawaii95 and other areas to which U.S. Army troops were sent,96 but these were not the subject of clinical reports.
LABORATORY AIDS IN DIAGNOSIS
The same laboratory procedures that were employed as diagnostic aids in epidemic typhus fever were also applied to murine typhus fever. The Weil-Felix Proteus OX-19 agglutination test and complement fixation and rickettsial agglutination tests with purified rickettsial antigens have the same degree of specificity and diagnostic values here as they have for epidemic typhus fever. Table 32 gives the results of each of these tests on sera from a nonvaccinated individual with murine typhus. The reader is referred to the laboratory section under epidemic typhus for detailed discussion of these and other diagnostic procedures which may be of value in murine typhus, such as the mouse-toxin neutralization test and strain isolation.
It will be recalled that while the complement fixation test with purified rickettsial antigens was specific for the homologous form of typhus, this test lost its high degree of specificity in patients with epidemic typhus fever who had been previously immunized with epidemic typhus vaccine of the
95Essential Technical Medical Data, United States
Army Forces, Pacific Ocean Areas, for July 1944.
Cox type,97 and the theory advanced by Zarafonetis to explain this finding has been discussed (p. 186). On inspection of table 31 it will be seen that a similar loss of specificity was found in tests on sera from murine typhus patients who had been vaccinated against epidemic typhus fever. Plotz and Wertman98 independently made the same observations. They had performed tests on sera from 147 cases of murine typhus in soldiers stationed in the United States. Of these, 135 had the typical serological response for murine typhus comparable to the pattern shown in table 32, but in 12 cases an unusual response was noted, as can be seen in table 30. These workers investigated these 12 patients with some care in an attempt to determine the factors responsible for the atypical serological findings.
Source: Plotz, H., and Wertman, K.: Modification of Serological Response to Infection With Murine Typhus by Previous Immunization With Epidemic Typhus Vaccine. Proc. Soc. Exper. Biol. & Med. 59: 248-251, June 1945.
It was found that all of these patients had received typhus vaccine some time or other within the preceding 2 years. The vaccine used consisted of formalinized epidemic rickettsiae with no murine rickettsiae whatsoever. All cases occurred in regions of the United States where murine typhus alone is known to exist and in some instances other cases of murine typhus were present in the same camp at the time these cases were admitted to the hospital. The clinical diagnosis of murine typhus seems to have been well substantiated. All cases developed a typical rash. A rise in OX-19 titers occurred in the late febrile period and early convalescence in 6 cases, while most of the others showed high titers. The febrile period varied from 8 to 23 days with an average of about 14 days. Unfortunately, no attempt was made to isolate the agents.
97See footnote 35 (3), p. 183.
These investigators note further that, while many of the specimens in these 12 vaccinated cases showed higher complement fixation titers to epidemic than to murine antigen, there was considerable cross-fixation and a number of specimens were equally responsive to both antigens (table 30). They contrast this with the nonvaccinated patients infected with epidemic typhus, in whom there are high titers to epidemic antigens with, as a rule, no considerable cross-fixation. Again, in nonvaccinated patients with murine typhus, the complement fixation titer is higher with homologous than with heterologous antigen, and there is little crossing (table 32). On the other hand, rickettsial agglutination, in the 12 nonvaccinated cases, usually showed a higher titer to the murine antigen, but in many instances there was only a twofold difference in titer, and here again cross-agglutination is marked. The same type of antibody response occurred whether the typhus vaccine had been given 2 years or 1 week before the attack of murine typhus and was not seen in patients vaccinated against typhus who subsequently became infected with atypical pneumonia, measles, infectious hepatitis, smallpox, meningitis, or other viral, bacterial, or protozoal infections. As regards symptoms and clinical course, they note, the previous vaccination against epidemic typhus had no apparent effect upon the severity of the subsequent attack of murine typhus.
Thus, the rickettsial agglutination test appeared to offer the most reliable means by which one might make the serological diagnosis of murine typhus in a patient who had previously been immunized with the Cox type of epidemic typhus vaccine.
Part IV. Summary
Our knowledge of typhus fever at the beginning of the war was so incomplete, and during the war was so greatly expanded, that it seems appropriate to sketch here the composite picture of epidemic typhus that now emerged.
Clinical picture-The incubation period of louseborne typhus fever varies from 7 to 20 days, with the usual onset about 10 to 12 days after infection occurs. A prodromal stage of ill-defined malaise probably exists for a few days, but is of no diagnostic value. In the majority of adult patients, the clinical onset is abrupt with malaise, chills or chilly sensations, followed by severe headache and fever. There is anorexia, and sometimes vomiting. The temperature rises rapidly during the first day or two to 104° F., or higher, where it remains throughout the greater part of the acute illness. The pulse rate usually exceeds 100 beats per minute and remains full at least throughout the first days of illness. Severe aches and pains appear early, and the thigh and calf muscles are sensitive to pressure. An
early symptom is a roaring sound in the ears, which may be followed by temporary deafness. Dyspnea and cough appear by the second or third day. The tongue and mouth become dry and fissured, and thirst is a common symptom. The patient is tense and anxious from the beginning, but mental disturbances do not usually appear until about the end of the first week. These may be stupor or a period of excitement, even of delirium.
There are no diagnostic features prior to the characteristic eruption, appearing usually between the fifth and seventh day of disease. Initially, it consists of faint rose-colored spots, 2 to 6 mm. in diameter, round to irregular in shape. The lesions first appear over the upper anterior chest wall, in the axillae and inner surfaces of the upper arms, on the abdomen, lower back, and buttocks. The rash usually develops rapidly and extends in a few hours to cover the back, the lower arms and dorsal aspects of the hands, and the legs to the knees. The face and scalp are spared; only rarely does the eruption involve the palms and soles (fig. 34). The characteristic lesion is macular at first, but may become papular after a few hours. At the beginning, the lesions will fade on pressure, but they usually become fixed within 24 hours. Also, as the disease progresses, the lesions increase in number and size and may become confluent. Along with the appearance of the rash, the conjunctivae become injected and the eyelids appear puffed. The face may take on a dusky, cyanotic hue. Typically, the eruption fades rapidly at the time of defervescence.
By the end of the first week, the patient enters the critical stage. The fever continues unabated, the delirium and cough are intensified. The heart rate is rapid and hypotension develops. The patient may be incontinent of urine and feces and may be all but helpless. In the absence of complications, there may be gradual improvement as the fever begins to fall some 2 weeks or more after its onset. Some patients undergo a crisis with return of the temperature to normal in 24 hours, while in others the decline may be gradual over a period of 2 or 3 days. As the fever disappears, the headache vanishes, the mind clears, and the appetite returns. Recovery of strength and nutrition is fairly rapid, but deafness and tinnitus may persist for several weeks.
The clinical picture can vary widely, depending on what organs are predominantly involved or on complications. Pathological studies have shown that the rickettsiae localize first in endothelial cells of the intima and then enter large mononuclear cells which collect about blood vessels. Proliferation of vascular endothelium and of mononuclear cells around blood vessels results in nodular accumulations. This focal, endothelial, proliferative, and infiltrative response to the infection occurs in the skin, brain, heart, skeletal muscles, spleen, adrenals, and other organs in varying degree. Clinically, the characteristic rash and signs referable to the central nervous system reflect the underlying lesions. The myocardium is also commonly affected, while the lungs may show a rickettsial pneumonitis.
The leukocyte count is frequently reduced during the first week, with neutropenia and a relative lymphocytosis. Eosinophils are absent or reduced during the febrile course. Mild normochromic anemia not uncommonly develops, but there is a return to normal values during convalescence. Albuminuria is uniformly present during the period of fever. Granular casts usually appear in large numbers in patients with azotemia. Elevation of the blood urea nitrogen is often observed during the second week of illness, especially in severely ill patients. The total serum proteins may be normal or slightly reduced, but reversal of the albumin-globulin ratio is commonly noted. This is due to an increase in serum globulin, the values for which usually range from 4 to 5 mg. percent. Reduction in the serum chlorides is also common. Apparently, the chlorides are not lost through excretion during the disease, since the values spontaneously return to normal after defervescence.
Diagnosis-During an epidemic of typhus fever, the diagnosis may be suspected before the appearance of the rash. A history of abrupt onset with chills, fever, severe headache, louse infestation, or contact with lice or with typhus patients leaves little doubt as to the nature of the illness. Certain other coexistent diseases may, however, complicate early diagnosis. Smallpox, louseborne relapsing fever, typhoid, and meningococcal meningitis may all be confused with early typhus. Once the characteristic rash has appeared there is usually little difficulty in making a clinical diagnosis, although meningococcemia, measles, and relapsing fever with exanthem must also be considered. Murine typhus is not clinically distinguishable from louseborne typhus in the individual case. Differentiation between these two forms of typhus fever, as well as establishment of the final diagnosis, is dependent upon certain laboratory studies. The diagnosis may be made by isolating the micro-organism from the blood of the patient and identifying it through biological and other tests. More practical, however, being less expensive and time consuming, are the serological tests, which include complement fixation with purified rickettsial antigens, rickettsial agglutination, and Weil-Felix Proteus OX-19 agglutination. These should be performed on two or more serum specimens obtained from the patient during the acute illness and convalescence in order to detect a significant change in antibody titer. Sera from patients with louseborne typhus fever, in complement fixation tests, yield higher titers with epidemic typhus antigen than with murine antigen. The same relationship obtains in rickettsial agglutination tests. With respect to the OX-19 test, a significant change in titer may be observed but is relatively nonspecific, since it occurs in murine typhus and Rocky Mountain spotted fever as well as in epidemic typhus fever. Usually, all three of these tests reveal diagnostic (fourfold or more) changes in titer with their respective antigens. Rarely, however, there may be a dissociation of response, and one of the tests may give completely negative results throughout. Sera from patients who have contracted epidemic typhus fever after vaccination against
FIGURE 34.-Typhus fever patient on U.S.A. Typhus Commission Ward, Fever Hospital, Cairo, Egypt. A. On 18 April 1943, the 10th day of disease, the eruption is clearly evident on the chest and upper arms. B. Same day, extent of rash on the back.
FIGURE 34.-Continued. C. Same day, although sparse, the eruption was also present on the palms. D. On 2 May, 24th day of disease, the rash has now disappeared and the patient is convalescing. Note loss of weight.
it exhibit much more cross-reaction in the complement fixation tests than do sera from unvaccinated patients, but the rickettsial agglutination test appears to retain specificity in vaccinated as well as in nonvaccinated cases.
Natural course-In the untreated case (that is, the unvaccinated patient given no specific therapy), typhus fever runs its course in 14 to 20 days unless terminated by death. The mortality varies in different epidemics and is also greatly influenced by age. An overall death rate of 20 to 30 percent was reached in Egypt and at Naples during World War II in patients 18 to 50 years old. At the Dachau Concentration Camp, however, the typhus death rate was only 9.1 percent. In past epidemics, the fatality rate has been as high as 70 percent. The disease is relatively mild in children, but it tends to be severe with a high mortality in old people.
Deaths are rare in the first week of illness. In severely ill untreated patients, evidence of increasing involvement of the central nervous system often appears during the second week of disease. They may become deeply stuporous, comatose, and die. Convulsions presage a fatal outcome. Other patients develop signs of renal insufficiency, and still others present the picture of peripheral vascular collapse during the second week. There is a striking correlation between clinical severity and the development of azotemia with elevated blood urea nitrogen and creatinine levels. These changes appear to be caused primarily by extrarenal factors, such as greatly increased protein breakdown, dehydration, and hypotension, rather than by a true diffuse renal lesion. Azotemia was detected in every fatal case of the Cairo series, although not every patient who exhibits this change will die. Survivors showed no evidence of renal impairment when tested several months after the acute episode.
The appearance of peripheral circulatory failure is usually indicative of impending death. The extremities become cold and cyanotic, the blood pressure drops to low levels, and the pulse becomes rapid. The basis for this peripheral vascular failure is unknown, but extensive involvement of the capillaries, injury to the vasomotor centers of the brain, and severe myocarditis are probably important contributing factors. Electrocardiographic findings in typhus fever are nonspecific and consist of low voltage, inverted T waves, depression of ST segments, and an increase in PR interval.
The most important complications are bacterial pneumonia, multiple skin abscesses, and parotitis. Although gangrenous involvement of the extremities has been associated with a number of typhus epidemics, it was rarely observed in World War II outbreaks, except at Belsen.
Immunity and relapse-Immunity is good in untreated subjects who recover from epidemic typhus fever. Delayed relapses do occur, however, and constitute Brill's disease. Relapses are common in patients who receive rickettsiostatic therapy during the first few days of illness, but uncommon if treatment is initiated after the eruption has appeared.
Therapy.-During World War II, PABA was found to have antirickettsial properties and was effective in the treatment of epidemic typhus fever in patients who had as well as in those who had not been vaccinated. Thoroughly studied, it was brought to the position of a safe and promising drug for clinical use.
Prophylaxis-Effective protection of the troops was accomplished by the use of a potent vaccine and its production in adequate quantities, and by improved methods of louse control.
ENDEMIC (MURINE) TYPHUS
Although the studies on murine typhus during World War II were relatively limited in comparison with those undertaken in connection with epidemic typhus fever and scrub typhus, there was accumulated nevertheless sufficient information upon which to base the following summary description of the disease.
Clinical picture-The incubation period from actual exposure to the onset of acute illness ranges from 8 to 16 days. Woodward noted that headache, backache, and arthralgia are frequently experienced during the fourth to sixth day after exposure. For a day or so prior to the onset of illness, prodromal symptoms such as nausea and general malaise are common. The disease then begins with chills or chilly sensations, headache, and fever. Nausea and vomiting frequently occur during this early period. Generalized aches and muscular weakness may be pronounced.
The clinical features of murine typhus resemble those of epidemic typhus except that in the average case the disease is less severe than in the majority of cases of epidemic typhus. In endemic typhus, the patient's temperature increases in stepwise fashion for 3 or 4 days until it reaches its maximum level, and then usually ranges between 103° and 104° F. until defervescence occurs. The total febrile course averages 12 days, but may be a few days longer or shorter. Defervescence is by lysis over 2 or 3 days. A rash is observed in about 80 percent of cases, typically appearing on the fifth day of illness, but it may be seen several days earlier or later. When present, its character and distribution are similar to that in epidemic typhus. Occurring in all degrees of intensity, it usually persists for about 5 days, but may be ephemeral or may remain evident for 10 days.
In addition to intense headache, which is usually frontal, the average patient with murine typhus exhibits mild stupor, prostration, and lethargy. Transient partial deafness occurs at times. As in epidemic typhus, some involvement of the respiratory tract is common. A dry, hacking cough develops, usually in the second week, and crackling rales may be heard in the base of the lungs. These are believed to be manifestations of interstitial pneumonitis of rickettsial origin.
The pulse rate is increased and is usually regular. Minor electrocardiographic changes of nonspecific nature may be detected for a brief period. Persistent hypotension is not uncommon, especially during the second week of acute illness, and is attributed to a combination of factors including extensive vasculitis of the capillaries of the skin and other organs and involvement of the brain with injury to vasomotor centers. Clinical signs of myocardial failure are usually lacking, but this does not rule out myocarditis, which has been found in fatal cases of epidemic typhus fever.
There are no characteristic changes in the formed blood elements. Moderate albuminuria is not uncommon. Azotemia may develop in severe cases and is believed to be largely due to extrarenal factors.
Diagnosis-An illness characterized by an abrupt onset with headache, chills or chilly sensations, fever, malaise, prostration, nonproductive cough, and later the appearance of a rash should suggest typhus fever among the diagnostic possibilities. Epidemiological considerations and characteristics of the rash may aid in arriving at a tentative clinical diagnosis, but final differentiation rests upon the use of appropriate laboratory tests. These include complement fixation with purified rickettsial antigens, Weil-Felix Proteus OX-19 agglutination, rickettsial agglutination, and isolation of the strain by animal inoculation. The last is not practical for routine use, but the serological tests are adequate and more practical. They should be performed on two or more sera obtained from the patient during the acute illness and convalescence to show a diagnostic change in antibody titer. In endemic typhus, titers will be considerably higher with endemic than with epidemic antigen in the complement fixation test. The same relationship obtains in rickettsial agglutination. A significant rise in OX-19 agglutination titer may be helpful, but it does not differentiate between endemic typhus, epidemic typhus, and Rocky Mountain spotted fever. Sera from patients who have previously received epidemic typhus vaccine, and later contracted murine typhus, exhibit much more cross-reaction in complement fixation tests than do sera from nonvaccinated persons. The complement fixation test, therefore, does not differentiate the two forms of typhus in these patients, but the rickettsial agglutination test, according to available evidence, retains specificity in such cases.
Natural course-The usual course in adults is uncomplicated, with subsidence of fever toward the end of the second week, followed by an uneventful convalescence. The disease is readily tolerated by children, but less well by elderly persons. The mortality is 1 to 2 percent. Complications are infrequent and usually consist of secondary infections which give rise to parotitis, otitis media, or bacterial pneumonia.
Immunity-After an attack of murine typhus, immunity is apparently of long duration. Recrudescence, in a manner analogous to Brill's disease, has not been reported.
Therapy.-Treatment is the same as for epidemic typhus fever. Smith99 and civilian workers100 independently demonstrated the beneficial effect of large doses of PABA in the management of murine typhus.
Prophylaxis-Control measures are directed at reducing the rat populations that serve as the reservoir of the disease and the rat ectoparasites that serve as the vectors. Rat control measures include general sanitation, rat poisoning, and ratproofing of buildings. The principal method of ectoparasite control is by DDT dusting of ratruns and harborages.101
Prophylactic vaccination, although possible, is not usually practical in view of the sporadic occurrence of cases.
The preventive, clinical, and laboratory events concerned with the typhus fevers during World War II represent a brilliant chapter in the history of medicine. Many contributions were outside the scope of this review and are detailed elsewhere.102 No historical summary of typhus would be complete, however, without acknowledgment of the keen stimulation and wise guidance provided by Brig. Gen. Stanhope Bayne-Jones and Brig. Gen. Leon A. Fox, Director and Field Director, respectively, of the United States of America Typhus Commission. The U.S. Army Medical Department can be justly proud of the contributions made by its members under the leadership of these men.
99Smith, P. K.: The Use of Para-Aminobenzoic Acid
in Endemic (Murine) Typhus Fever. J.A.M.A. 131: 1114-1117, 3 Aug. 1946.