History

CHAPTER VII

The Typhus Fevers

Chris J. D. Zarafonetis, M.D.

Part I. Epidemic Typhus

Epidemic typhus fever is an acute febrile disease caused byinfection with Rickettsia prowazeki. It is a louseborne infection and ischaracterized clinically by sustained high fever, headache, malaise, and lateran 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 exanthematiqu? (French), el tabardillo (Spanish), and hassinchifusu (Japanese).

For centuries, epidemics of typhus fever have been associatedwith war, revolution, and famine, and have indeed, in the past, been a factoraffecting the outcome of wars. The death toll exacted in some epidemics has beenestimated in millions of lives. An account of the historical role of typhusfever has been written by Zinsser,^l and Strongand his associates²have documentedthe great Serbian epidemic of 1915.

Clinically, no differentiation was made between typhoid feverand 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 thepresence of typhus in the New World. That typhus is transmitted by Pediculushumanus var. corporis was discovered by Nicolle, Comte, and Conseilin 1909. The causative agent, R. prowazeki, was first described in 1916 by DaRocha-Lima. For many years, it was believed that there was only one form oftyphus fever, but it is now known that the epidemic louseborne form and theendemic fleaborne typhus are caused by different micro-organisms. It has beenfurther shown that epidemic typhus fever may be recrudescent in a patient yearsafter the original illness, in the disorder known as Brill's disease.

EPIDEMIOLOGY

Typhus fever exists in many parts of the world, with important foci in theBalkans, 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 feedingupon typhus patients during the febrile period. The rickettsiae multiply in thecells lining the intestinal tract of the louse. A week

¹Zinsser, Hans: Rats, Lice and History. New York: Little, Brown and Co., 1934.
²Strong, Richard P., Shattuck, George C., Sellards, A. W., Zinsser, Hans, and Hopkins, J. Gardner: Typhus Fever With Particular Reference to the Serbian Epidemic. Cambridge, Mass.: Harvard University Press, 1920.

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or 10 days after the vector has become infected, theparasitized cells rupture and large numbers of rickettsiae begin to appear inits feces. Lice prefer the normal temperature of the body and usually remainclose to their human host. If the temperature is raised by fever or lowered bydeath, however, they will migrate to a new host. Here, lice suck blood anddefecate as they feed, and when the site of the bite is scratched, the infectedfeces are rubbed into the skin. This appears to be the principal means by whichthe infection is passed from man to man. It is also possible to acquire it bycrushing an infected louse upon the skin, or by having dried infected feces comeinto contact with the conjunctivae or the mucous membranes of the respiratorytract. Infection with typhus rickettsiae is eventually fatal to the louse.

Conditions that predispose to louse infestation naturallypredispose to epidemics of typhus fever. The scene is set by crowding,inadequate housing, lack of bathing facilities, lack of fuel, and such continuedcold weather that people wear their garments for long periods of time. Oncelouse infestation is prevalent, introduction of the infection, either from apatient with typhus or from one with the recrudescent (Brill's) disease, may setoff an epidemic. The chaotic effects of war and famine, shifting populations,and the breakdown of orderly processes of government contribute conditions thatfavor spread of the infection.

At the beginning of World War II, it was evident thatAmerican troops would be exposed to typhus fever in most oversea theaters ofoperations. It was recognized that few physicians in the Armed Forces would havehad experience with a disease conspicuous by its absence from the continentalUnited States. Against this background, the United States of America TyphusCommission was created by the Secretary of War on 22 October 1942 in response toa staff-approved recommendation of The Surgeon General, initiated by Col. (laterBrig. Gen.) James S. Simmons, MC, and established by Executive order ofPresident Roosevelt on 24 December 1942.³ Theorder 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 comprehensivemandates and authorizations of this broadly conceived Executive order, and ofthe impetus given to the work by the director, field director, and members ofthe Commission, typhus investigation was intensified, leading to the developmentof specific diagnostic procedures, improved methods of treatment, thelarge-scale production of a potent vaccine, and excellent louse-controlmeasures. For detailed information regarding epidemiology and preventivemeasures, and a history of the Typhus Commission, the reader is referred to thebrilliant account by Stanhope Bayne-Jones in another volume in the history ofthe 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.
⁴Bayne-Jones, Stanhope: Typhus Fevers. In Medical Department, United States Army. Preventive Medicine in World War II. Volume VII. Communicable Diseases: Arthropodborne Diseases Other Than Malaria. [In preparation.]

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CLINICAL EXPERIENCE

Although epidemic typhus fever posed a constant threat tosoldiers 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 measuresthat were implemented for the protection of U.S. troops in areas where epidemicsof louseborne typhus were prevalent among civilian populations. As one result ofthis splendid record, there was no opportunity for medical officers in variousstation and general hospitals to accumulate extensive experience with epidemictyphus in our troops. The clinical studies to be recorded here are, therefore,largely those performed by members of the Typhus Commission, and are generallyconcerned with the disease as observed in civilian populations. This is incontrast to the observations on scrub typhus in the several excellent studiesmade by other medical officers and units in addition to the contributions of theU.S.A. Typhus Commission (pp. 116-138).

TABLE 13.-Epidemic typhus in French North Africa, Egypt, and Iran, 1930-44

Year	Number of reported cases
Year	French North Africa	Egypt	Iran¹
1930	529	288	(²)
1931	930	265	1,167
1932	965	2,298	1,544
1933	1,671	7,865	327
1934	1,456	7,536	1,212
1935	1,977	3,151	619
1936	2,182	2,757	202
1937	8,921	2,083	116
1938	11,377	2,867	16
1939	9,353	4,239	86
1940	3,547	4,135	397
1941	21,726	9,324	245
1942	77,335	23,941	1,102
1943	27,340	40,084	12,885
1944	6,226	18,533	6,436

¹Data pertain to cities only.
²Data are not available.

Source: (1) Stowman, K.: Typhus During the War. Epidemiol.Inform. Bull. 1 (7): 289-310, 30 Apr. 1945. (2) Current Reports on thePrevalence 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 FeverHospital, Egypt, in March 1943.⁵ The Ministryof Health of the

⁵Minutes, Conference on Typhus, National Research Council, 22 June 1944.

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Egyptian Government provided the study ward and space forlaboratories. During the 1943 and 1944 seasons, 159 patients with typhus feverwere admitted to this ward, and numerous other cases were observed in otherwards of the hospital. With three exceptions, all of the patients studied on theCommission ward were males. Their ages ranged from 10 to 70 years, the greatmajority falling in the 21- to 35-year age group. In general, the patients wereselected as early in the disease as possible. The majority were admitted betweenthe 5th and 10th day of illness. A few were admitted on the first day ofdisease, while in four instances, patients were actually under observationbefore the onset of illness.

TABLE 14.-Incidenceof epidemic typhus fever (louseborne) in the U.S. Army, by area and year, 1942-45

[Preliminary data based on sample tabulationsof individual medical records]
[Rate expressed as number of cases per annum per 1,000 average strength]

Area	1942-45		1942		1943		1944		1945
Area	Number of cases	Rate	Number of cases	Rate	Number of cases	Rate	Number of cases	Rate	Number of cases	Rate
Continental United States	---	0.00	---	0.00	---	0.00	---	0.00	---	0.00
Overseas:
Europe	10	0.00	---	0.00	---	0.00	---	0.00	10	0.00
Mediterranean¹	16	.01	1	.04	12	.03	3	0	---	0
Middle East	14	.10	1	.17	8	.15	---	0	6	.12
China-Burma-India	63	.14	1	.11	25	.63	12	.07	25	.11
Southwest Pacific	---	0	---	0	---	0	---	0	---	0
Central and South Pacific	1	0	---	0	1	0	---	0	---	0
North America²	---	0	---	0	---	0	---	0	---	0
Latin America	---	0	---	0	---	0	---	0	---	0
Total overseas	104	0.01	3	0.01	46	0.03	15	0.00	40	0.01
Total Army	104	0.00	3	0.00	46	0.01	15	0.00	40	0.01

¹Includes North Africa.
²Includes Alaska and Iceland.

This section of the chapter will be restricted to aconsideration of the unvaccinated subjects who received no special therapybeyond supportive measures. There were 64 such "untreated" casesstudied on the Commission ward. The severity of the clinical course of thedisease was estimated for each patient after discharge from the hospital. Theprincipal factors which influenced the estimation of severity were the intensityof 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 referableto 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-

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monia, otitis media, parotitis, furunculosis, and gangrene.⁶On the basis of these criteria, these cases were grouped as follows:

B. Cases with minimal signs and symptoms, yet definitely diagnosed as typhuson clinical evidence.

C. Cases of moderate severity, showing slight prostration, involvement of thecentral nervous system, cardiovascular changes, or mild complications.

D. Severe typhus cases with pronounced prostration, involvement of thecentral nervous system, cardiovascular changes, or serious complications.

E. Cases of such severe illness that at some point in the clinical course afatal outcome was expected.

F. Fatal cases.

Of the 64 cases of "untreated" typhus fever, therewere 2 in the B group, 14 in C, 26 in D, 7 in E, and 15 in F, the fatal cases, amortality of 23 percent. It was of particular interest that 33 (52 percent) ofthe patients developed nitrogen retention (nonprotein nitrogen over 45 mg.percent) during the disease. All 15 fatal cases were in this group, and nopatient died who throughout his illness had normal concentration of nonproteinnitrogen in the blood.

The following case histories, taken from a Commission publication,⁷will serve to illustrate typhus fever classified as severe (E or F):

Case 1 (classified as E; severe, withneurological involvement)-The patient, male,aged 25, was admitted on the sixth day of disease with headache as his chiefcomplaint. Temperature 40.7? C. p.r. Pulse 108. Respirations 36. Blood pressure126 mm. Hg systolic and 66 mm. diastolic. Weight 121 pounds. The patient wasmoderately well developed and nourished. He appeared mentally clear and notacutely ill. There was no tinnitus or deafness. The skin was dark; no evidenceof a typhus rash was seen. The conjunctivae were negative. The tongue was whitecoated and moist. The chest was clear to percussion and auscultation.Examination of the heart showed nothing remarkable.

Laboratory data on admission-Hemoglobin83 percent (CuSO₄); erythrocytes 4,500,000; leukocytes 7,550, with 81percent polymorphonuclear cells. Urine was amber in color, cloudy, reactionacid, and specific gravity 1.028. A few squamous epithelial cells, 1-2 granularcasts per low-power field, 1-3 leukocytes per high-power field were seen in thecentrifugated sediment. The concentration of nonprotein nitrogen was 46 mg. per100 cc. of blood. The plasma proteins were 6.8 gm. per 100 cc.

Hospital course (chart 4).-Throughoutthe first week of hospitalization the patient's fever remained high and the rashappeared, with intense conjunctival injection and the development of petechiaein the left conjunctival sac. The patient, actively delirious, became verytalkative and attempted to get out of bed. Intake by mouth continuedsatisfactorily until the 12th day of disease when subcutaneous injections of 5percent dextrose in saline and normal saline became necessary for the next 12days.

On the 13th day he became more stuporous andthen semicomatose. He lay with half-opened eyes, breathing quietly. Facialgrimaces and grinding of the teeth were noted. Fluid intake by mouth practicallyceased. He was put on constant bladder drainage on this day because of urinaryretention. 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.
⁷Yeomans, A., Snyder, J. C., Murray, E. S., Ecke, R. S., and Zarafonetis, C. J. D.: Azotemia in Typhus Fever. Ann. Int. Med. 23: 711-753, November 1945.

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CHART 4.-Clinical and laboratory findingsin patient with "E" severity typhus fever

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17th day of disease. The rash gradually faded out during thisperiod and the conjunctival suffusion disappeared.

On the 17th day slight improvement was noted in his mentalstate. He stared about the ward, his mouth open in a wide grimace. When spokento he replied in a series of unintelligible whining sounds. There was noindication that he recognized people. The rash was no longer visible.

In the next 2 days he was able to obey simple commands. It wasevident that he was almost totally deaf. On the 20th day his temperature reachednormal levels. Examination showed hyperactive knee jerks and ankle jerks butnormal plantar response. An area of skin necrosis appeared over the coccyx.

On the 22d day the catheter was removed. When he was spoken toit was obvious that he was attempting to reply, but he could not articulate andthe 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 graduallyincreased.

On the 27th day the patient was found to have not onlyhyperactive 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 wassteady but slow. The ability to stand and walk unassisted returned before theability to form words. At the time of discharge 68 days after the onset of thedisease, 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 patientshowed progressive improvement. Mentally he appeared alert. There was noresidual deafness. The reflexes in the lower extremities remained hyperactive,however, and speech was still slow, labored, and monotonous in tone. Examinationof the urine showed normal concentrating power, no albumin, and a negative urinesediment. The anemia that had developed during the disease was no longerpresent.

Case 2 (classified as F; fatal, with postmortem)-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. Hgsystolic and 64 mm. diastolic. Weight 116 pounds. The patient appearedmoderately ill, mentally clear, with rapid respirations, and no cough. A fewpoorly defined maculopapular lesions were noted over the chest, abdomen, andarms. The conjunctivae appeared moderately injected. The tongue was moist. A fewcrepitant rales were heard in the right midlung field posteriorly. Examinationof 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, butwas found enlarged 3 cm. below the costal margin by percussion.

Laboratory data on admission-Hemoglobin72 percent (CuSO₄); red cells 4,110,000; white cells 4,300, with 76percent polymorphonuclear cells. Urine was amber in color, reaction acid,specific gravity 1.023, albumin 2+,8-10 white cells per high-powerfield, and an occasional granular cast was seen in the centrifugated sediment.The concentration of nonprotein nitrogen was 30 mg. per 100 cc. of blood. Theplasma proteins were 6.5 gm. per 100 cc.

Hospital course (chart5).-In spite of frequent sponging, the patient continued to runa high fever from the fourth to the ninth day of disease. On the fifth day, themaculopapular rash increased, but the macules were still scanty and poorlydefined. On the sixth day, the patient became disoriented. On the eighth day hewas quite drowsy and vomited twice. His general condition, however, appearedsatisfactory. On the ninth day he became semicomatose. The pulse rate hadincreased to between 130-140 beats per

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CHART 5.-Clinical and laboratory findings in a fatal caseof epidemic typhus fever

minute. The blood pressure fell. The respirations were rapid. The neck wasresistant to passive flexion. Examination of the heart and lungs was negative.Spinal puncture revealed an initial pressure of 90 mm., and the dynamics werenormal. Seven cubic centimeters of spinal fluid was withdrawn. The finalpressure was 60 mm. The cell count of the spinal fluid was 5 per cu. mm. The Pandy test was negative. An electrocardiogram showed lowvoltage of the QRS complexes. The patient was given 1,000 cc. of 5 percentdextrose 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. Hewas given 100 cc. of concentrated human albumin intravenously. Subcutaneousinjections 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 adecrease in heart rate and a rise in blood pressure. The state of oliguriacontinued, however. There was no increase in the rash from the fifth day.

On the morning of the 11th day the patient had a generalized convulsiveseizure and died.

At post mortem examination 1 hour after death, the interesting findings wereas follows: The rash, which had been scanty throughout his illness, was notdiscernible. No gross areas of pneumonitis were noted in the right lung; theleft lung was crepitant throughout; the bronchi appeared normal. The heartweighed 330 gm.; no gross abnormalities were seen on the epicardial orendocardial surfaces; the ventricular walls were

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of normal thickness; the coronary arteries were patent. Theliver weighed 2,430 gm.; its was grayish in color, firm and rubbery inconsistency; the surface was lobulated, with numerous white fibrotic areas inthe depressions between the lobules. On section the cut surface was gray. Areasof dense fibrosis were present throughout the organ. Numerous adult schistosomeswere obtained from the blood in the portal vein. The spleen weighed 770 gm.; thesurface was mottled with numerous white, bluish, and reddish areas, some ofwhich were firm in consistency. On section the pulp was firm and deep red incolor. The surface patches extended a few millimeters into the spleen substanceand appeared to be demarcated by a narrow zone of hemorrhage.

The right kidney weighed 210 gm.; there were a few pinpoint hemorrhagicspots on its surface. On section the cortex appeared to be slightly pale. Thekidney pelvis appeared normal. The left kidney weighed 190 gm., with findingssimilar to those seen in the right kidney. The ureters appeared normal andpatent. 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 bluishand brownish discoloration. There were numerous elevated nodules of 0.5 to 0.7cm. in diameter with smooth surfaces. These were not pedunculated andwere pale green to blue black in color. The findings in the liver, bladder, andlarge bowel were secondary to an extensive Schistosoma infection.

Pathological physiology-The observation that there was ahigh incidence of nitrogen retention in their typhus cases led Yeomans and hisassociates to analyze the factors that might contribute to its development. Theyreasoned that-

* * * a fundamental consideration * * * [is] that the caloric and proteinintake of nearly all typhus patients is grossly insufficient. There is goodreason to believe that the destruction of the body tissues must be considerable* * *. In order to prevent the accumulation of nitrogenous metabolites in theblood, the excretion of an adequate [amount] of urine * * * is necessary. In thepresence of a greatly increased protein catabolism it is apparent thatdehydration with a diminished output of urine will have considerable effect uponthe degree of azotemia observed.

Another factor * * * in the more critically ill patients * * * is the onsetof renal insufficiency, most often associated with a rapid fall in bloodpressure. [This] * * * is of serious prognostic import. In our experience * * *the majority of these patients died with evidences of overwhelming rickettsialinfection or complicating conditions, such as pneumonia, [but] a rapiddiminution in kidney function was almost without exception the first indicationthat the patient would probably succumb to the disease. The * * * renalinsufficiency 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 renalfailure. At present we have no evidence to indicate that the loss of renalfunction observed in these critically ill patients was due to other thanextrarenal factors.

In French Morocco, Maj. Theodore E. Woodward, MC, of the U.S.A. TyphusCommission collaborated with Maj. (later Lt. Col.) Edward F. Bland, MC, 6thGeneral Hospital, in a study of 30 native patients with typhus fever.⁸ Theydraw a composite picture of the pathological physiology of severe typhus asfollows:

The patient is acutely ill and very toxic, with a significantly low arterialtension and a labile pulse. Usually, unless actively supported, the patientbecomes 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, 30Sept. 1944.

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red cells decrease and plasma proteins fall with aconsiderable loss of the albumin fraction, indicating a reduced colloidalosmotic pressure. All factors indicate a drop of blood volume with the patternof hypoproteinemia, hypochloremia, and hemodilution without blood destruction.The unstable circulation results in lowered glomerular filtration pressure, andhence oliguria and anuria occur. The kidney, partially damaged by the specificpathologic condition and called on to eliminate an increased amount ofnitrogenous waste, is unable to function normally unless adequately supported byfluids. Lowered blood volume means less adequate filling of the heart duringdiastole and hence lowered cardiac output. Each beat of the heart is lessefficient. The use of cardiac stimulants under these conditions is ineffectual,but when the volume of the blood is restored the organ can operate moreefficiently.

Woodward and Bland note that the typhus lesion had been demonstrated byWolback and his associates in heart muscle, in the kidney, and in almost everyother organ. However, the degree of both cardiac and renal changes they observedwas not disproportionate to the pathological changes occurring elsewhere, andfrom their clinical studies it appears "unlikely that cardiac failure assuch is often a significant factor in the outcome of the fatal case." Intreatment, they advocate "general supportive measures to increase thecirculating blood volume."

Metabolic studies-These observations focused attention on the azotemiaand hypochloremia associated with a high proportion of typhus fever cases. Sincea better understanding of electrolytes and protein metabolism was deemedessential for appropriate supportive treatment, Tierney and Yeomans⁹ undertookmetabolic studies in cases of typhus fever on the Commission ward in Cairo.

Tierney and Yeomans determined the carbon dioxide content andthe chlorides of the serum in 34 cases. They found the serum chlorides to be lowin 62 percent of the patients during the first 2 weeks of disease, but the serumcarbon dioxide content was appreciably reduced in only four cases. Explanationwas sought for the low serum chlorides in the early stages of typhus. The dietsof these patients were probably poor in salt prior to hospitalization, but thiswas not an important factor since there was no conspicuous chloride deficit inpatients admitted to the Commission ward with relapsing fever and typhoid fever.Perspiration was not a factor, as it was rarely observed; indeed, failure toperspire was noted in typhus patients not only in the dry climate of Egypt butalso in moist climates. The salt was not lost in the urine, for urinaryexcretion was in relation to the concentration of chlorides in the serum; whenserum chlorides fell below normal levels, the urinary chlorides diminishedmarkedly. The fact that the serum chlorides returned to normal spontaneously inspite of a poor salt intake was taken as evidence that the salt was notlost by the body and that the lowered chloride concentration was therefore dueto expansion of the extracellular fluid volume. During the early stage oftyphus, the patients frequently have nonpitting

⁹Tierney, N. A., and Yeomans, A.: Metabolic Studies inLouse-Borne Typhus; Observations on Serum Electrolyte Pattern, Serum ProteinPartition, and Nitrogen Balance. J. Clin. Investigation 25: 822-837, November1946.

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edema; in the later stage, shortly before defervescence thereis often a fairly marked diuresis. These observations are in keeping with thesuggestion that early in the disease there is an increase in extracellularfluids, which would lower the serum chlorides, and later in the disease there isa loss of extracellular fluid by diuresis with a resultant increase in serumchlorides. The pH was normal in all of the patients except one who had renalfailure and acidosis. The total base was also normal in all but one of thesubjects studied. In all instances, the quantity of undetermined acid anions wasincreased in the majority of cases equaling that found in severe metabolicacidosis.

The total serum proteins were normal in approximately 75 percent of thepatients, but the majority showed a depression of the albumin fraction and avery striking elevation of the globulin fraction to over 40 percent in theaverage case. An electrophoretic analysis¹⁰ of sera obtained from aseverely ill patient on the ward of the Cairo Unit of the Typhus Commissionshowed that the relative proportion of albumin and the albumin to globulin ratiowas markedly reduced on the fourth day of fever and through convalescence. Thealpha and beta globulins were practically unaffected, but the gamma globulin wasstrikingly increased on the fourth day and was even higher in convalescence.

Nitrogen balance studies were performed on 21 subjects. Eight of the patientswere 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 norelationship between nitrogen output and intake or between protein destructionand azotemia. A high-protein, high-caloric diet decreased nitrogen wastage andloss of body weight during the acute phase of typhus. Indeed, positive nitrogenbalance was achieved in five of the patients studied.

Dietary management-From these and other observations on the Commissionward, 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 diligentnursing, the average patient will ingest at least 90 gm. of protein and 2,500calories a day. If the patient is too ill to take the diet, Amigen may be givenintravenously.

2. The routine administration of large amounts of sodium chloride withoutdetermining the serum chlorides should be avoided. By including in the diet orin the parenteral fluids 4 to 6 gm. of sodium chloride a day, the serumchlorides should be kept within normal limits and good state of hydrationachieved. Usually, the fluid intake should be maintained between 3 and 4 litersdaily.

3. The urine output should be at least 1 liter a day, and preferably 1.5liters. As a marked drop in the urine output is an ominous sign, particularly

¹⁰Dole, V. P., Yeomans, A., and Tierney, N. A.: Electrophoretic Changes inthe Serum Protein Pattern of a Patient With Typhus Fever. J. Clin. Investigation26: 298-300, March 1947.

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if associated with a fall in the arterial blood pressure, plasma or bloodtransfusions in such cases are urgently required.

4. In cases of shock or impending shock, plasma or bloodtransfusions are indicated. The effect of plasma or blood transfusions onhypoalbuminemia is transient. In order to produce any significant change, verylarge amounts of plasma over a period of days would be required.

5. Acid salts, such as ammonium chloride, are obviously contraindicatedbecause of the increase in undetermined acids in the blood.

Epidemic in Italy-The clinical observations that havebeen 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, andoften chaotic, conditions throughout Europe and the Far East. In a fewinstances, efforts were made to glean clinical data even under the most adverseof circumstances. These reports will be mentioned briefly.

The epidemic at Naples, Italy, during 1943 and 1944 involvedsome 1,407 cases within the city itself and 492 cases outside Naples. Vigorousapplication of delousing measures quickly brought this epidemic under control.This historic accomplishment has been detailed by Bayne-Jones.¹¹ Here, itwill suffice to note that the case fatality rate was about 22.6 percent.Woodward,¹² in his report of the activities of the flying squadrongroup for typhus control outside Naples, recorded brief observations on 257cases diagnosed on the basis of clinical findings, along with serological tests.Of interest was the relatively high incidence in children, many of whom showed acharacteristic 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 tothe 21st Army Group, recorded the typhus fever epidemic that occurred at theBelsen Concentration Camp, Belsen, Germany.¹³ This camp was taken by theBritish Second Army on 15 April 1945. Among the 61,000 inhabitants, there waswidespread suffering from starvation, typhus, dysentery, tuberculosis, and otherdiseases. Typhus had been prevalent in the camp for 4 months, and there wereapproximately 3,500 cases at the time of liberation. Practically all of theinternees were heavily infested with lice.

Davis stated that the appraisal and diagnosis of cases was peculiarlydifficult in this group. Prostration, semistupor, dehydration, loss of weight,weakness, tremors, and a petechial rash, which are considered characteristic oftyphus, were so common in the starving, louse-infected people that he

¹¹Bayne-Jones, Stanhope: Epidemic Typhus in theMediterranean Area During World II. In Rickettsial Diseases of Man. Washington:American Association for the Advancement of Science, 1948, pp. 1-15.
¹²Woodward, T. E.: History of Flying Squadron Group for Typhus Controlin Italy. To the Field Director, U.S.A. Typhus Commission, 29 Mar. 1944.
¹³Davis, W. A.: Typhus at Belsen. I. Control of the Typhus Epidemic. Am. J. Hyg. 46: 66-83, July1947.

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found these signs of little value. The rash was mild; very few had ecchymoses, and the usual finding was a scattered petechialexanthem best seenafter the patient had been washed. Gangrene was common, particularly drygangrene of the toes. Pleuritic pain was a frequent complaint in the post-typhusperiod. About 30 cases of parotitis were observed that required incision.Several patients had polyneuritic leg pains, which may have reflected vitamin Bdeficiency exacerbated by the increased metabolic demands of fever. Nostatistics 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 April1945. Measures were taken to control the disease, and special clinicalfacilities were made available to the Typhus Commission¹⁴at the 116thEvacuation Hospital. On 16 May 1945, six nurses from the 59th EvacuationHospital arrived and began their duties on the Typhus Commission Service, aspecial 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 serumtherapy as discussed in the section ontreatment (p. 192). Here, the data on 121 untreated controls are of interest.These were male patients of various nationalities in the wards of the 116thEvacuation Hospital, ranging in age from 17 to 58 years, with an average age of28 years. The duration of fever averaged 16.2 days in this group.

Of particular interest is the observation that the typhus fever encounteredat Dachau was clinically a mild disease. Fewer patients were seen withfull-blown rashes than in other epidemics. There appeared to be less prostrationand delirium, and a shorter convalescence. To be sure, there were some severecases, but not so many as had been expected. The comparative mildness of thedisease was surprising to Commission observers who had seen patients in Cairo,Naples, and elsewhere, and had anticipated that the general debility of theDachau patients would predispose them to a considerable mortality. The fatalityrate 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 encounteredamong civilian populations in other areas of the European Theater of Operations,U.S. Army,¹⁵and in Japan and Korea,¹⁶ butcircumstances prevented the undertaking of special clinical studies during theseepidemics.

¹⁴A Report on the Activities of the U.S.A. Typhus Commission at the DachauConcentration 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.
¹⁵Gordon, John E.: Louse-Borne Typhus Fever in the European Theater ofOperations, U.S. Army, 1945. In Rickettsial Diseases of Man. Washington:American Association for the Advancement of Science, 1948, pp. 16-27.¹⁶Scoville, Addison B., Jr.: Epidemic Typhus Fever in Japan and Korea. In Rickettsial Diseases of Man. Washington: American Association for the Advancement ofScience, 1948, pp. 28-35.

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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-Earlywork by Da Rocha-Lima(1918) and Weigl (1920) suggested that killed suspensions of typhus-infectedlice or infected louse feces could endow some immunity as vaccines. However,these and other methods advanced for vaccine preparation up to 1938 were notpractical for large-scale production. It was a highly significant discovery,therefore, when Cox¹⁷demonstrated in 1938 that rickettsiae could begrown in the yolk sac of the developing chick embryo. Cox and Bell¹⁸soonprepared an epidemic typhus vaccine which consisted of a killed suspension ofmicro-organisms grown in yolk sacs and purified by centrifugation. Subsequentmodifications included an ether-extraction technique devised by Craigie¹⁹andthe incorporation of soluble antigen in the vaccine.²⁰ The resultantproduct was not only satisfactory from the standpoint of potency but was alsofeasible for commercial production. The final product used by the U.S. Armyconsisted of a 10-percent yolk-sac suspension of the Breinl strain of R.prowazeki, extracted with ether; it contained both killed microorganisms andsoluble substances. Up through 1943, the initial vaccination for U.S. Armypersonnel consisted of three injections of the vaccine, 1.0 cc. each,administered subcutaneously at intervals of 7 to 10 days, with stimulating dosesgiven every 6 months in endemic areas. As the vaccine was improved in potencythrough improvement in production, the initial immunization series was reducedin mid-1944 to two doses of vaccine, with

¹⁷Cox, H. R.: Use of Yolk Sac of Developing Chick Embryo as Medium forGrowing Rickettsiae of Rocky Mountain Spotted Fever and Typhus Groups. Pub.Health Rep. 53: 2241-2247, 23 Dec. 1938.
¹⁸Cox, H. R., and Bell, E. J.:Epidemic and Endemic Typhus: Protective Value for Guinea Pigs of VaccinesPrepared From Infected Tissues of Developing Chick Embryo. Pub. Health Rep. 55:110-115, 19 Jan. 1940.
¹⁹Craigie, J.: Application and Control of Ethyl-Ether-Water InterfaceEffects to the Separation of Rickettsiae From Yolk Sac Suspensions. Canad. J.Research, Sect. E. 23: 104-114, June 1945.
²⁰(1) Plotz, H.: Report on the Testing of Four DifferentTyphus Vaccines in Guinea Pigs, 20 Mar. 1942, to Col. George R. Callender, MC,Director, Army Medical School, Army Medical Center, Washington, D.C. (2)Topping, N. H., and Shear, M. J.: Studies of Antigens in Infected Yolk Sacs.Pub. Health Rep. 59: 1671-1675, 29 Dec. 1944.

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stimulating doses at the beginning and in the middle of the typhus season (1November and 1 February in the Northern Hemisphere).²¹

As might be expected, a satisfactory field trial of vaccineof the Cox type was one of the principal objectives of the Typhus Commissionwhen it was formed in 1942.²² In January 1943, the field group of theCommission, with the cooperation of the Egyptian Ministry of Public Health,began a study on the effect of the vaccine in a large number of personsintimately exposed by their occupations to naturally acquired typhus fever. Thisstudy was continued through the epidemics of 1943 and 1944. The subjects wereemployees of the Cairo Fever Hospital at Abassia and the Embaba Hospital.Because of the exceptionally large numbers of patients with typhus beingadmitted to these hospitals, the hospital staff was unusually exposed to theinfection, and in addition many of the employees lived in areas of the citywhere attack rates were high. Before 1943, these workers had not been vaccinatedagainst typhus. During 1943 and 1944, vaccine of the Cox type was, accordingly,administered to all employees who desired it. Careful records were kept on morethan 800 employees at Abassia and over 500 at Embaba. Most of those whocontracted febrile illnesses, whether vaccinated or not, were seen by one ormore of the Commission members. During the course of these two typhus seasons, agroup of 61 postvaccination cases were observed.

Despite the mild course that distinguished many of thesecases, Ecke and his associates²³ usually found it possible to recognize thedisease on clinical grounds alone, and laboratory tests confirmed the diagnosisin almost every case. In some patients, however, the diagnosis of typhus wasmade only by a rise in titer in the Weil-Felix and complement fixation testsduring illness or in early convalescence. The diagnostic significance of theselaboratory aids had been worked out by Zarafonetis in studies of 100 knownfebrile illnesses other than typhus and 16 definite cases of postvaccinationtyphus. In brief, he found that, on the one hand, nontyphus febrile illnesses donot evoke high complement fixation titers in the sera of patients who have hadmultiple doses of vaccine of the Cox type. On the other hand, typhus infectionsregularly do stimulate high complement fixation titers in the sera of vaccinatedpatients. Similar results were usually obtained with the Weil-Felix test. Sointerpreted, these laboratory aids could be relied upon in those cases where theclinical evidence alone was inadequate for diagnosis, either because ofinconspicuous symptoms or insufficient observation (p. 179).

²¹Sadusk, J. F., Jr.: Typhus Fever in the United States ArmyFollowing Immunization: Incidence, Severity of the Disease, Modification of theClinical Course, and Serologic Diagnosis. J.A.M.A. 133: 1192-1199, 19 Apr. 1947.
²²See footnote 3, p. 144.
²³Ecke, R. S., Gilliam, A. G., Snyder, J. C., Yeomans, A..Zarafonetis, C. J. D., and Murray, E. S. The Effect of Cox-Type Vaccine onLouse-Borne Typhus Fever; An Account of 61 Cases of Naturally Occurring TyphusFever in Patients Who Had Previously Received One or More Injections of Cox-TypeVaccine. Am. J. Trop. Med. 25: 447-462, November 1945.

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These postvaccination cases were arbitrarily classified in the categoriesdevised 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 definitediagnosis of typhus on clinical evidence alone was not possible, the finaldiagnosis being made only with the aid of laboratory data." The cases werefurther grouped according to the amount of vaccine received and the intervalbetween the last inoculation and the onset of illness.

The course of typhus fever in vaccinated Egyptians was recorded by the TyphusCommission observers, as follows:

Group 1 (three doses of vaccine at least 21 days prior to onset).-Clinicalnotes from the records of five patients who were thoroughly studied on theCommission ward illustrate some of the features of postvaccination typhus.

Case 1.-Three doses of vaccine, the last dose 39 daysbefore onset. Male, aged 45 years. This patient had a severe chill the firstday combined with frontal headache and, later, joint pains. Rash was moderate.His mild course was marked latterly by the development of bilateral costovertebral painand microscopic hematuria. After12 days of moderate elevation of temperature he continued to maintain alow-grade fever until the 21st day. (The importance of his hematuria in relationto 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 andmalaise. The rash was fleeting but definite. With the history and the rash nodifficulty 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 daysbefore onset. The patient, male, aged 45 years, appeared to be at least 55. Hewas never especially ill during his course. He developed a tremor of his limbs,almost parkinsonian in character. This disappeared during convalescence. Feverlasted 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; saidhe felt "weak," but had no specific complaint. There was nothing tobe found but a very few fleeting macules requiring careful search. There was noconjunctival injection. Fever lasted 10 days. Clinical classification ofseverity: B.

Case 5-Five doses of vaccine, the last dose 79 days before onset. Anobese male, aged 33 years. He complained of generalized body pains, especiallyin the knees, and said he felt "feverish." He had severe headache.There was some tinnitus and slight deafness. His course was mild. Fever lasted 8days. Clinical classification of severity: B.

The average duration of fever for all the patients in group 1 was 10? 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 weremales, average age 31.8 years.

Group 2 (two doses of vaccine at least 21 days prior to onset).-The sevenpatients in group 2 had an average duration of fever of 12 days. The cases wereclassed as follows: 4 in B, 3 in C. Four patients were females, average age 19years. Three patients were males, average age 28 years.

Group 3 (one dose of vaccine at least 21 days prior to onset).-The 11patients in group 3 had an average duration of fever of 12.7 days. The cases

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were classed as follows: 2 in B, 8 in C, and 1 in D. Five patients werefemales, 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).-Therewere 17 patients in group 4. The average duration of fever in the nonfatal caseswas 15 days. The cases were classed as follows: 4 in B, 8 in C, 4 in D, and 1 inF. There were 12 females, average age 23.6, and 5 males, average age 27.8years.

In discussing these results, Ecke and his coworkers pointed out that, beforethe vaccination program was undertaken, typhus fever among the employees of theCairo Fever Hospital was characteristically severe. The relatively few employeeswho remained unvaccinated and contracted typhus during the study period werelikewise severely stricken. By contrast, among those who had received two ormore doses of Cox vaccine 21 days or more before the onset of illness (groups 1and 2), there were no severely ill patients, that is, D, E, or F cases, whereastwo-thirds of the unvaccinated patients in the same age groups fell into thesevere groups, D, E, or F. (Compare with the 64 nonvaccinated cases summarizedon p. 147.) On the basis of these observations, and insofar as attenuation ofclinical course is concerned, it was postulated that adequate vaccinationagainst typhus could be defined as two or more doses of Cox-type vaccine ofstandard potency administered more than 21 days before the onset of typhus.

On the basis of their observations during this study, Ecke and his coworkersrecommended that vaccination be included in epidemic control programs.

Sadusk²⁴ consolidated much of the information regardingepidemic typhus fever that occurred in U.S. Army personnel subsequently toimmunization. His report contains details of five cases, three in members of theTyphus Commission. These case histories will illustrate the course of typhusfever in vaccinated Americans and, at the same time, will serve as a reminder ofthe added health hazards to which medical officers are at times exposed in lineof duty.

Case 1-A 41-year-old male officer, member of the U.S.A.TyphusCommission, for almost a month before the onset of illness was engaged in typhusresearch 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 grindinginfected louse feces for injecting into experimental animals. During thepreceding 2 years, this officer had received a total of 22.0 cc. of vaccine insingle 1.0 cc. doses. Five cubic centimeters of this vaccine was of anexperimental lot and contained both epidemic and murine virus. The last dose ofvaccine was given on 1 March 1944.

On 21 May 1944, the patient had a mild headache, generalmalaise, and felt feverish. Although the headache became more severe and thetemperature ranged between 100.0? and 101.0? F. during the next 3 days, hecontinued his work. On the sixth day, 26 May,

²⁴See footnote 21, p. 157.

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he took to his bed because of headache, fatigue, andmalaise. Backache was marked. The next day he reported to a medical dispensarywhere physical examination revealed a few pink papules on the left palm andwrist, a temperature of 99.2? F., and a pulse rate of 100. The rash haddisappeared 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 waspermitted 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-Felixreaction was negative with both Proteus OX-19 and OX-2 antigens and thecomplement fixation titer was 1:8 with epidemic antigen and 1:4 with murineantigen. By the end of the first week of disease the Proteus OX-19 titer roseto 1: 20, and in the second week it rose to 1: 80. It reverted to negative inthe 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 (withepidemic 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 thepatient described in case 1, for a month prior to onset of illness. Althoughexposed daily, he recalled that he was dangerously exposed on 11 June 1944 whenhe assisted with the handling and grinding of infected louse feces in largeamounts. During the period from 23 December 1941 to 10 October 1943, he receiveda total of 12.0 cc. of typhus vaccine in 1.0 cc. increments. On 22 November 1943he received 1.0 cc. epidemic typhus vaccine and on 10 April an additional andfinal dose of 1.0 cc. of vaccine. Although the Weil-Felix reaction wasnegative with both Proteus OX-19 and Proteus OX-2 antigen, the complementfixation titer with epidemic antigen was 1: 8, 3 days before and 11 days afterthe last dose of vaccine.

On 23 June 1944, the patient awakened in the morning with amild but troublesome frontal headache which persisted through most of the day,and the following day recurred together with malaise and easy fatigability. Histemperature was 101.0? F. As these symptoms persisted with an increase in bothseverity and extent of the headache, he was admitted to the hospital late in theafternoon of the next day, 25 June. The following day his temperature was100.4? F., pulse rate was 80, respiratory rate 20, blood pressure was 106systolic and 60 diastolic. Although he did not appear acutely ill, he complainedof headache, chilly sensations, and nausea. Physical examination revealed only amarked injection of the scleral conjunctivae. Later in the afternoon histemperature rose to 102.0? F. and a diffuse macular eruption appeared over theanterior chest, arms, shoulders, and flanks with an erythematous blush thatdisappeared upon pressure. He continued that afternoon and night to have slightchills. By the next morning the rash had definitely faded but his headache,which was now generalized, became exceptionally severe. Chills continued, and heappeared quite ill. There were intermittent, drenching sweats, and he complainedof severe backache and general malaise. The temperature rose to 103.2? F. thatnight with a pulse rate of only 90. The respiratory rate was normal. Althoughthe temperature fell to 99.2? F. the following morning (28 June) and remainedbelow 100.6? F. throughout the course of the day, severe headache, malaise,sweating, and occasional chills persisted. He vomited several times and on oneoccasion there was a transient amnesia. During the course of the next 2 days,these symptoms persisted but the temperature remained relatively low and therash became increasingly less evident, and disappeared completely by 1 July. On29 June the physician reported that the patient appeared to be disoriented for abrief 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 inchart 6, with rapid fall in temperature by lysis, subsidence of headache,malaise, nausea, and vomiting, and rapid increase in serological titers fortyphus fever. On 30 June, there was a left earache which disappeared within 48hours without specific

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CHART 6.-Clinical course and early serologicalfindings in a moderately severe case of epidemic typhus in a vaccinatedindividual

therapy. Temperature was normal by 3 July. On 5 July he was permitted out ofbed 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 cellcount was 4,600,000, the hemoglobin was 95 percent, and the leukocyte count wassaid to be 6,300 with 45 percent stab cells, 33 percent polymorphonuclearneutrophils, 20 percent lymphocytes, and 2 percent monocytes. On 3 July theblood count was as follows: red cells 4,650,000, hemoglobin 95 percent,leukocytes 5,600 with 15 percent stab cells, 53 percent polymorphonuclearneutrophils, 18 percent lymphocytes, and 14 percent monocytes. Urine examinationon 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 phaseof the disease. The Weil-Felix reaction with Proteus OX-19 antigenremained 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. Itwas still positive at 1:80 on the 124th day but when next checked, almost 2years after the onset of the disease, it was found to be negative. Complementfixing 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. Thetiter began to fall after the

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31st day and when last checked almost 2 years later, the titer was stillpositive at 1: 20. Specific rickettsial agglutinations were negative at thattime. The temperature and pulse record, along with other pertinent findingsduring the acute phase of this patient's disease, are shown in chart 6.

Case 3-A 36-year-old male officer, memberof the U.S.A.Typhus Commission, was engaged in typhus control work in Hokkaido, Japan. On10 November 1945, he was heavily exposed in the room of a Japanese hospital todust containing suspended louse feces from the clothing of a patient with activetyphus. From 17 February to 28 July 1944 he had received a total of 4.0 cc. oftyphus vaccine in 1.0 cc. doses. On 9 May and 1 October 1945, he receivedadditional 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 murineantigen, and rickettsial agglutination 1: 40 with epidemic antigen and negativewith murine antigen.

On 22 November 1945, the patient experienced chilly sensations andgeneralized malaise. The following day headache, apathy, anorexia, andirritability 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 dryhacking cough set in and he vomited once. The next day, sixth day of disease, herefused hospital admission but finally took to bed in his quarters. Headachebecame excruciating in severity, temperature rose to 102.2? F., and nausea andcough persisted. Although the temperature rose to 103.8? F. the night of theseventh day and he became drowsy, there was suddenly a feeling of relative wellbeing the following day with sudden resolution of fever by crisis and profusesweats. He was afebrile by the 9th day, and was out of bed on the 10th day, andback to work on the 13th day, although he tired easily on exertion. The bloodpressure 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 completeblood count at an outpatient clinic showed 4,620,000 red cells, 90 percenthemoglobin, and 6,600 leukocytes with a differential of 64 percent segmentedneutrophils, and 36 percent lymphocytes. On the 12th day, urine was negativeexcept for a faint trace of albumin with a few leukocytes in the microscopicexamination. These findings had disappeared by the following day. On the 21stday, electrocardiographic tracing was normal in all four leads. The heart ratewas 84, the PR interval was 0.16 second, sinus rhythm was present, QRS complexeswere 0.06 second, T waves were upright in all leads, and there were no STchanges.

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 withepidemic antigen began to rise by the end of the first week, reached its peak at1: 1,280 at the end of the third week, and was still positive by the ninthmonth. Rickettsial agglutination did not rise until the second week but reachedits peak at that time with a titer of 1: 640 with epidemic antigen. It was stillpositive by the ninth month.

The pertinent serological data on the three cases just mentioned are given intable 15, and the essential clinical features of these and two other vaccinatedcases are summarized in table 16. Of particular interest is the method ofinfection. In each instance, there was evidence to indicate inhalation orconjunctival absorption of infected louse feces.

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TABLE 15.-Serologicalfindings and immunization record in three cases of epidemic typhus feverincurred subsequent to immunization with typhus fever vaccine

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TABLE 16.-Clinicalsummary of five cases of epidemic typhus fever incurred subsequent toimmunization with typhus fever vaccine

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Sadusk's report was in keeping with other observations thatthe clinical course of epidemic typhus is greatly modified when infection occurssubsequently to vaccination (chart 7). Fever is much lower and of shorterduration than in nonvaccinated cases, the extent and duration of rash arediminished, circulatory and nervous symptoms are lessened, and the incidence ofcomplications is minimal. If hospitalization is necessary, the length of it isreduced. The only symptom that is regularly present in vaccinated cases issevere headache.

CHART 7.-Clinicalcomparison of vaccinated and unvaccinated groups of typhus fever cases amongemployees of the Cairo Fever Hospital, El Abbasa, Egypt

Following is the only case known to have occurred in our troops in Sicily.²⁵The patient, a private with the 77th Field Artillery, was admitted to the 59thEvacuation Hospital, Palermo, Sicily, in the summer of 1943. His history andclinical 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 typhusin June 1941, and a recall dose was given in June 1943. No record wasobtainable. 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.

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long stay, and arrived in Sicily on 14 July 1943. He does notknow 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 dayof disease, 26 August, a maculopapular rash appeared on the trunk, thighs, andarms, gradually increasing in amount, intensity and distribution for the next 5days and being heaviest on the limbs (fig. 11). In spots it was petechial andhemorrhagic and did not fade on pressure. No tache noir or regionallymphadenitis was detected. There was a macular rash on buccal mucosa. Thepharynx was slightly reddened. Between the fourth and eighth day, the enlargedspleen was palpable. On the third and seventh day, he had 5,100 and 7,500 WBCnormally differentiated and urine specimens were negative except for lowspecific gravity. The boy was very ill, lost weight and strength. There were afew loose bowel movements between the seventh and ninth days. A blood culture onthe fifth day was negative. Weil-Felix tests with the three Proteus typeswere entirely negative on the ninth day in an Italian laboratory. On the 11thday, the Proteus OX-19 was positive 1: 40, Proteus OX-2 waspositive 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 waspositive 1: 640, OX-2 was positive 1: 1,280, and OX-K was negative. A guinea piginoculated on the 11th day, when temperature was normal for the first time, didnot develop scrotal reaction. After fever subsided, the patient graduallyrecovered strength, weight, and appetite. No complications or sequelae werepresent 1 month after onset.

Only three confirmed cases of typhus occurred among U.S. troops serving inthe European theater, despite its prevalence among the civilian populations.²⁶Two infections were contracted in the Rhineland and one in the Inner Reich. Allthree patients had mild attacks of the disease, as indicated by the followingbrief case summaries:²⁷

Case 4.-A captain of the Medical Corpsinvestigated a typhus outbreak at Fischbach, Germany, on 23 March 1945. He wasintimately exposed to the disease while examining and disinfecting patients butdoes not recall ever having found lice on his person. On 9 April, he developed amacular rash. He was never delirious, stuporous, or disoriented. Hisconvalescence was rapid and uneventful. A Weil-Felix test on 17 April waspositive in a serum dilution of 1: 640. The patient had not received astimulating 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 becameill on the same day. This patient's illness was even less severe, with no rashat any time. He remained on quarters status, and returned to duty 15 April. Astimulating dose of typhus vaccine had been administered on 23 March 1945, theday previous to his exposure to the disease. The stimulation antedating that wasin September 1944.

Case 6-A sergeant of the15th 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 forseveral days. On 22 April he was transferred to a general hospital with thediagnosis 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 clinicaldifference of opinion as to the identity of the disease.

²⁶See footnote 15, p. 155.
²⁷Gordon, John E.: A History of Preventive Medicine in the European Theater of Operations, U.S. Army, 1941-45, vol. I, pt. III, p. 48. [Official record.]

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CHART 8.-Temperaturechart and pertinent laboratory findings of the only known case of typhus feveroccurring among U.S. Army troops in Sicily, 1943

FIGURE11.-Appearance of maculopapular rash on trunk, thighs, and arms on third dayof disease.

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The Craigie (British Army) vaccine.-Thecases of typhus fever acquired after vaccination that have thus far beendescribed occurred in soldiers who had received vaccine of the Cox type employedin all U.S. Armed Forces, containing, as has been noted, soluble antigen andkilled rickettsial micro-organisms of epidemic typhus (R. prowazeki). Britishtroops, on the other hand, were inoculated with the Craigie vaccine, whichconsisted of two parts of epidemic (R. prowazeki) and one part ofmurine typhus (Rickettsia mooseri) antigens. Soluble substances as wellas killed micro-organisms were included in the Craigie vaccine. In Germany,observing the typhus epidemic at Belsen, Davis²⁸also had an opportunity to estimate the value of this vaccine under epidemicconditions, collecting data on 14 cases of typhus in British personnel who hadbeen vaccinated more than 24 days before the onset of their fever. Theirclinical courses were milder and shorter than is seen in typical epidemic typhusin nonvaccinated persons, with no deaths and no serious complications. He notedas significant "the absence of serious complications * * *. Parotitis,gangrene, conjunctivitis, deafness due to typhus, epistaxis, pulmonaryconsolidation, and pleuritic pains were never observed in the British, althoughall were to be seen in the typhus patients from the concentration camp. Theirrash was never extensive, rarely developed into true petechiae which would notblanche on pressure, and never formed ecchymoses. Delirium was observed in only2 cases, and in these it was brief. Roentgenograms of the chest were reported asnormal or 'marked increase in bronchovascular markings throughout bothlungs.'" Determinations of blood nonprotein nitrogen were made on 10patients 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 whohad only one or two doses of Craigie vaccine after exposure to typhus at Belsenand 41 cases of typhus in well-nourished Germans who had no vaccine. From acomparison of the three groups as shown in table 17, and other data, it wasconcluded that Craigie vaccine was of definite value in shortening the courseand reducing the severity of epidemic typhus fever when given in two or moredoses from 24 to 100 days before the onset of the disease.

The course of epidemic typhus fever was thus shown to bemodified favorably by prior vaccination with vaccine of either the Cox or theCraigie type. The observations regarding the effectiveness of these twovaccines, however, were not made under controlled or even similar conditions,and it is not possible to draw conclusions as to their relative effectivenessfrom 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.

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TABLE 17.-Comparisonof typhus in three groups at Belsen Concentration Camp, Belsen, Germany

Number	Nationality	Vaccination history	Age (years)	Average age (years)	Duration of fever (days)	Average duration of fever (days)	Deaths (number)
14	British	Two to five doses Craigie vaccine, all given more than 24 days before illness.	20-56	31.8	6-13	8.7	0
16	Hungarians	One to two doses Craigie vaccine, none given more than 16 days before illness.	18-38	28.8	9-15	13.6	0
41	Germans	No vaccine	20-52	25.9	13-24	14.9	2

Source: Modified from Davis, W. A.: Typhus atBelsen. II. Clinical Course of Epidemic Typhus in Persons Who Had ReceivedCraigie Typhus Vaccine. Ann. Int. Med. 34: 448-465, February 1951.

PATHOLOGY

Two important studies of the pathology of epidemic typhusfever were undertaken during World War II. The first of these,²⁹by Maj. Arthur C. Allen, MC, and Dr. Sophie Spitz, at the Army Institute ofPathology (now Armed Forces Institute of Pathology), Washington, D.C., entaileda comparison of the histological preparations and protocols of 78 cases of scrubtyphus (tsutsugamushi disease), 24 cases of epidemic (louseborne) typhus, 12cases of Rocky Mountain spotted fever, and lung sections of 2 cases of AmericanQ fever. Since the principal emphasis of this study was placed on the changesinduced by scrub typhus, the main findings of the authors are given in thechapter dealing with that infection (p. 132). However, a number of otherobservations were made which are relevant here. The histology of the cutaneouslesion is described, as follows:

The macule of epidemic typhus histologicallywas essentially similar to that of scrub typhus, although several differenceswere found. In the first place, although capillary thrombi were present in allof the available sections of macules of scrub typhus as against only 15, or 65percent, of the macules in epidemic typhus, the thrombi were considerably moreconspicuous in the latter disease. They were more prominent not only becausemore thrombi occurred in a single section, but because they were larger and wereassociated with more pronounced endothelial changes. In epidemic typhus, theaffected endothelial cells tended to be larger, more hyperchromatic, and moreoften disintegrated into chromatin dust, the last being a feature observed alsoin the capillaries of other organs, including the glomerular capillaries.Secondly, there was a tendency to the occurrence in epidemic typhus of anecrotizing arteritis and thrombo-arteritis, not found in scrub typhus. Thenecrosis might extend through the entire wall of the artery, unlike the lesserdegree of involvement that is stated to occur in the experimental animalinfected 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.

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the rickettsiae of epidemic typhus. Indeed, inthe human skin of cases of epidemic typhus there may be infarct-like hemorrhagicsuppurative necrosis of the portions of corium in association with severearteritis. Thirdly, whereas no significant changes were noted in the epidermisof the macule of scrub typhus, minor changes consisting of focal spongiosis,patchy parakeratosis and focal "liquefaction degeneration" of thebasal layers were infrequently observed in the skin of patients with louse-bornetyphus.

The interstitial myocarditis and interstitial pneumonitis of epidemic typhuswere intermediate in intensity between that produced by scrub typhus and byspotted fever.

Changes in the adrenal glands of patients with epidemic typhus were similarto those of scrub typhus, except that there was a more conspicuous focalmononuclear reaction. In addition, a few cases of epidemic typhus exhibitedinflammatory and degenerative changes of capillaries and arterioles of bothparenchymal and adventitial tissues.

Similarly, lesions in the kidneys from patients with epidemic typhusqualitatively resembled those of scrub typhus but were considerably morepronounced. "Acute diffuse glomerulonephritis was found in 18, or 78percent, of the cases; acute focal glomerulitis in 3, or 13 percent, andessentially normal glomeruli in 2, or 9 percent. The glomerular alterations werebasically those of scrub typhus, differing in more marked swelling andhyperchromasia of the endothelial cells, more frequent occurrence of thrombosisof the glomerular capillaries and fragmentation of the endothelial cells.Similarly, focal interstitial infiltrations, calcific bodies, hemoglobin castsof the distal convolutions, and phlebitis, arteritis, and arteriolitis were moreconspicuous in epidemic typhus."

A comparison was made between reactions in the brain and meninges in epidemicand scrub typhus. It was found that-

1. Although the meningitis of scrub typhus is slightly morefrequent and extensive than the qualitatively similar reaction in epidemictyphus, the involvement of the substance of the brain is considerably greater inthe latter disease.

2. The distribution of lesions in the gray and white matter inthe two diseases is the same: in both the white matter is spared, in contrastwith Rocky Mountain spotted fever.

3. In the current series the case incidence of involvement ofthe cortex in epidemic typhus is much greater than in scrub typhus. The actualconcentration of nodules in the pons, medulla, and basal ganglia in epidemictyphus is more pronounced than in the cortex. The pons and medulla are sites ofpredilection also in scrub typhus.

Several distinct histologic differences between scrub typhusand epidemic typhus are noted:

4. The nodules tend to be larger in epidemic typhus, averaging55 to 75 cells as against 15 to 40 cells, and about 120 to 180 μ asagainst 60 to 120 μ.

5. There is somewhat greater cellular pleomorphism in thenodules of epidemic typhus, especially in the larger. Karyorrhexis is common inthe cells of the nodule of epidemic typhus and rare in that of scrub typhus.

6. In epidemic typhus, the capillaries of thenodules show much more obvious evidence of damage in the form of markedlyenlarged endothelial cells, karyorrhexis of endothelial cells, and thrombosis ofcapillaries. Similar changes are found in arterioles without associated nodules.

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The character of the tissue reaction in these cases, such as fibrinoiddegeneration of collagen, necrosis of lymph nodes and spleen, the predominanceof plasma cells and basophilic macrophages, and the acute glomerulo-nephritis,led these observers to postulate that rickettsiae may exert hyperergic effectsin addition to the better known diffuse vascular phenomena caused by them.

The second important investigation of the pathology ofepidemic typhus was initiated by the collection of material from 23 fatal casesstudied by the U.S.A. Typhus Commission in Cairo, Egypt, during 1943-45, whichwas reviewed by Spitz and Allen. This, along with material from additionalcases, was subsequently studied by members of the Committee on Pathology,Division of Medical Sciences, National Research Council, in collaboration withthe Armed Forces Institute of Pathology. The splendid report³⁰of this group was not issued until 1953 but because of its broad scope andpertinence to other work discussed in this chapter, the summary statement ofthis study is quoted, as follows:

This paper describes the lesions encountered in an epidemic oftyphus which occurred in Cairo during 1943-1945. The findings have been comparedto those observed by Wolbach, Todd, and Palfrey in the Warsaw epidemic of 1918and by others since that time in order to bring together in one report all theknown facts abort the pathology of epidemic typhus.

The patients studied in the Cairo epidemic were Egyptiansbetween the ages of 10 and 70 years. Some of them were undernourished, but therewas no clinical or pathological evidence of avitaminosis, and some hadclinically inactive schistosomiasis. The patients were admitted to the hospitalduring the first 2 weeks of their disease, and the clinical diagnosis oflouse-borne typhus was confirmed in many cases by the Weil-Felix and complementfixation tests. In same instances rickettsiae were recovered from blood or fromnormal lice fed on the patients, and each strain isolated showed thecharacteristics of louse-borne typhus. Two patients were given para-aminobenzoicacid, without clinical or pathological effects. The other patients received nospecific antityphus treatment, and none had been vaccinated against typhus. In14 patients special efforts were made to reduce secondary bacterial infection byusing sulfonamides and penicillin when necessary. This paper and the reports ofthe United States of America Typhus Commission on the clinical and laboratoryfeatures constitute one of the few comprehensive accounts of an epidemic oftyphus in Egypt or, indeed, in any tropical country. It seems likely, in view ofthe discovery of antibiotics that may be effective in the treatment of thedisease and of the development of satisfactory vaccines, that there may neveragain be a similar opportunity to study an epidemic of typhus which has not beensignificantly modified either by treatment or by complicating infection.

The lesions discovered in the Cairo patientswere essentially the same as those described in other epidemics in differentparts of the world and in experimental animals. The wide dissemination ofvascular and other lesions in the skeletal muscles, which was well illustratedby the frequent involvement of the muscles of the tongue, was more apparent inCairo cases than in others, probably because abundant material was available formicroscopic examination. Evidence was obtained by the demonstration ofrickettsia-

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.

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like bodies in sections of the lungs, which suggests, but doesnot prove, that a true rickettsial pneumonia may exist. Interstitial orchitisand prostatitis of a type not ordinarily seen in other infectious diseases wasalso observed.

New information has been obtained concerning the topography oflesions in the central nervous system and the effect of the duration of theillness on the intensity of the reaction. So-called microinfarcts have beendemonstrated for the first time in the brains of patients who died from epidemictyphus.

Glomerulonephritis did not occur in the Cairo patients, and areview of published articles has led to the conclusion that its occurrence hasnot been proved. The bulk of the evidence supports the idea that renal failurein epidemic typhus is probably due to extrarenal factors, such as increasedprotein catabolism, dehydration, and reduction of arterial blood pressure,rather than to primary renal damage brought about by direct action of therickettsiae. We have not been able to convince ourselves that lower nephronnephrosis occurs.

The pathological observations that have been briefly described here are wellillustrated in the Committee's report; selected prints are reproduced as figures12 through 32, through the courtesy of the Archives of Pathology.

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FIGURE12.-(Top) Capillary in derma showing swelling and proliferation of endotheliumto point of occlusion. Slight perivascular accumulation of mononuclear cells. (X430)

FIGURE13.-(Bottom) Finely granular capillary thrombus, with pericapillary collectionof mononuclear cells in derma. (X 312)

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FIGURE14.-(Upper left) Necrosis and thrombosis of dermal capillary(A), with many perivascular mononuclear cells of different types. A small nerve(B) is included. (X 730)

FIGURE15.-(Upper right) Swelling and proliferation of endothelium ofcapillary in tongue. (X 730)

FIGURE16.-(Lower left) Same case as shown in figure 15. Occlusion ofcapillary in tongue by swelling and necrosis of endothelium. Pronouncedexudation of mononuclear cells in the surrounding tissues. (X 875)

FIGURE17.-(Lower right) Myocardium. Focal swelling and necrosis of capillaryendothelium and perivascular infiltration of mononuclear cells withhyperchromatic nuclei. (X 875)

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FIGURE18.-(Top) A large cerebral nodule showing its relation to acapillary in the most compact part. (X 600)

FIGURE19.-(Lower left) Mural thrombus in subendocardial arteriole,without perivascular infiltration. (X 350)

FIGURE20.-(Center) Same case as shown in figure 19. Granular thrombusin arteriole in submucosa of trachea and cellular infiltrate beneath basementmembrane of mucosa. (X 290)

FIGURE21.-(Right) Cellular thrombus in arteriole of testis. (X 195)

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FIGURE22.-(Upper left) Point of attachment of base of mitral valve,with disruption of elastica, edema (mucoid), infiltration of mononuclear cells,and production of fibroblasts. (X 312)

FIGURE23.-(Upper right) Acute interstitial myocarditis, with diffuseinfiltration of mononuclear cells. (X 312)

FIGURE24.-(Lower left) Same case as shown in figures 19 and 20. Acuteinterstitial myositis of tongue, with infiltration of mononuclear cells. (X 155)

FIGURE25.-(Lower right) Small nodule of mononuclear cells in skeletalmuscle attached to thyroid gland. (X 234)

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FIGURE26.-(Top) Mononuclear infiltrate in corticomedullary junction of kidney.Numerous cells have abundant basophilic cytoplasm and an eccentrically placednucleus similar in chromatin pattern to that of plasma cells. Some of these arewithin the lumen of the small vessel, and the remainder are interstitial betweenthe renal tubules. Numerous red blood cells are visible in the neighboring loopsof Henle. The patient was a 30-year-old male, the duration of whose illness wasnot known. (X 400)

FIGURE27.-(Lower left) Focal interstitial orchitis about a dilated capillary. Theexudate is composed of large mononuclear cells, plasma cells, and lymphocytes.(X 300)

FIGURE28.-(Lower right) Mononuclear cells forming interstitial exudate in acutemyocarditis. Myocardial fibers are preserved. (X 875)

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FIGURE29.-(Upper left) Same case as shown in figure 23. Nodules in posterior lobe ofpituitary identical with those in the brain and spinal cord. (X 250)

FIGURE30.-(Upper right) Same case as shown in figure 21. Hyperplasia of sinusoidalendothelium of the liver and infiltration of mononuclear cells. (X 250)

FIGURE31.-(Lower left) Lung, alveolar exudate showing many rickettsia-like bodies incytoplasm of polymorphonuclear leukocytes. Nyka stain. (X 1,450)

FIGURE32.-(Lower right) Pancreas, infiltration of mononuclear cells in theinterlobular septum, dilatation of acini, and inspissation of secretion. (X 205)

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DEVELOPMENT AND USE OF LABORATORY AIDS IN DIAGNOSIS

Along with the advances in louse-control measures andimmunization, and extension of fundamental knowledge of the clinical andpathological aspects of the disease, progress was also made during World War IIin the development of diagnostic laboratory procedures for epidemic typhusfever. The most active work in this connection was performed at the Division ofVirus and Rickettsial Diseases, Medical Department Professional Service Schools,Army Medical Center, Washington, D.C., at the Cairo Unit of the U.S.A. TyphusCommission, and at the National Institutes of Health in Bethesda, Md.

Weil-Felix test-In 1916, Felix³¹demonstrated that sera from patients with epidemic typhus fever wouldagglutinate suspensions of Proteus microorganisms. Although it was soonrecognized that these bacteria were not etiologically related to typhus fever,the agglutination of Proteus organisms was quickly developed into adiagnostic test for typhus. Further study revealed that Proteus vulgaris organismscould be dissociated into a motile flagellated "H" type and anonmotile unflagellated "O" type. The diagnostic agglutinin thatappears in the blood of typhus fever patients is the somatic "O" type.Additional experience prior to World War II indicated that suspensions of the ProteusOX-19 strain were agglutinated by sera from typhus fever cases; that OX-19 andanother strain, Proteus OX-2, were often agglutinated by Rocky Mountainspotted fever sera; and that suspensions of still another variant, ProteusOX-K, were agglutinated by scrub typhus sera (p. 133). There remained, however,conflicting statements as to the time of appearance of the agglutinins duringthe course of illness, and concerning what constituted a significant ordiagnostic titer. Accordingly, early in 1943, Plotz sought to determine the riseand fall of the various types of demonstrable antibodies in cases of epidemictyphus fever. Serial serum specimens were obtained from 32 untreated andunvaccinated typhus fever cases studied by members of the Typhus Commission inCairo. Blood specimens were obtained early in the disease, during the course ofillness, and as long after convalescence as possible. It was thus possible toestablish patterns of antibody dynamics in cases confirmed, in 21 instances, asepidemic typhus by isolation of the strain. The results of the variousserological tests performed on these sera were summarized in an important seriesof papers from the Army Medical School.³²

³¹Felix, A.: Die Serodiagnostik des Fleckfiebers. Wien. klin. Wchnschr. 29: 873-877, 13 July 1916.
³²(1) 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.] (2) Plotz, H., Wertman, K., and Bennett, B. L.: The Serological Pattern in Epidemic Typhus Fever. II. The Weil-Felix Reaction. Division of Virus and Rickettsial Diseases, Army Medical School, Army Medical Center, Washington, D.C., 1944. [Official record.] (3) 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.]

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In these cases, there was usually a high Proteus OX-19agglutination titer, a low OX-2, and a negative OX-K reaction. A rise in titerwas found in all cases when early and late specimens were compared. A test wasregarded as having diagnostic significance when the titer rose fourfold,occurring, in this group of cases, by the 5th to the 13th day of disease. Testson followup sera showed that the titer had fallen to insignificant levels withinabout 3 months after the onset of illness. Table 18 shows the characteristicpattern as observed in one of these patients.

TABLE 18.-Weil-Felix Proteusagglutination tests in epidemic typhus (case 1344) strainisolated

Day of disease	Serum titer with Proteus-
Day of disease	OX-19	OX-2	OX-K
4th	0	0	0
5th	0	0	0
6th	0	0	0
8th	1:20	0	0
10th	1:320	1:20	0
12th	1:1,280	1:40	0
14th	1:640	1:40	0
19th	1:640	1:160	0
20th	1:640	1:80	0
23d	1:640	1:80	0
25th	1:320	1:80	0
27th	1:160	1:40	0
115th	1:20	1:20	0
286th	1:20	1:10	0
713th	1:40	0	0

Source: Wertman, Kenneth: The Weil-Felix Reaction. InRickettsial Diseases of Man. Washington: American Association for theAdvancement of Science, 1948, pp. 184-189.

Using the identical macroscopic agglutination technique asemployed in the Division of Virus and Rickettsial Diseases, Zarafonetis³³performed Weil-Felix tests on 1,002 sera from 203 cases of epidemic typhusfever. Two or more serum samples were tested from each of the patients who hadbeen studied clinically in Egypt, Greece, Yugoslavia, and the DachauConcentration Camp in Germany. All of these patients had survived their disease,and sufficient time had elapsed for the development of antibodies if they wereto 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.]
³³Zarafonetis, 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.

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Proteus OX-19 agglutination results is given in table19. An agglutination titer of 1: 160 or more developed in 191 (or 94 percent) ofthese subjects. Sera in five cases were entirely negative, sera in four othersgave complete agglutination only to a dilution of 1: 40, and in three more, to1: 80. Of interest was the finding that the complement fixation tests yieldeddiagnostic titer changes in all of these patients. Thus were the Weil-Felix andcomplement fixation reactions found to be dissociated phenomena. A similardissociation was also demonstrated for the Weil-Felix and rickettsialagglutination responses. (See p. 185.) This significant observation isillustrated in table 20.

TABLE 19.-Weil-Felix ProteusOX-19 agglutination results on1,002 sera from 203 patients with typhus fever

Maximum titer¹	Cases	Cases cumulative	Percent	Percent cumulative
Negative	5	203	2.5	100.0
1:40	4	198	2.0	97.5
1:80	3	194	1.5	95.5
1:160	9	191	4.4	94.0
1:320	13	182	6.4	89.6
1:640	21	169	10.3	83.2
1:1,280	24	148	11.8	72.9
1:2,560	30	124	14.8	61.1
1:5,120 and over	94	94	46.3	46.3
Total	203		100.0

¹Complete agglutination in dilution given.
Source: Zarafonetis, C. J. D.: The Serological Reactions in the RickettsialDiseases of Man. In Rickettsial Diseases of Man. Washington: AmericanAssociation for the Advancement of Science, 1948, pp. 179-183.

Wertman³⁴summarized the wartimeexperience with the Weil-Felix reaction and constructed the following table toindicate the usual findings in the various rickettsial diseases of man (table21). He pointed out that, despite the introduction of specific diagnosticreagents, the Weil-Felix reaction remained a valuable laboratory aid, asfollows:

* * * The value of the Proteusagglutination test is that these antibodies appear somewhat earlier than thespecific ones. The antigen is easy to prepare and the technic can be performedin any diagnostic laboratory. It should be emphasized, however, that asignificant test is one in which a rise in antibody titer can be demonstratedand no single titer should be regarded as significant. Since one rickettsialdisease cannot be differentiated from another by means of this test, it must beregarded as only a diagnostic aid. The demonstration of the presence of specificantibodies, either complement fixing or rickettsial agglutinating, is necessaryto 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.

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TABLE 20.-Serologicalfindings in three typhus cases with negative Weil-Felix OX-19 agglutinationresults

Case	Day of disease	Serological findings
		Weil-Felix OX-19	Complement fixation		Rickettsial agglutination
		Weil-Felix OX-19	Epidemic	Murine	Epidemic	Murine
666	8	Negative	1:640	1:40	1:640	1:320
	15	1:20	1:2,560¹	1:320	1:10,240	1:5,120
	22	Negative	1:1,280	1:160	1:5,120	1:2,560
	30	....do...	1:1,280	1:80	1:2,560	1:1,280
	90	....do...	1:160	1:10	1:160	1:40
2048	5	....do...	1:256	Negative	1:280	1:320
	10	....do...	1:1,024	1:8	1:5,120	1:1,280
	15	....do...	1:512	Negative	1:2,560	1:640
	112	....do...	1:32	....do...	1:80	1:80
3696	12	....do...	1:64	....do...	1:320	1:160
	17	....do...	1:1,024	....do...	1:1,280	1:640
	34	....do...	1:1,024¹	....do...	1:640	1:640
	43	....do...	1:1,024	....do...	1:640	1:320
	47	....do...	1:512	....do...	1:640	1:160
	77	....do...	1:512	....do...	Negative	Negative
	117	....do...	1:128	....do...	....do...	Do.

¹End point titer was not reached.
Source: Zarafonetis, C. J. D.: The Serological Reactions in the RickettsialDiseases of Man. In Rickettsial Diseases of Man. Washington: AmericanAssociation for the Advancement of Science, 1948, pp. 179-183.

TABLE 21.-The usualWeil-Felix reactions in rickettsial diseases

Diseases	Proteus
Diseases	OX-19	OX-2	OX-K
Epidemic typhus	+ + + +	+	0
Murine typhus	+ + + +	+	0
Scrub typhus	0	0	+ + + +
Q fever	0	0	0
Rocky Mountain spotted fever	+ + + +	+	0
Rocky Mountain spotted fever	+	+ + + +	0

Source: Wertman, Kenneth: The Weil-Felix Reaction. In RickettsialDiseases of Man. Washington: American Association for the Advancement ofScience, 1948, pp. 184-189.

Wertman further describes the limitations of the Weil-Felixreaction:

In the first instance, it is impossible todifferentiate epidemic typhus, murine typhus, and Rocky Mountain spotted feverby this technic. * * * Secondly, positive reactions have been reported with serafrom cases other than those of rickettsial origin. * * * Lastly, the Proteus agglutininsin rickettsial infections disappear in late convalescence: therefore, the testcannot be employed as a survey tool to determine the qualitative or quantitativedegree of past infection in a given area.

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The next step was to determine what serological changes were induced byvaccination as carried out in U.S. troops with vaccine of the Cox type. In aseries of serological studies at the Cairo laboratory of the Typhus Commission,³⁵it was demonstrated, first, that a 1.0 ml. stimulating dose of typhus vaccine in100 multivaccinated individuals resulted in no significant change in Weil-Felixagglutination 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, noanamnestic reactions were detected when these tests were performed on sera from104 febrile patients who had previously been vaccinated. Finally, serologicaltests were performed on serial serum specimens from 29 cases of suspectedepidemic typhus developing subsequently to vaccination. Here, it was found thatthe titer changes in Proteus OX-19 agglutination tests were greater thanthose in the first and second groups and were, furthermore, of sufficientmagnitude to have diagnostic significance. Examples of results in typhus casesoccurring after vaccination are given in table 15.

Complement fixation tests with rickettsial antigens-Numerousinvestigators were aware of the limitations of the Weil-Felix tests and stroveto develop specific rickettsial antigens for use in complement fixation andagglutination tests. The preparation of pure suspensions of rickettsiae insufficient quantity was an obstacle until, in 1938, Cox introduced the yolk-sacculture method. Using this method of rickettsial cultivation, Bengtson³⁶prepared antigens and successfully performed complement fixation tests upon serafrom murine typhus cases. In 1942, Craigie³⁷demonstrated that rickettsiae could be separated from yolk-sac suspensionsby ether extraction, thereby eliminating most of the embryonic egg materials.This made available essentially pure suspensions of rickettsiae for use asantigens in serological tests and vaccines. Indeed, Wertman³⁸later showed that this method actually increased the specificity of therickettsial suspensions by removing about half of the syphilitic antigensnormally present in tissues of the embryonic chick. Plotz and his associates³⁹soon noted that sera from both epidemic and murine typhus patients gavecomplement fixation titers with both epidemic and murine antigens. Theseinvestigators found that by repeated washing and centrifugation of therickettsial suspensions a "soluble substance" present in thesupernatant 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.
³⁶Bengtson, I. A.: Complement Fixation in Endemic Typhus Fever. Pub. Health Rep. 56: 649-653, 28 Mar. 1941.
³⁷See footnote 19, p. 156.
³⁸Wertman, K.: Nonspecific Complement-Fixing Antigen in Embryonic Egg Tissues. J. Lab. & Clin. Med. 30: 112, February 1945.
³⁹See footnotes 32 (1), p. 179; and 20 (1), p. 156.

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also served to eliminate the remainder of the syphilitic antigen. Theresuspended rickettsial suspensions were then shown to be essentially specificfor homologous sera. Thus was made possible the serological differentiationbetween epidemic and endemic typhus, with obvious epidemiological as well asclinical significance.

This specific complement fixation test was used in severallaboratories, but comprehensive data for nonvaccinated cases were recordedprimarily at the Army Medical School and by the Cairo Unit of the TyphusCommission. At the Army Medical School, Plotz and his coworkers performedsystematic complement fixation tests on the sera from the Cairo series of 32unvaccinated patients with typhus fever (p. 179). All of these patients showed arise in titer in tests with epidemic antigen; 56 percent gave positivecomplement fixation by the 10th day, 78 percent by the 12th day, and 100 percentby the 16th day of illness. Most of them gave fixation with epidemic antigen andno fixation with murine antigen (table 22). Where cross-fixation did occur, thetiter with homologous (epidemic) antigen was always higher than with murineantigen. All cases showed persistence of complement fixing antibodies, even whenspecimens taken many months after onset of the disease were examined.

TABLE 22.-Complementfixation test results in case 1344, epidemictyphus-strain isolated

Day of disease	Serum titer with-
Day of disease	Epidemic antigen	Murine antigen
4th	0	0
5th	0	0
6th	0	0
8th	0	0
10th	1:20	0
12th	1:1,280	0
14th	1:1,280	0
19th	1:640	0
20th	1:640	0
23d	1:640	0
25th	1:640	0
27th	1:640	0
115th	1:80	0
286th	1:40	0

Source: Plotz, H., Wertman, K., and Bennett, B. L.: TheSerological Pattern in Epidemic Typhus Fever. I. The Development of ComplementFixing Antibodies. Division of Virus and Rickettsial Diseases, Army MedicalSchool, Army Medical Center, Washington, D.C., 1944. [Official record.]

Employing the same technique and antigens prepared by theDivision of Virus and Rickettsial Diseases, Zarafonetis⁴⁰performed complement fixation tests on 1,002 sera from 203 cases of typhusfever, with results sum-

⁴⁰See footnote 33, p. 180.

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marized in table 23. Almost all of the cases were epidemictyphus fever, confirmed in many instances by isolation of the strain. In onlytwo patients did the complement fixation titer with murine antigen equal orexceed that obtained with epidemic antigen. Sera from two of the cases failed todevelop titers in complement fixation tests with either epidemic or murinetyphus antigens, while both showed good responses in Weil-Felix OX-19 andrickettsial agglutination tests. From the serological findings in these twocases (table 24), it appears that the rickettsial agglutination response isdissociated from the antibody that gives rise to complement fixation. From thisand from similar observations with the Weil-Felix test (p. 181), it is seen thatall three of the serological reactions occur independently of one another, andone test may be negative while the other two give a positive finding for typhusfever.

TABLE 23.-Complementfixation results on 1,002 sera from 203 patients with typhus fever

Maximum titer	Purified epidemic antigen				Purified murine antigen
Maximum titer	Cases	Cases cumulative	Percent	Percent cumulative	Cases	Cases cumulative	Percent	Percent cumulative
	Number	Number			Number	Number
Negative	3	203	1.5	100.0	124	203	61.1	100.0
1:8 or 1:10	0	200	0	98.5	11	79	5.4	38.9
1:16 or 1:20	2	200	1.0	98.5	16	68	7.9	33.5
1:40	3	198	1.5	97.5	21	52	10.3	25.6
1:64 or 1:80	18	195	8.9	96.0	12	31	5.9	15.3
1:128 or 1:160	28	177	13.8	87.1	4	19	2.0	9.4
1:256 or 1:320	37	149	18.2	73.3	8	15	3.9	7.4
1:512 or 1:640	46	112	22.6	55.1	5	7	2.5	3.5
1:1,024 or over	66	66	32.5	32.5	2	2	1.0	1.0
Total	203		100.0		203		100.0

Source: Zarafonetis, C. J. D.: The SerologicalReactions in the Rickettsial Diseases of Man. In Rickettsial Diseases ofMan. Washington: American Association for the Advancement of Science, 1948, pp.179-183.

It now remained to determine the effect of vaccination per seon the complement fixing antibodies. Tests were made on sera taken before and 2weeks after a 1.0 ml. stimulating dose of typhus vaccine in 100 multivaccinatedsubjects (p. 183). Sera from 21 of these individuals gave epidemic complementfixation titers ranging from 1:4 to 1:32 before the stimulating dose, while 2weeks later sera from 70 of the subjects were positive in dilutions ranging from1:4 to 1:128. Where there was an increase in complement fixation titer as aresult of booster vaccination, there was a tendency to return to the previouslevel within 8 weeks after the booster injection.

The question of anamnestic reactions was studied in 104 persons who had beenimmunized with vaccine of the Cox type at some time before the

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TABLE 24.-Serologicalfindings in two cases of typhus fever with negative results in complementfixation tests

Case	Day of disease	Serological findings
		Weil-Felix OX-19	Complement fixation		Rickettsial agglutination
		Weil-Felix OX-19	Epidemic	Murine	Epidemic	Murine
16261	4	1:160	Negative	Negative	-	-
	6	1:1,280	...do...	...do...	Negative	1:160
	8	1:5,120¹	...do...	...do...	1:40	1:1,280
	10	1:5,120¹	...do...	...do...	1:160	1:2,560
	12	1:5,120¹	...do...	...do...	1:160	1:10,240
	15	1:5,120¹	...do...	...do...	1:320	1:5,120
	17	1:5,120¹	...do...	...do...	1:320	1:5,120
D-857	4	1:160	...do...	...do...	1:160	1:40
	11	1:1,280	...do...	...do...	1:1,280	1:320
	18	1:1,280	...do...	...do...	1:1,280	1:160
	24	1:640	...do...	...do...	1:320	1:80

febrile illness that led to their hospitalization (p. 183).No significant increase in complement fixing antibodies occurred in them as aresult of the nontyphus fevers.

With these studies as background, Zarafonetis and hiscoworkers,⁴¹studying 29 vaccinatedpatients with probable epidemic typhus fever, found that the diagnosis could bemade serologically provided the possible effects of vaccination per se wereevaluated as well. A higher degree of cross-fixation was encountered in thesetests than had been found in nonvaccinated patients with epidemic or murinetyphus fever. An example is shown in table 25. This patient was proved to haveepidemic typhus fever by isolation of the strain. The high degree ofcross-fixation present in the sera was not due to a peculiarity of the strainitself, since sera from guinea pigs infected with it gave high titers incomplement fixation tests with epidemic antigen but were negative in tests withmurine antigen. Because of the observed cross-fixation, it was deemedunjustifiable to attempt differentiation between epidemic and murine typhus invaccinated persons on the basis of the complement fixation test alone.

In seeking an explanation for the cross-fixation, it was noted that the samelots of antigen were used in both the vaccinated and the unvaccinated groups andin the latter revealed no lack of specificity. Again, tests on sera from guineapigs infected with two strains isolated from the vaccinated patients gaveclear-cut identification of epidemic typhus fever. Accordingly,

⁴¹See footnote 35 (3), p. 183.

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TABLE 25.-Serologicalfindings in a patient with epidemic typhus fever¹contracted after receiving 5.0 cc. of Cox-type vaccine

Day of disease	Serological findings
	Weil-Felix OX-19	Complement fixation
	Weil-Felix OX-19	Epidemic	Murine
8th	Negative	1:4	Negative
19th	1:160	1:512	1:512
30th	1:160	1:512	1:512
40th	1:80	1:512	1:256
83d	Negative	1:512	1:128
162d	...do...	1:256	1:16

¹Verified by strain isolation.
Source: Zarafonetis, C. J. D.: The Serological Reactions in the RickettsialDiseases of Man. In Rickettsial Diseases of Man. Washington: AmericanAssociation for the Advancement of Science, 1948, pp. 179-183.

with the antigens known to be specific and the possibility of"intermediate" strains ruled out, it appeared that the increasedamount of cross-fixation was the result of the vaccination itself. Furthermore,in vaccinated subjects without typhus there was a higher amount ofcross-fixation than one would expect. It appeared, therefore, that vaccinationintroduces some factor that gives rise to cross-fixation and that this is simplyexaggerated by subsequent infection. The following hypothesis was advanced:

Several workers have noted the presence of a soluble substancein epidemic and murine rickettsial suspensions derived from infected yolk sacs.This soluble substance is common to both strains and if present in antigens usedin complement fixation tests is responsible for cross-fixation with heterologoussera. Plotz and his coworkers removed this soluble antigen from rickettsialsuspensions and these purified rickettsial antigens gave little or noheterologous fixation. The antigens used in this laboratory are similarlypurified rickettsial suspensions and have demonstrated their specificity innonvaccinated typhus cases.

While this soluble material is responsible for cross-fixationin complement fixation tests, it also has immunogenic properties. Topping andhis associates have found that this material produced positive Weil-Felixreactions in rabbits, and that guinea pigs were immunized as judged by thestimulation of immunity to challenge with guinea pig passage material. They alsofound that it produced complement fixing antibodies when injected into guineapigs. These findings were considered sufficient to warrant the retention of thesoluble material in vaccine preparations such as are in use today.

Thus, antigens for complement fixation testsare purified by removing the soluble substance, while vaccines retain it for itsimmunogenic properties. Therefore, an individual vaccinated with Cox-typeepidemic typhus vaccine receives both epidemic rickettsiae and solublesubstance. It seems reasonable to assume that an immunogenic response will beelicited by both of these components of the vaccine, though this may notnecessarily be detected in serologic tests. Subsequent infection with typhusrickettsiae stimulates a further antibody response, including a solublesubstance component which fixes complement in the presence of both epidemic andmarine antigens. In other words, a complement fixing antibody against bothepidemic and murine rickettsiae results from inocula-

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tion with vaccine containing a solublesubstance. This antibody gives rise to cross-fixation, thus tending tocounteract the specificity of antigens purified by removing the solublesubstance.

Rickettsial agglutination-Limited agglutinationstudies with rickettsial suspensions had been performed by a number ofinvestigators prior to World War II. In most of the early tests, a microscopictechnique was used, but with the development of methods for producing largeryields of rickettsiae, macroscopic tests offered promise of practicalapplication. Stuart-Harris and his associates,⁴²using epidemic and murine suspensions prepared from the lungs of mice infectedby the intranasal route, detected agglutinins in guinea pig and humanconvalescent sera. They concluded that differences between epidemic and murinetyphus could be demonstrated by rickettsial agglutination. Van Rooyen andBearcroft⁴³ were the first to employsuspensions of epidemic and murine typhus micro-organisms prepared from yolk-saccultures and purified by the Craigie extraction technique. They used amacroscopic agglutination technique with sera from patients with typhus feverand concluded that a differential diagnosis between epidemic and murine typhuswas possible with this test.

Plotz and Synder⁴⁴ undertook an evaluationof rickettsial agglutination with purified antigens similar to those employed inthe complement fixation studies that have been described (p. 183). Again, thespecimens tested consisted of the sera obtained from the 32 unvaccinatedpatients in Cairo. Agglutinins occurred in rising titer in all cases during thecourse 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 thatfound with the murine typhus antigen, but there is more cross-reaction here thanwas noted in the complement fixation tests on the same specimens (table 22). Inextending the test to sera from patients with other diseases, it was found thattiters were obtained at times. These workers concluded, therefore: "Sinceepidemic and murine agglutinins may occur in convalescent specimens from casesof Rocky Mountain spotted fever, occasionally in high titer, caution should beobserved in evaluation of this test when used as a diagnostic procedure."

Regrettably, routine rickettsial agglutination tests were notperformed in the Cairo laboratory of the Typhus Commission partly because theprocedure utilizes about 10 times the amount of antigen employed in complementfixation. In the vaccinated patients with epidemic typhus fever, the serologicaltests did not, therefore, include rickettsial agglutination. Data obtained intests on sera from one such patient, however, are given in table 15 (case 3). Inthe 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.
⁴³Van Rooyen, C. E., and Bearcroft, W. G. C.: Typhus Rickettsial Agglutination Tests in the Middle East Forces and Egypt. Edinburgh M.J. 50: 257-272, May 1943.
⁴⁴See footnote 32 (1) and (4), pp. 179-180.

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TABLE 26.-Rickettsial agglutination test results in case 1344-strain isolated

Day of disease	Serum titer with-
Day of disease	Epidemic antigen	Endemic antigen
4th	0	0
5th	0	0
6th	0	0
8th	1:80	1:40
10th	1:640	1:160
12th	1:2,560	1:160
14th	1:5,120	1:1,280
19th	1:10,240	1:1,280
20th	1:10,240	1:1,280
23d	1:10,240	1:1,280
25th	1:5,120	1:640
27th	1:5,120	1:640
115th	1:160	1:40
286th	1:80	1:10

Source: Plotz, H., and Snyder, J. M.: The Serological Patternin Epidemic Typhus Fever. IV. Rickettsial Agglutination. Division of Virus andRickettsial Diseases, Army Medical School, Army Medical Center, Washington,D.C., 1944. [Official record.]

has been suggested that the rickettsial agglutination testmay be more specific in vaccinated individuals than is the complement fixationtest.⁴⁵ Further information on the antibodyresponses of patients acquiring epidemic typhus fever after vaccination would berequired to establish this point.

Neutralizing antibody test-In1940, Gildemeister and Haagen⁴⁶ described theassociation of a toxin with living marine typhus rickettsiae grown in yolk sacsof developing chick embryos. These workers were interested in producing avaccine and, among other questions to be answered, wished to establish whetherrickettsiae grown by this technique had kept their pathogenicity for white mice.Accordingly, they injected a suspension of yolk sac infected with R. mooseriintraperitoneally 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 ofthis finding revealed that this effect was due to the presence of a rickettsialtoxin and that the toxin was destroyed by heating to 60^? C., or bytreating with formalin; that is, it was destroyed by procedures used to kill therickettsiae. Finally, they demonstrated that convalescent serum from eitherepidemic 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.
⁴⁶Gildemeister, E., and Haagen, E.: Fleckfieberstudien. I. Mitteilung: Nachweis eines Toxins in Rickettsien-Eikulturen (Rickettsia mooseri). Deutsche Med. Wchnschr. 66: 878-880, 9 Aug. 1940.

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Following the report of Gildemeister and Haagen, Bengtson andher coworkers⁴⁷found that a toxicsubstance was present in yolk-sac cultures defected with epidemic typhusrickettsiae. Henderson and Topping⁴⁸ thenshowed that this toxic substance could be neutralized by convalescent epidemictyphus serum, and devised a neutralization test in mice which was adopted by theNational Institutes of Health as the standard potency test for typhus vaccines.At about the same time, Hamilton⁴⁹ demonstratedthat the toxins associated with suspensions of living epidemic and murine typhusrickettsiae were immunologically separable as were the antibodies thatneutralized them.

Plotz and Bennett⁵⁰undertook an evaluation of the mouse neutralization test as a possiblelaboratory tool for use in the diagnosis of typhus fever. Employing some 13,000mice, they carried out neutralization tests on the serial serum specimensobtained from the 32 Cairo cases of epidemic typhus fever. In recording theresults of this study, complete protection indicated that all mice testedat a given serum dilution survived; partial protection, that oneor more but not all of the animals survived; and no protection, thatall the mice in a group died. For uniformity in recording, the 50 percent endpoint of each titration was determined by the method of Reed and Muench. Table27 illustrates the neutralization titers obtained in tests on sera from one ofthe Cairo cases. Actually, neutralizing antibody appeared during the course ofillness in all of the cases studied; 28 percent developed neutralizingantibodies by the 6th day, 75 percent by the 8th day, and 100 percent by the11th day. The curve of neutralizing antibody response was quite similar to thatobtained in Weil-Felix Proteus OX-19 agglutination tests on the samesera.

Of additional interest were the results obtained by the sameauthors when epidemic typhus neutralization tests were performed with specimensof serum from cases of Rocky Mountain spotted fever. The patients from whom thespecimens were obtained had not been given any typhus vaccine, nor did they havea history of typhus fever. Neutralizing antibodies for epidemic toxin werefound, however, in 11 cases of Rocky Mountain spotted fever studied. Thisfinding indicated that the epidemic neutralizing antibody was not restricted toepidemic typhus fever, and hence, these workers concluded that the mouseneutralization test is not reliable as an indication of a past infection withtyphus.

Isolation and identification of R. prowazeki strains-Isolationof the causative agent and identification of it through appropriate means isclassically 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, pp. 25-29.
⁴⁸U. S. Public Health Service, Federal Security Agency: National Institute of Health Bulletin No. 183, Studies of Typhus Fever. Washington: U.S. Governincnt Printing Office, 1945, pp. 41-56.
⁴⁹Hamilton, H. L.: Specificity of the Toxic Factors Associated with the Epidemic and Murine Strains of Typhus Rickettsiae. Am. J. Trop. Med. 25: 391-395, September 1945.
⁵⁰See footnote 32 (3), p. 179.

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TABLE 27.-Epidemic neutralizing antibody findings in case 1344-strain isolated

Day of disease	50 percent end point titer final dilution	Day of disease	50 percent end point titer final dilution
4th	0	19th	2,580
5th	0	20th	1,444
6th	0	23d	1,618
8th	25	25th	1,618
10th	90	27th	722
12th	645	115th	161
14th	2,048	286th	51

Source: Plotz, H., and Bennett, B. L.: The Serological Patternin Epidemic Typhus Fever. III. The Neutralizing Antibody. Division of Virus andRickettsial Diseases, Army Medical School, Army Medical Center, Washington,D.C., 1944. [Official record.]

isolation of R. prowazeki was, therefore, oftenperformed in the field laboratories of the U.S.A. Typhus Commission in order toestablish a firm basis for the observations made in their variousinvestigations. In addition to the obvious importance of strain isolation fordiagnostic purposes, it was also desirable for laboratory comparison of immunityrelationships between strains that were isolated during epidemiological surveysin various parts of the world. Strains of R. prowazeki were alsoavailable for special vaccine production if differences in immunogenicproperties from the Breinl strain (employed in the U.S. Army vaccine) had becomemanifest. Strains were used further in the laboratory evaluation ofchemotherapeutic agents and in the preparation of antigens for serologicaltests.

Guinea pigs were, of course, invaluable in the initialisolation of typhus fever organisms, either from the ground clot of blood drawnfrom 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 licefor use in such studies.⁵¹ Pill boxescontaining approximately 200 lice each, and prepared with a fine-mesh clothscreen through which the lice could feed, were often carried by members of theTyphus Commission to distant points of survey. The lice were fed on theirpersons until such time as an appropriate case of suspected typhus fever wasfound. The pill box would then be attached with adhesive tape to the patient'sleg for about 10 days, At the end of this feeding period, the louse box wascarefully removed and sealed in an envelope, not to be opened again until theworker had returned to the laboratory, often hundreds of miles distant from thepatient. At the laboratory, the material was carefully ground and injected intoguinea 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.

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example, one officer⁵² was able to isolatein Cairo 10 strains of R. prowazeki from partisan soldiers illwith typhus in Yugoslavia during March 1945.

Supplies of guinea pigs were limited so that field studies were oftenhampered. For this reason, the observation of Snyder and his coworkers⁵³that two desert rodents, namely, Gerbillus gerbillus and Gerbilluspyramidum, were susceptible to experimental typhus infection proved to bevaluable 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, ashas been noted. However, the embryonated egg was not widely used for directisolation of rickettsiae from the blood of patients ill with typhus fever, andthe degree of successful strain isolation that might be achieved through thistechnique remains to be determined.

TREATMENT

The treatment of epidemic typhus fever may be considered in two broadcategories. First are the general supportive measures including good nursing,particular attention to diet, fluids and electrolytes, and appropriatemanagement of complications as they arise. These measures have been outlined (p.153) with the observations and reasoning on which they were based, and needlittle exposition here.

Supportive therapy-Diligent nursing care isrequired throughout the febrile period and also during convalescence. Theposition of semistuporous patients should be changed often to prevent both skinand pulmonary complications. The oral cavity should be cleansed frequently in aneffort to prevent parotitis. Careful attention must be given to fluid intake andoutput. As much as 4,000 cc. of fluids may be required daily, preferablyadministered orally. Supplemental intravenous fluids should be given whenevernecessary to maintain fluid balance. With respect to diet, high protein andcaloric intake is associated with less loss of weight and a shorter period ofconvalescence. In severe cases, nourishing protein and carbohydrate mixtures maybe given via an indwelling stomach tube. Delirium and extreme restlessness maybe controlled by chloral hydrate or paraldehyde, but barbiturates actunpredictably.

The present discussion is chiefly concerned with specific treatment,including serotherapy, the use of antibiotics, and chemotherapy, and someconsideration is given to prophylaxis.

Serotherapy-Immune serum had been used by anumber 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.
⁵³Snyder, J. C., Zarafonetis, C. J. D., and Liu, W. T.: The Susceptibility of the Rodents, Gerbillus gerbillus and Gerbillus pyramidum, to Experimental Typhus Infection. Proc. Soc. Exper. Biol. & Med. 59: 110-112, June 1945.

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valescent serum generally showed no noticeable effect on thecourse of the disease, while there were conflicting reports regarding theefficacy of sera obtained from animals that had recovered from experimentallyinduced typhus. With improved techniques for the growth of large quantities ofrickettsiae, however, the hyperimmunization of animals was facilitated. Refined,concentrated antityphus serum was prepared from rabbits hyperimmunized withsuspensions of infected yolk sacs of developing chick embryos.⁵⁴Serum prepared in this manner was shown to have a strikingly protective effectin experimental typhus.⁵⁵

Knowledge of this laboratory experience prompted Yeomans,Snyder, and Gilliam⁵⁶ to undertake a clinicaltrial of hyperimmune rabbit serum in patients admitted to the ward of the TyphusCommission at the Cairo Fever Hospital. This study was begun in April 1943; 25patients with typhus were treated. All were skin tested for sensitivity to theserum, and, if negative, serum therapy was administered. The total amount ofserum 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 wasfound to be related to the duration of illness at the time treatment wasinstituted. The results in 10 patients treated on the second and third day ofthe 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 inclinical severity from the "untreated" controls, except that therewere no fatal cases. Of the 25 patients who received hyperimmune rabbit serum, 7developed mild serum sickness.

Another opportunity to test the efficacy of serum therapypresented itself to the U.S.A. Typhus Commission group working at the DachauConcentration Camp in May and June 1945.⁵⁷ Tenpatients admitted to the Commission ward were given hyperimmune antityphusrabbit serum on the following dosage schedule: In the first 24 hours afteradmission, 0.5 cc. per pound of body weight; on the second and third days, 0.25cc. per pound of body weight. All of the serum was injected intramuscularly inthe buttocks after appropriate skin testing. Owing to limited supply, theaverage amount administered to these subjects was less than was given to thepatients in the Cairo series. This may be the explanation for results lessimpressive than those obtained in the Cairo study. The illness in four patientswas mild; four were moderately ill, and one was severely ill. The 10th patienttreated 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.
⁵⁵Wyckoff, R. W. G., and Bohnel, E.: Therapeutic Effect in Guinea Pigs of Hyperimmune Epidemic Typhus Antiserum. Proc. Soc. Exper. Biol. & Med. 49: 712-715, April 1942.
⁵⁶Yeomans, A., Snyder, J. C., and Gilliam, A. G.: The Effects of Concentrated Hyperimmune Rabbit Serum in Louse Borne Typhus. J.A.M.A. 129: 19-24, 1 Sept. 1945.
⁵⁷See footnote 14, p. 155.

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onset of typhus fever. The average duration of fever in thetreated 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 arickettsiocidal effect, for Plotz and his coworkers⁵⁸isolated rickettsiae from 11 of the Cairo patients after the serum had beengiven. From the prolonged incubation periods noted in isolating thesemicro-organisms in guinea pigs, it was postulated that the serum may haveexerted a rickettsiostatic effect. Finally, these workers suggested that thebeneficial clinical effect attributed to hyperimmune rabbit serum was due to itsability to neutralize the toxic substance elaborated by typhus rickettsiae.

Antibiotics-In 1944, crude commercial penicillinwas shown to inhibit the growth of typhus rickettsiae in the yolk sac⁵⁹and markedly to reduce, or even completely prevent, mortality from murinetyphus infection in mice.⁶⁰ Clinical trials ofpenicillin, however, were limited in both the number of cases treated and thedosages administered. For example, Col. William S. Stone, MC, Chief, PreventiveMedicine, Medical Section, North African Theater of Operations, U.S. Army, andCaptain Woodward of the Typhus Commission made available to British workers inItaly⁶¹ 4 million Oxford units of penicillinfor trial in the treatment of epidemic typhus fever. Four patients were treated,none before the sixth day of disease. The total amount of penicillin dosageranged 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 theTyphus Commission ward in Cairo.⁶² Yeomans andhis coworkers could not determine on the basis of this limited experiencewhether penicillin given early, and in what were then considered "largeamounts," did or did not affect the course of typhus. The potentialusefulness of penicillin for the treatment of secondary bacterial infectionssuperimposed on typhus fever, however, was recognized by them soon after thisantibiotic became available.

Postwar studies by Greiff and Pinkerton⁶³with pure crystalline penicillin fractions revealed important differences in therickettsiostatic activity of the different fractions. Penicillin X was aboutfour times as effective on a unit basis as penicillin G, and there weredifferences in the potency of other fractions. From this, it would appear thatthe 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.
⁵⁹Greiff, D., and Pinkerton, H.: Inhibition of Growth of Typhus Rickettsiae in the Yolk Sac by Penicillin.Proc. Soc. Exper. Biol. & Med. 55: 116-119, February 1944.
⁶⁰Moragues, V., Pinkerton, H., and Greiff, D.: Therapeutic Effectiveness of Penicillin in Experimental Murine Typhus Infection in dba Mice. J. Exper. Med. 79: 431-437, April 1944.
⁶¹Medical Research Council, Special Report Series No. 255, Chemotherapeutic and Other Studies of Typhus. London: His Majesty's Stationery Office, 1946, pp. 78-81.
⁶²See footnote 6, p. 147.
⁶³Greiff, D., and Pinkerton, H.: The Rickettsiostatic Action of Crystalline Penicillin Fractions in Embryonate Eggs. Proc. Soc. Exper. Biol & Med. 68: 228-232, June 1948.

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could have been due to varying proportions of the penicillinfractions in the preparations used. These workers concluded that the clinicaltrials referred to above were invalidated by the use of low doses, started latein the course of the disease, by the small number of cases, and by the fact thatfractions of proved potency against R. prowazeki were not employed. Theeffectiveness of penicillin in human rickettsial infection, therefore, remainedundetermined.

The newer broad-spectrum antibiotics were not discovereduntil after the period under review and so are not included here, but theirimportance will be indicated at the end of the discussion of therapy.

Chemotherapy-A new chapter inthe treatment of epidemic typhus fever and other rickettsial diseases was begunduring World War II with the observation that PABA exhibited antirickettsialactivity in vivo. This was discovered independently by Snyder, Maier, andAnderson in 1942⁶⁴ and by Greiff, Pinkerton,and Moragues in 1944.⁶⁵ Its use was suggestedto the former group by the apparently deleterious effect of sulfonamides on thecourse of experimental typhus infection and the knowledge that PABA andsulfonamides are metabolic antagonists. The second group of workers first triedPABA in in effort to enhance the action of penicillin. Still a third discoveryof the inhibitory effect of PABA on the growth of typhus rickettsiae was made in1944 by Takemori, working at the Hygienic Institute in Dairen, Manchuria .⁶⁶

The letter report of Snyder and his associates was circulatedin laboratories known to be concerned with rickettsial diseases. At the ArmyMedical School, Hamilton, Plotz, and Smadel⁶⁷undertook a systematic study of the effect of PABA and related substances on thegrowth of rickettsiae. Inoculating the test compound directly into the yolk sacsof infected chick embryos, which were allowed to develop until death resultedfrom rickettsial infection, they found a marked difference in survival time ofthe treated eggs as compared with the controls (chart 9). In addition, it wasshown by direct count of rickettsiae in eggs, opened after an arbitrary periodof time, that their numbers had been greatly reduced in those treated with PABAin 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].
⁶⁵Greiff, D., Pinkerton, H., and Moragues, V.: Effect of Enzyme Inhibitors and Activators in the Multiplication of Typhus Rickettsiae. I. Penicillin, Para-Aminobenzoic Acid, Sodium Fluoride, and Vitamins of the B Group. J. Exper. Med. 80: 561-574, December 1944.
⁶⁶Takemori, N.: The Actions of Sulfonamide Compounds and p-Aminobenzoic Acid on the Virus of Lymphogranuloma Inguinale and Typhus Rickettsiae in Vitro. Japanese Med. J. 2: 1-8, February 1949.
⁶⁷Hamilton, H. L., Plotz, H., and Smadel, J. E.: Effect of p-Aminobenzoic Acid on the Growth of Typhus Rickettsiae in the Yolk Sac of the Infected Chick Embryo. Proc. Soc. Exper. Biol. & Med. 58: 255-262 March 1945.

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suggesting a toxic effect of excessive PABA. Even so, thenecessity for using quantities of PABA up to 2 mg. to inhibit rickettsial growthin an egg suggested the possibility that a nonspecific effect might be involved.Accordingly, two isomers, ortho- and meta-aminobenzoic acid, as well asacetyl-p-aminobenzoic acid (both sterilized by heat and sterilized by Seitzfiltration), sulfanilamide, sodium benzoate, and benzoic acid were tested inconcentrations equivalent to the maximal dose of PABA (4 mg. per egg). With theexception of the heat-sterilized acetyl derivative, none of these substances hadany apparent effect on either the time of death or the number

CHART 9.-Effectof para-aminobenzoic acid on time of death in chick embryos infected with Rickettsiaprowazeki

of rickettsiae. Heating hydrolyzes a certain portion ofacetyl-PABA into PABA, which is the probable explanation for the aboveobservation. These studies clearly indicate that the inhibition of growth byPABA is due to a specific action of the drug.

An outstanding series of investigations by Greiff⁶⁸and his colleagues shed further light on the mechanism of action of PABA inrickettsial infections, as shown by Greiff in the discussion which follows.

The rickettsiostatic action ofpara-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 (becauseof 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.

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striking example of the inhibition of anintracellular parasite by a compound usually regarded as a vitamin. Pinkertonand Bessey showed that in riboflavin-deficient rats, practically moribund fromtyphus, riboflavin had a striking "chemotherapeutic" action, causingrapid recovery from what appeared to be overwhelming and certain fatalinfection. With the sudden resumption of cellular respiration when the missinglink is furnished, the normal resistance of the rat is restored. With this factin mind we have been interested in learning the mechanism of action of PABA, andparticularly in determining whether or not this compound like other compoundsand conditions found to discourage rickettsial growth, causes an increase in thecellular metabolic rate.

In conjunction with our earlier work, we proved conclusivelythat cyanide had no effect on the rickettsiostatic action of PABA. From thisfact we concluded that PABA either acted directly on the rickettsiae, in amanner similar to the action of sulfadrugs on bacteria, or that PABA, liketoluidine blue, increased cell respiration by short-circuiting the cyanidesensitive system of respiratory enzymes.

Recently we have developed a reliable methodfor measuring the oxygen consumption and carbon dioxide output of fertile eggs.In 3 separate experiments, we have found that the injection of PABA into theyolk sac markedly increases the oxygen consumption. The effect is noted after adelay of about 5 days, which is perhaps caused by slow absorption of theprecipitated compound from the yolk sac. From the 5th to the 10th days afterinjection (almost exactly the period of active rickettsial multiplication) theoxygen consumption continues to be 25-50 percent above that of the uninjectedcontrol eggs. This of course does not prove that the rickettsiostatic action ofPABA 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 reasonableassumption.⁶⁹

Greiff commented further in summarizing the work of his group:

Conditions such as low temperature andriboflavin deficiency, which decrease the rate of cellular metabolism, favor thegrowth of rickettsiae. Higher temperatures and certain dyes and other agentswhich increase cellular metabolism are unfavorable to rickettsial growth. Ourexperiments indicate that the activity of the cyanide sensitive respiratoryenzyme (cytochrome oxidase) is one essential factor in the protection of cellsagainst rickettsial multiplication. In the case of toluidine blue andpara-aminobenzoic acid, however, rickettsiostatic activity is correlated withincreased cellular respiration brought about by mechanisms which arecyanide-insensitive.

Clinical studies designed to determine the therapeutic effectof PABA in epidemic typhus fever were begun on the ward of the Cairo Unit of theTyphus Commission in 1943. Yeomans, Snyder, Murray, Zarafonetis, and Ecke⁷⁰were able to report in 1944 that the drug had a favorable influence on theclinical course of patients whose treatment was begun in the first week of thedisease. These studies were continued through 1945, both in Cairo and at theDachau Concentration Camp,⁷¹ and a summary ofthe results of treatment of a cumulative total of 95 patients suffering fromtyphus 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.
⁷⁰See footnote 6, p. 147.
⁷¹See footnote 14, p. 155.
⁷²Snyder, J. C., Yeomans, A., Clement, D. H., Murray, E. S., Zarafonetis, C. J. D., and Tierney, N. A.: Further Observations on the Treatment of Typhus Fever With Para-Amino-Benzoic Acid. Ann. Int. Med. 27: 1-27, July 1947.

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The most carefully controlled observations were made inCairo. Here, patients were placed alternately in control and PABA-treatedgroups. The study groups were composed of 39 male Egyptian patients, ages 18 to48, suffering from epidemic typhus fever. The diagnosis was based on theclinical course, serological findings, and, in 19 instances, isolation of R.prowazeki from the blood or from normal lice fed on the patients during thefebrile period. None of the patients had been vaccinated against typhus fever orgave a history of a previous attack of the disease. Most were somewhatunderweight but appeared to be in good physical condition otherwise. A few ofthe patients were subsequently found to have subclinical schistosomiasis, butnone was excluded because of this finding. One PABA-treated patient developed anexacerbation of amebic dysentry during convalescence from typhus, but his casewas included in the results. The patients were in the first week of illness whenthey were placed in the control and PABA-treated groups in automatic rotation.

CHART 10.-Comparisonof temperatures of 20 para-aminobenzoic acid treated patients and 19 alternatecontrol patients, Cairo, Egypt, 1944 and 1945

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,

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17.9 days (chart 10). The incidence of complications was higher in thisgroup, and there were six fatal cases.

In the 20 patients treated with PABA, mean values were as follows: Age, 28.5years; duration of illness when treatment was started, 4.4 days; duration offever, 12.8 days. The incidence of complications was less than in the controlgroup, and there was one death in this series.

The treatment regimen to be followed with PABA was evolvedonly after considerable experimentation. Yeomans and his coworkers⁷³outlined the plan of therapy, as follows:

In all instances, PABA was administered bymouth. The initial dose varied from 4 to 8 gm. In the majority of cases, theinitial dose was followed by 2 gm. every 2 hours unless the concentration in theblood attained excessive values. Adjustments in dosage were made in relation tofluid intake and urinary output. The fluid intake in nearly all instances wasadequate to maintain the output of urine between 1,500 and 3,000 cc. in 24hours.

The effort was made to keep the concentrationof PABA in the blood between 10 and 20 mg. per 100 cc. PABA is absorbed andexcreted very rapidly, so that a 2-hourly schedule of administration was decidedon as that most likely to produce a relatively constant blood level.Determinations made at various times during treatment indicated that the2-hourly schedule was effective in maintaining a satisfactory concentration ofPABA throughout the period of therapy.

PABA was continued for varying lengths of time in the firstcases. Subsequently, it was decided that treatment should be continued until thepatient's rectal temperature was 37.5? C. (99.5? F.) or less for 24 hours. Theaverage amount of PABA for each case was approximately 127 gm. The patients whoare the subject of discussion in this study received PABA for at least 3 days.

Nausea and vomiting attributable to PABAoccurred in the first few cases. Thereafter, in order to lessen gastricirritation, sufficient sodium bicarbonate was given to neutralize the PABA. Theacidity of the urine was determined at least once daily during therapy. Theamount of sodium bicarbonate was varied as required to keep the urineapproximately neutral in reaction. After this plan was adopted, vomiting wasencountered very infrequently.

PABA was available in tablets of 0.5 gm. eachand in capsules of 0.3 gm. each. Neither form was suitable for administration totyphus patients, who could not be persuaded to swallow the large numbers oftablets or capsules required for each dose, but they took powdered PABA readilyif it was suspended in water or partially dissolved in a sufficient volume of 5percent sodium bicarbonate solution to render the mixture slightly alkaline. Theusual amount was 2 gm. of powdered PABA with 25 cc. of sodium bicarbonatesolution.⁷⁴ After swallowing the mixture, the patient was quicklygiven water to take away the slightly unpleasant taste of the drug. This methodof administration was entirely satisfactory in most instances.

Premature withdrawal of PABA therapy was followed by a mild febrile periodwhich probably represented a mild recrudescence of the disease. For

⁷³See footnote 6, p. 147.
⁷⁴Postwar experience in the treatment of hundreds of nontyphus patients has shown that a chilled, 10 percent aqueous solution of pure prescription-grade potassium para-aminobenzoate (Potaba) is much more readily tolerated than the relatively crude mixtures employed during these typhus studies. In retrospect, it would seem that even better results could be achieved in typhus with Potaba if the need should ever arise again.

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this reason, it was found advisable to continue the initial course of PABAfor 48 hours after the patient's temperature had returned to normal.

At no time were crystals of PABA ever noted in the urine ofthe patients treated. There was detected, however, a slight tendency toleukopenia during this form of therapy. Snyder and his coworkers⁷⁵found the mean of the lowest counts was 5,200 per cubic millimeter for 19control patients, while the mean for the 20 patients treated with PABA was 4,100per cubic millimeter, but the difference was not statistically significant.Analysis of the differential leukocyte counts did, however, reveal a slight butstatistically significant reduction in the percentage of segmented neutrophils(69.9 percent was the mean for the controls, and 55.1 percent was the mean forthe treated group) and an increase of a similar percentage in the lymphocytes.The differences in percentages of monocytes, eosinophils, and basophils were notsignificant. Although slight depression of the neutrophils was attributable tothe administration of PABA, no instance of true agranulocytosis was encounteredin these studies.

PABA was thus discovered to have important antirickettsialactivity and, through studies as just described, was brought to the position ofa safe and promising drug for clinical use during World War II. Its importancein the management of epidemic typhus fever and other rickettsial diseases wasshort lived as a result of the postwar development of broad-spectrumantibiotics.⁷⁶ The wartime studies with PABAmay yet be shown, however, to have great significance both from the standpointof rickettsial growth factors and as a clue to certain intracellular metabolicprocesses.

⁷⁵See footnote 72, p. 197.
⁷⁶PABA has since been supplanted by the broad-spectrum antibiotics, which have greatly simplified the treatment of epidemic typhus fever. Properly used, these will reduce the mortality of the disease very nearly to zero. Chloramphenicol, Aureomycin (chlortetracycline), and Terramycin (oxyltetracycline) are all effective, and usually bring about dramatic improvement within 24 to 72 hours after institution of therapy. Woodward and Parker (Woodward, Theodore E., and Parker, Robert T.: Clinical Application and Mode of Action of Antibiotics in Rickettsial and Virus Diseases. In The Dynamics of Virus and Rickettsial Infections. New York: The Blakiston Company, Inc., 1954, pp. 437-457.) consider the following dosage schedules to be optimal. For chloramphenicol, the initial oral dose is 50 mg. per kilogram of body weight, and for Aureomycin and Terramycin, 25 mg. per kilogram of body weight is given. Maintenance doses are calculated on the basis of 50 mg. per kilogram per day for chloramphenicol, and 25 mg. per kilogram per day for Aureomycin and Terramycin. The total daily requirement is given in equally divided doses at 6- to 8-hour intervals. Administration of the antibiotic employed is continued until the patient has improved and has been afebrile for about 24 hours. When oral medication is not feasible, the intravenous route may be used. The initial dose of chloramphenicol should be calculated on the basis of 20 mg. per kilogram of body weight, and Aureomycin and Terramycin on the basis of 5 to 10 mg. per kilogram of body weight. Subsequent daily requirements are calculated in the same manner, divided into four equal doses which are administered at 6-hour intervals. Undesirable side effects such as nausea, vomiting, glossitis, diarrhea, and proctitis are more commonly encountered with Aureomycin and Terramycin than with chloramphenicol. The newer related antibiotic, terracycline, appears to be equally effective with less toxicity. There have been no reports of hemopoietic depression from the short-term use of chloramphenicol in rickettsial diseases.
Cortisone has been combined with broad-spectrum antibiotic therapy in rickettsial diseases. Headache was promptly relieved, toxicity disappeared, the appetite returned, and the fever lasted less than 2 days on average. The addition of cortisone to the treatment regimen should especially be considered in late, severely ill, extremely toxic patients.

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Prophylaxis.-Prevention ofepidemic typhus fever was made practicable during World War II with theproduction of adequate quantities of a potent vaccine and by improved methods oflouse control.

Personnel in the Armed Forces of the United States were vaccinated withantityphus vaccine of the Cox type. Although 104 cases of epidemic typhus weredetected in U.S. troops, there was not a single death. Typhus contracted aftervaccination is, therefore, relatively mild and rarely if ever causes death.Furthermore, lice fed on patients who were vaccinated before acquiring typhusdevelop very few rickettsiae in comparison to lice fed on unvaccinated patients.Thus, vaccination not only alters the susceptibility of the individual but, whenused on a broad scale, also serves to reduce the epidemic potential of thedisease.

In the complementary effort to prevent the disease bydestroying the vector, a number of agents were developed, the most effectivebeing DDT (dichlorodiphenyltrichloroethane). A 10 percent DDT powder dusted intothe clothing was found to provide almost complete protection against lice for 3weeks or more.⁷⁷DDT or otherinsecticide powders are of greatest importance when conditions prevail which arefavorable for an epidemic. During World War II, the vigorous application ofdelousing measures in the prevention or prompt control of typhus epidemics wasan historic accomplishment in the annals of preventive medicine.⁷⁸

Part II. Brill's Disease

It is now recognized that Brill's disease is clinicalrecrudescence of a previous epidemic typhus infection. The causativemicro-organism, R. prowazeki, may remain latent in an individual foryears following the original infection. As immunity wanes, and possiblyinfluenced by still undetermined factors, the rickettsiae are activated and giverise to illness which often resembles that associated with the primaryinfection.

HISTORICAL NOTE

Nathan Brill first described the disorder in 1898 and again in 1910 as anacute infectious disease of unknown origin. His reports were based on the studyof 221 cases occurring sporadically in New York City during more than a decadeof observation. Brill's clinical description is classic. He also noted thatWidal tests and blood cultures were negative and called attention to thesimilarity of the disease to typhus fever.

Additional cases were soon reported by others, and in 1912, Anderson andGoldberger 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).
⁷⁸See footnote 4, p. 144.

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related to Mexican typhus. At that time, it was believed thatthere was only one form of typhus fever, but during the next 30 years, it wasclearly established that there were two distinct varieties; namely, louseborneepidemic typhus and fleaborne murine typhus. In the absence of epidemiologicalevidence incriminating either lice or fleas, however, the position of Brill'sdisease remained uncertain until Zinsser offered an explanation in 1934. Onepidemiological grounds, Zinsser postulated that Brill's disease resulted fromrecrudescence of an old typhus infection which had been acquired in Europe. Thistheory was further supported by the fact that three strains of rickettsiae whichhe and Castaneda had recovered from patients with Brill's disease gavebiological reactions similar to those induced by R. prowazeki.

EPIDEMIOLOGY

Brill's disease occurs sporadically and infrequently amongindividuals who have previously had epidemic typhus fever. The originalinfection may have been acquired from a few years to as long as 50 years or morein the past. Subjects who continue to live in typhus zones may serve as theinterepidemic reservoir of epidemic typhus fever.⁷⁹On the other hand, Brill's disease in individuals who have migrated to nontyphusareas presents no epidemic problem. The incidence of Brill's disease is notknown, but it is very small in proportion to the total number of cases ofepidemic typhus fever.

CLINICAL PICTURE

The typical case resembles a mild to moderately severe attack of epidemictyphus fever as described in the preceding section. All of Brill's originalcases exhibited a rash, as it was a required feature for diagnosis. It is nowrecognized, however, that many mild cases occur without all eruption at any timeduring the course of illness.

The febrile course varies from a few days in mild cases to 2weeks or more in severe attacks. If an eruption is present, it may be sparse andevanescent or it may be moderately extensive. Headache and malaise persist untilthe fever subsides. The mortality is low, possibly 1 or 2 percent. The greatmajority of patients have a prompt convalescence and complications are rare.

DIAGNOSIS

The clinical diagnosis of Brill's disease may be made in apatient who has lived at some previous time in an epidemic typhus area and whoseillness 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).

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pearing on the fourth to sixth day of disease. In caseswithout a rash, the remaining criteria should lead to the consideration ofBrill's disease in the differential diagnosis.

From the foregoing, it is evident that the specific diagnosisof Brill's disease must rest on other than clinical findings alone. In thisarea, Col. Harry Plotz, MC, made a highly significant contribution during WorldWar II,⁸⁰ demonstrating that complementfixation tests with purified rickettsial antigens could be applied to thespecific diagnosis of epidemic typhus and murine typhus. The followingserological evidence substantiates this point of view:

In 23 cases of Brill's disease examined all showed a positivecomplement fixation with an epidemic rickettsial antigen. In 10 cases there wasfixation with an epidemic rickettsial antigen and no fixation with an endemicrickettsial antigen. In 13 cases there was some cross-fixation but in allinstances where this occurred the titer obtained was higher with epidemicantigen. The pattern of fixation in this disease resembles that obtained inepidemic typhus fever.

Absorption tests were performed on specimens of serum fromBrill's disease where cross-fixation had occurred. An endemic rickettsialantigen removed all the endemic antibody with slight effect upon the titer ofepidemic antibody. On the other hand, a similar treatment of the serum with anepidemic rickettsial antigen resulted in the removal of both the epidemic andendemic antibody; no selectivity of absorption was observed. These results wouldindicate that the endemic rickettsial antigen pattern was different from that ofthe antigenic pattern of the epidemic strain. The removal unselectively of bothendemic and epidemic antibodies by the epidemic antigen suggests that the lattermay be a more complete or complex antigen than the endemic antigen.

The results obtained in Brill's disease arehighly significant for the epidemiology of typhus fever. They would indicatethat mild cases of epidemic typhus actually exist in the United States. Thedisease is not transmitted from person to person in this country simply becausethe louse vector is not present. Furthermore, these results indicate that oneattack 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 loweredthe virus multiplies and induces a mild attack. If these cases should occur in alouse-infested community the disease might readily spread from person to person.The observations on Brill's disease strongly suggest that man serves as thereservoir for epidemic typhus between outbreaks just as the rat does in endemictyphus.

Plotz further stated: "The complement fixation test now provides a toolwith which surveys of the prevailing types of typhus in a region can bedetermined."⁸¹

Thus, recrudescence of rickettsial activity occursunpredictably in a small percentage of persons who have had epidemic typhusfever. The factors which give rise to this phenomenon are not known, so that thespecific

⁸⁰Plotz, H.: Complement Fixation in Rickettsial Diseases. Science 97: 20-21, 1 Jan. 1943.
⁸¹It should be noted that while agglutinins for suspensions of Proteus OX-19 develop almost uniformly during initial attacks of epidemic typhus fever, a similar response is often lacking during the recrudescent disease (Murray, E. S., Pć P., Sielski, S., Broz. V., Ljupsa, F., Gaon, J., Pavlević, R., and Snyder, J. C.: Brill's Disease. IV. Study of 26 Cases in Yugoslavia. Am. J. Pub. Health 41: 1359-1369, November (Pt. 1) 1951). This is comparable to the Proteus OX-K findings in second attacks of scrub typhus.

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prevention of Brill's disease is not feasible at this time.Fortunately, other measures kept the incidence of epidemic typhus fever in ourtroops to a minimal level and, thereby, reduced the likelihood of Brill'sdisease in them to zero. The importance of Brill's disease to the U.S. ArmyMedical Service, therefore, lies in its epidemiological implications amongcivilians 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 withR. mooseri (syn. Rickettsia typhi) transmitted to man by ratfleas. Many of the terms applied to louseborne typhus have also been used in thepast in referring to cases of endemic typhus. Clinically, the disease is similarto epidemic typhus, but it usually runs a milder course.

Probably the first clinical description was written in 1913by 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 epidemictyphus 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 swellingwas produced in male guinea pigs by the intraperitoneal injection of bloodobtained from cases of typhus fever in Texas. Mooser extended observations alongthis line in 1928 and emphasized that this biological reaction wascharacteristic for a Mexican strain of typhus.⁸²In contrast, scrotal swelling was not a feature in guinea pigs infected withstrains of classical or louseborne typhus rickettsiae. Meanwhile, Maxcy andHavens conducted extensive epidemiological studies on the typhus cases whichoccurred in the Southern and Southeastern United States. On the basis of theseinvestigations, Maxcy, in 1926, postulated a rodent reservoir for this form oftyphus, and suggested that transmission of the disease to man was accomplishedby fleas.⁸³ This theory was confirmed in 1931by Dyer and his associates who isolated the causative micro-organism from ratfleas obtained at a typhus focus in Baltimore, Md.⁸⁴

EPIDEMIOLOGY

Murine typhus occurs as a natural infection of rats and certain other rodentsin 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.
⁸³Maxcy, K. F.: An Epidemiological Study of Endemic Typhus (Brill's Disease) in the Southeastern United States. Pub. Health Rep. 41: 2967-2995, 24 Dec. 1926.
⁸⁴Dyer, R. E., Rumreich, A., and Badger, L. F.: Typhus Fever; A Virus of the Typhus Type Derived From Fleas Collected From Wild Rats. Pub. Health Rep. 46: 334-338, 13 Feb. 1931.

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among rodents by fleas, lice, and mites. The rat flea, Xenopsyllacheopis, is the principal vector involved in human infections. The causativemicroorganism, R. mooseri, may persist for long periods of time in thebrain tissues of reservoir hosts. Similarly, it has been shown that once fleashave become infected, their feces may contain rickettsiae for at least 52 daysand presumably for the remainder of their lives. Rickettsiae present in dry fleafeces may remain infectious for long periods of time.

Human infections are acquired through the rubbing of infected feces into thefleabite wound or into an abrasion from scratching. Infection may also resultfrom ingestion of food contaminated by infected flea feces or rat urine and fromcontamination of the oral or nasal mucosa with these excreta.

Cases of murine typhus occur sporadically throughout theworld. In the United States, about 97 percent of the cases have been reportedfrom Alabama, Georgia, Florida, Louisiana, Mississippi, North Carolina, SouthCarolina, Tennessee, and Texas (fig. 33).⁸⁵Other 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 encounteredin port cities and in rural areas south of 33^? N. latitude. Belowthis line, the long warm season and field storage of crops permit rats to liveand multiply outdoors throughout most of the year, thereby enhancing theepidemiological potential for this disease. Although approximately 300 caseswere reported in the United States in 1931, the number later increased greatlyand reached a peak of 5,353 in 1944 (chart 11).

CLINICAL EXPERIENCE

Murine or endemic typhus was not an item of diagnosis in the U.S. Armymedical statistics until 1940; all forms of typhus were included in a singlefigure prior to that time. From a practical standpoint, therefore, theexperience of the U.S. Army Medical Department with murine typhus did not becomemeaningful until 1940 and thereafter.

During World War II, there were 787 cases of murine typhus inthe 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 offleaborne typhus than of the louseborne disease. Bayne-Jones has discussed indetail the basis for the less effective control measures of murine typhus duringthe 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.
⁸⁶See footnote 4, p. 144.

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FIGURE 33.-Counties in 11 Southern States reporting cases of endemic typhus fever,1922-39 and 1943-45. (Reproduced by permission of the American Association forthe Advancement of Science.)

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CHART 11.-Totalreported cases of murine (fleaborne) typhus in the United States, 1931-45

TABLE 28.-Incidence ofendemic typhus fever (fleaborne) in the U.S. Army, by area and year, 1942-45

[Preliminary data based on sample tabulations of individual medical records]
[Rate expressed as number of cases per annum per 1,000 average strength]

Area	1942-45		1942		1943		1944		1945
Area	Number of cases	Rate	Number of cases	Rate	Number of cases	Rate	Number of cases	Rate	Number of cases	Rate
Continental United States	497	0.03	72	0.03	165	0.03	160	0.04	100	0.03
Overseas:
Europe	5	0.00	---	0.00	---	0.00	5	0.00	---	0.00
Mediterranean¹	12	.01	---	0	8	.02	4	.01	---	0
Middle East	9	.06	---	0	1	.02	8	.17	---	0
China-Burma-India	34	.08	---	0	7	.18	12	.07	15	.07
Southwest Pacific	87	.05	10	.14	39	.21	33	.06	5	0
Central and South Pacific	123	.10	13	.09	65	.22	35	.08	10	.03
North America²	1	0	---	0	---	0	1	.01	---	0
Latin America	18	.05	3	.03	1	.01	4	.05	10	.14
Total overseas³	290	0.03	26	0.04	122	0.07	102	0.03	40	0.01
Total Army	787	0.03	98	0.03	287	0.04	262	0.03	140	0.02

¹Includes North Africa.
²Includes Alaska and Iceland.³Includes one admission aboard transport in 1943.

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Despite the relatively high incidence of endemic typhus, thesporadic and unpredictable occurrence of cases generally prevented clinicalstudies 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.⁸⁷Since Jamaica had become a military base for U.S. forces as a result of thelend-lease agreement of 1940, the presence on this island of typhus in any formwas a matter of concern to the Medical Department of the Army. The first case oftyphus to be recorded in Jamaica was observed by Captain Woodward in December1941. The patient was a native laborer who complained of fever, headache, andgeneralized pains on admission to the Army hospital. He was moderately toxicand, 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. for14 days and fell by lysis. In spite of careful search, no rash was observed. Hisskin was caf? au lait in color, and a slight rash may have been missed. TheWeil-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 testsindicated that this patient had murine typhus. This case directed attention tothe 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 inthe hospitals at Kingston. The clinical and laboratory findings in this groupwere summarized as follows:

The onset is usually sudden with severe headache, generalizedpains, and temperature which is maintained for about 14 days when it falls byrapid lysis. Rash was only seen in 7 cases. In these cases the rash wasmaculopapular in character. No rash was observed in 26 cases but may have beenmasked in some instances by the dark skin of the natives. However, somepatients, who were carefully observed, showed no rash, and hence the possibilityof 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 risingagglutination titer was observed. Specimens of serum examined for complementfixing antibodies were positive at least late in all cases. In the sera of mostpatients, complement fixing antibodies were present which reacted with anendemic rickettsial antigen but not with an epidemic rickettsial antigen. In afew cases, convalescent sera had relatively large amounts of complement fixingantibody against an endemic antigen and small amounts against an epidemicantigen.

This study was particularly important in that it proved that endemic typhuswas indigenous to Jamaica and had not been introduced by U.S. Army engineertroops in 1941, as had been rumored in some quarters.

A number of workers had voiced suspicion that murine typhus was present inthe 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.

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Loranger to establish its endemicity there during the latter part of WorldWar II. The following case was recorded in their report:⁸⁸

On 23 April 1945, an American soldier became suddenly ill witha headache and chill soon followed by fever, general malaise, nausea, andvomiting. At this time and for the 3 previous weeks he was billeted in a largewarehouse in San Juan del Monte, a township bordering the outskirts of Manila,Philippine Islands. Rats (Rattus norvegicus) had been seen andsubsequently trapped in this structure which is situated in close proximity tonative dwellings. Social contact in the latter was not denied.

Until 26 April when the patient was admitted to the 5th FieldHospital, the fever, headache, and general malaise continued. These were thepresenting symptoms with the physical examination at this time essentiallynegative. The subsequent 2 weeks' febrile course was of a remittent natureranging from 99.4? to 104.4? F. On the 15th day the temperature was normal andremained so except for minimal sporadic elevations to 99.4? F. Chills,headache, pains in the chest, abdomen, and lower back were the predominantsymptoms 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 thelower extremities and feet at which time the individual macule was fixed ondigital pressure. Remnants of the petechial-like lesions were observed until the15th 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 skinmanifestations after the 20th day.

During the early phases of the second week the temperature washigh, the patient was moderately toxic with moderate weakness and prostration.The severest phase lasted 4 days until the ninth day when he was symptomaticallymuch improved. Moderate lymphatic glandular enlargement was observed. There wereno lesions whatever suggestive of a primary eschar. A slight cough with fleetingpulmonary rales was not remarkable. Delirium and severe central nervous systemfindings were not observed. By the 13th to 15th day all outward signs ofweakness and prostration had disappeared and the patient became steadilystronger.

The treatment, entirely symptomatic, included parenteralphysiological saline and glucose solutions, small blood transfusions,supplemental iron, calcium, and vitamins.

Laboratory findings.-Repeated examinations of bloodsmears for malaria parasites were negative. Urinalyses were within normallimits. Numerous blood counts on 27, 28, and 29 April, 3, 4, 6, and 19 May werenormal with the white count ranging from 5,500 to 7,900, and normal differentialcounts. Red blood cells ranged from 3.8 to 4.5 millions. Stool examinations werenoncontributory. Agglutination with the O and H antigens of typhoid and the Aand B antigens of paratyphoid fever were negative and two spaced blood culturesshowed no growth. Diagnosis was established by the serial examinations ofrepeated blood specimens as shown in table 29.

Comment.-Theclinical features of continued pyrexia for 2 weeks with headaches, absence ofmarked central nervous system manifestations, and the appearance of a macularbody rash on the sixth febrile day (without primary eschar) are stronglysuggestive findings of murine typhus fever. A biopsy of one of the late skinlesions demonstrates the capillary changes and perivascular accumulation ofcells so frequently observed in rickettsial diseases collectively. Theserological findings are unquestionably significant. The patient developedincreasing titers of Proteus OX-19 agglutinins, as shown by testsperformed employing suitable control serums. Agglutinins for Proteus OX-Kdid not appear. More significantly, complement fixation on serial specimens ofserums 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.

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purified murine (yolk-sac culture) rickettsiaeas antigen clearly demonstrated antibodies of sufficient diagnostic titer (table29). The low titer of 1: 6 using an epidemic typhus antigen is within the normalrange of cross fixation frequently observed when these two closely relatedantigens 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.

TABLE 29.-Serological studies on an American soldier with murine typhus

Day of illness	Proteus OX-19	Agglutination OX-K	Complement fixation
Day of illness	Proteus OX-19	Agglutination OX-K	Murine	Epidemic
7th	0	0	---	---
16th	1:2,560	---	---	---
19th	1:2,560	0	1:384	1:6
24th	1:2,560	0	1:96	1:6
31st	1:1,280	0	1:96	0

Source: Woodward, T. E., Philip, C. B., andLoranger, G. L.: Endemic Typhus in Manila, Philippine Islands; Report of Casesand Identification of the Murine Rickettsial Agent in Domestic Rats byComplement 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 18percent of rats trapped in Manila gave evidence of endemic typhus infection asdetected by complement fixation tests with purified rickettsial antigens.

Woodward also observed murine typhus in Morocco.⁸⁹There, Dr. Georges Blanc of the Pasteur Institute undertook to determine theefficacy of a living murine typhus vaccine in human volunteers. This study gaveWoodward an opportunity to follow closely the incubation period and clinicalcourse of endemic typhus. Although no clinical report was issued, the pertinentobservations made at that time were incorporated in his later description of thedisease.⁹⁰

Murine typhus was encountered by other U.S. Army medical officers, but noseries of cases was reported as a clinical study. Scoville, Bennett, Wertman,and Gauld,⁹¹ for example, obtained data on 15cases which occurred in Nashville, Tenn., during September 1944, focusing uponserological aspects of the disease. Similarly, Plotz and Wertman⁹²described 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.
⁹⁰Woodward, Theodore E.: Endemic (Murine) Typhus Fever: Symptomatology. In Rickettsial Diseases of Man. Washington: American Association for the Advancement of Science, 1948, pp. 134-138.
⁹¹Scoville, A. J., Jr., Bennett, B. L., Wertman, K., and Gauld, R. L.: The Serological Pattern in Typhus Fever. II. Murine. Am. J. Hyg. 47: 166-176, March 1948.
⁹²Plotz, 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.

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of murine typhus contracted after immunization with epidemictyphus vaccine (table 30), again with the emphasis on the serological findings,which are to be discussed.

TABLE 30.-Serologicalresults found in individuals who were previously immunized with epidemic typhusvaccine and who subsequently contracted murine typhus

Zarafonetis⁹³reported theepidemiological, clinical, and laboratory findings in two U.S. Army enlisted menwho 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.

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West Africa, at the time of their illness. Brief summaries oftheir case histories follow.

A 27-year-old private (case 1) was admitted on 5 July 1944with the diagnosis of acute tonsillitis. He had a 1-day history of sore throatand difficulty in swallowing, and there were associated complaints of jointpains and aching. Physical examination was essentially negative except forevidence of tonsillar involvement. Temperature at that time was 99.6? F. On thefollowing day, the patient complained of a headache which was not relieved byaspirin and other analgesics and which persisted for several days thereafter. On9 July the patient experienced a chill and complained of generalized aching. Histemperature reached 102.4? F., which was the maximum attained during hishospitalization. From 9 July until 24 July, he continued to run a low-gradefever. At no time was there a rash evident. Serum taken on 12 July was tested atthe Pasteur Institute at Dakar and found to agglutinate Proteus OX-19 indilution of 1: 200. Serum was tested again on 18 July and this time agglutinatedOX-19 to a titer of 1: 1,000. On the basis of the laboratory findings adiagnosis of typhus was made.

The second case was that of a 23-year-old T/5 (case 2) who wasadmitted on 18 July with complaint of severe headache and pain in the chest for24 hours prior to admission. His physical examination at that time wasessentially negative except for an admission temperature of 101.6? F. On 25July, the 10th day of disease, a fine macular rash appeared over the chest andarms.

The rash had practically disappeared by 27 July. Fever hadbeen 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 thebasis of epidemiological evidence. Durieux and other French workers hadconcluded from extensive studies of typhus in French West Africa that thelouseborne form of this disease did not exist there. However, some 200 cases ofrelatively mild typhus had been diagnosed during the preceding decade, with only1 death recorded. The strains of rickettsiae that had been isolated from some ofthese cases were all identified as R. mooseri. At the time the Americansoldiers contracted their illness, two other cases, both unrelated, occurred inthe native population. Because of an outbreak of plague in Dakar, both soldiershad remained within their military establishments for over a month prior to theonset of their illness. An intensive antirat campaign was underway, and manyrats were known to have been present in the areas where these soldierscontracted their typhus. Both patients were aware of frequent fleabites prior totheir illness but recalled no contact with lice.

On this evidence, Zarafonetis concluded that both patients had murine typhusand were of particular interest as instances in which epidemic typhusvaccination had been followed by murine typhus infection.⁹⁴The 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 tomurine typhus during World War II. To be sure, many individual cases wereobserved in

⁹⁴See footnote 35 (3), p. 183.

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Hawaii⁹⁵and other areas to whichU.S. Army troops were sent,⁹⁶ but these werenot the subject of clinical reports.

TABLE 31.-Serologicalfindings in two cases of probable murine typhus fever occurring in vaccinatedindividuals at Dakar, French West Africa

LABORATORY AIDS IN DIAGNOSIS

The same laboratory procedures that were employed asdiagnostic aids in epidemic typhus fever were also applied to murine typhusfever. The Weil-Felix Proteus OX-19 agglutination test and complementfixation and rickettsial agglutination tests with purified rickettsial antigenshave the same degree of specificity and diagnostic values here as they have forepidemic typhus fever. Table 32 gives the results of each of these tests on serafrom a nonvaccinated individual with murine typhus. The reader is referred tothe laboratory section under epidemic typhus for detailed discussion of theseand other diagnostic procedures which may be of value in murine typhus, such asthe mouse-toxin neutralization test and strain isolation.

It will be recalled that while the complement fixation test with purifiedrickettsial antigens was specific for the homologous form of typhus, this testlost its high degree of specificity in patients with epidemic typhus fever whohad been previously immunized with epidemic typhus vaccine of the

⁹⁵Essential Technical Medical Data, United States Army Forces, Pacific Ocean Areas, for July 1944.
⁹⁶See footnote 4, p. 144.

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Cox type,⁹⁷ and the theoryadvanced by Zarafonetis to explain this finding has been discussed (p. 186). Oninspection of table 31 it will be seen that a similar loss of specificity wasfound in tests on sera from murine typhus patients who had been vaccinatedagainst epidemic typhus fever. Plotz and Wertman⁹⁸independently made the same observations. They had performed tests on sera from147 cases of murine typhus in soldiers stationed in the United States. Of these,135 had the typical serological response for murine typhus comparable to thepattern shown in table 32, but in 12 cases an unusual response was noted, as canbe seen in table 30. These workers investigated these 12 patients with some carein an attempt to determine the factors responsible for the atypical serologicalfindings.

TABLE 32.-Serologicalresults in a nonvaccinated individual infected with murine typhus fever (case 1)-strainisolated

Day of disease	Serological results
	Weil-Felix			Complement fixation		Rickettsial agglutination
	OX-19	OX-2	OX-K	Epidemic	Murine	Epidemic	Murine
5th	0	0	0	0	0	0	0
7th	1:80	0	0	0	0	0	1:160
9th	1:640	1:160	1:40	0	0	1:80	1:1,280
11th	1:640	1:160	1:80	0	0	1:160	1:2,560
13th	1:640	1:160	1:40	0	0	1:320	1:5,120
14th	1:640	1:80	1:40	0	0	1:320	1:5,120
16th	1:640	1:80	0	0	0	1:320	1:5,120
18th	1:320	0	0	0	1:80	1:320	1:5,120
20th	1:160	0	0	0	1:160	1:640	1:10,240
22d	1:160	0	0	0	1:320	1:640	1:10,240
31st	1:160	0	0	0	1:320	1:320	1:5,120
75th	0	0	0	1:40	1:320	1:40	1:1,280
123d	0	0	0	1:40	1:320	0	1:160

Source: Plotz, H., and Wertman, K.: Modification ofSerological Response to Infection With Murine Typhus by Previous ImmunizationWith Epidemic Typhus Vaccine. Proc. Soc. Exper. Biol. & Med. 59: 248-251,June 1945.

It was found that all of these patients hadreceived typhus vaccine some time or other within the preceding 2 years. Thevaccine used consisted of formalinized epidemic rickettsiae with no murinerickettsiae whatsoever. All cases occurred in regions of the United States wheremurine typhus alone is known to exist and in some instances other cases ofmurine typhus were present in the same camp at the time these cases wereadmitted to the hospital. The clinical diagnosis of murine typhus seems to havebeen well substantiated. All cases developed a typical rash. A rise in OX-19titers 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 to23 days with an average of about 14 days. Unfortunately, no attempt was made toisolate the agents.

⁹⁷See footnote 35 (3), p. 183.
⁹⁸See footnote 92, p. 210.

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These investigators note further that, while many of the specimens in these12 vaccinated cases showed higher complement fixation titers to epidemic than tomurine antigen, there was considerable cross-fixation and a number of specimenswere equally responsive to both antigens (table 30). They contrast this with thenonvaccinated patients infected with epidemic typhus, in whom there are hightiters to epidemic antigens with, as a rule, no considerable cross-fixation.Again, in nonvaccinated patients with murine typhus, the complement fixationtiter is higher with homologous than with heterologous antigen, and there islittle crossing (table 32). On the other hand, rickettsial agglutination, in the12 nonvaccinated cases, usually showed a higher titer to the murine antigen, butin many instances there was only a twofold difference in titer, and here againcross-agglutination is marked. The same type of antibody response occurredwhether the typhus vaccine had been given 2 years or 1 week before the attack ofmurine typhus and was not seen in patients vaccinated against typhus whosubsequently became infected with atypical pneumonia, measles, infectioushepatitis, smallpox, meningitis, or other viral, bacterial, or protozoalinfections. As regards symptoms and clinical course, they note, the previousvaccination against epidemic typhus had no apparent effect upon the severity ofthe subsequent attack of murine typhus.

Thus, the rickettsial agglutination test appeared to offerthe most reliable means by which one might make the serological diagnosis ofmurine typhus in a patient who had previously been immunized with the Cox typeof epidemic typhus vaccine.

Part IV. Summary

EPIDEMIC TYPHUS

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 sketchhere the composite picture of epidemic typhus that now emerged.

Clinical picture-The incubationperiod of louseborne typhus fever varies from 7 to 20 days, with the usual onsetabout 10 to 12 days after infection occurs. A prodromal stage of ill-definedmalaise probably exists for a few days, but is of no diagnostic value. In themajority of adult patients, the clinical onset is abrupt with malaise, chills orchilly sensations, followed by severe headache and fever. There is anorexia, andsometimes vomiting. The temperature rises rapidly during the first day or two to104? F., or higher, where it remains throughout the greater part of the acuteillness. The pulse rate usually exceeds 100 beats per minute and remains full atleast throughout the first days of illness. Severe aches and pains appear early,and the thigh and calf muscles are sensitive to pressure. An

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early symptom is a roaring sound in the ears, which may befollowed by temporary deafness. Dyspnea and cough appear by the second or thirdday. The tongue and mouth become dry and fissured, and thirst is a commonsymptom. The patient is tense and anxious from the beginning, but mentaldisturbances do not usually appear until about the end of the first week. Thesemay be stupor or a period of excitement, even of delirium.

There are no diagnostic features prior to the characteristiceruption, 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 anteriorchest 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 fewhours to cover the back, the lower arms and dorsal aspects of the hands, and thelegs to the knees. The face and scalp are spared; only rarely does the eruptioninvolve the palms and soles (fig. 34). The characteristic lesion is macular atfirst, but may become papular after a few hours. At the beginning, the lesionswill fade on pressure, but they usually become fixed within 24 hours. Also, asthe disease progresses, the lesions increase in number and size and may becomeconfluent. Along with the appearance of the rash, the conjunctivae becomeinjected and the eyelids appear puffed. The face may take on a dusky, cyanotichue. Typically, the eruption fades rapidly at the time of defervescence.

By the end of the first week, the patient enters the criticalstage. The fever continues unabated, the delirium and cough are intensified. Theheart rate is rapid and hypotension develops. The patient may be incontinent ofurine 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 ormore after its onset. Some patients undergo a crisis with return of thetemperature to normal in 24 hours, while in others the decline may be gradualover 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 isfairly rapid, but deafness and tinnitus may persist for several weeks.

The clinical picture can vary widely, depending on whatorgans are predominantly involved or on complications. Pathological studies haveshown that the rickettsiae localize first in endothelial cells of the intima andthen enter large mononuclear cells which collect about blood vessels.Proliferation of vascular endothelium and of mononuclear cells around bloodvessels 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 nervoussystem reflect the underlying lesions. The myocardium is also commonly affected,while the lungs may show a rickettsial pneumonitis.

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The leukocyte count is frequently reduced during the first week, withneutropenia and a relative lymphocytosis. Eosinophils are absent or reducedduring the febrile course. Mild normochromic anemia not uncommonly develops, butthere is a return to normal values during convalescence. Albuminuria isuniformly present during the period of fever. Granular casts usually appear inlarge numbers in patients with azotemia. Elevation of the blood urea nitrogen isoften observed during the second week of illness, especially in severely illpatients. The total serum proteins may be normal or slightly reduced, butreversal of the albumin-globulin ratio is commonly noted. This is due to anincrease in serum globulin, the values for which usually range from 4 to 5 mg.percent. Reduction in the serum chlorides is also common. Apparently, thechlorides are not lost through excretion during the disease, since the valuesspontaneously 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 ofabrupt onset with chills, fever, severe headache, louse infestation, or contactwith lice or with typhus patients leaves little doubt as to the nature of theillness. Certain other coexistent diseases may, however, complicate earlydiagnosis. Smallpox, louseborne relapsing fever, typhoid, and meningococcalmeningitis may all be confused with early typhus. Once the characteristic rashhas appeared there is usually little difficulty in making a clinical diagnosis,although meningococcemia, measles, and relapsing fever with exanthem must alsobe considered. Murine typhus is not clinically distinguishable from lousebornetyphus in the individual case. Differentiation between these two forms of typhusfever, as well as establishment of the final diagnosis, is dependent uponcertain laboratory studies. The diagnosis may be made by isolating themicro-organism from the blood of the patient and identifying it throughbiological and other tests. More practical, however, being less expensive andtime consuming, are the serological tests, which include complement fixationwith purified rickettsial antigens, rickettsial agglutination, and Weil-Felix ProteusOX-19 agglutination. These should be performed on two or more serum specimensobtained from the patient during the acute illness and convalescence in order todetect a significant change in antibody titer. Sera from patients withlouseborne typhus fever, in complement fixation tests, yield higher titers withepidemic typhus antigen than with murine antigen. The same relationship obtainsin rickettsial agglutination tests. With respect to the OX-19 test, asignificant change in titer may be observed but is relatively nonspecific, sinceit occurs in murine typhus and Rocky Mountain spotted fever as well as inepidemic 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 givecompletely negative results throughout. Sera from patients who have contractedepidemic typhus fever after vaccination against

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FIGURE34.-Typhus fever patient on U.S.A. Typhus Commission Ward, Fever Hospital,Cairo, Egypt. A. On 18 April 1943, the 10th day of disease, theeruption is clearly evident on the chest and upper arms. B. Same day, extent ofrash on the back.

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FIGURE34.-Continued. C. Same day, although sparse, the eruption was also present onthe palms. D. On 2 May, 24th day of disease, the rash has nowdisappeared and the patient is convalescing. Note loss of weight.

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it exhibit much more cross-reaction in the complementfixation tests than do sera from unvaccinated patients, but the rickettsialagglutination test appears to retain specificity in vaccinated as well as innonvaccinated cases.

Natural course-In the untreated case (that is,the unvaccinated patient given no specific therapy), typhus fever runs itscourse in 14 to 20 days unless terminated by death. The mortality varies indifferent epidemics and is also greatly influenced by age. An overall death rateof 20 to 30 percent was reached in Egypt and at Naples during World War II inpatients 18 to 50 years old. At the Dachau Concentration Camp, however, thetyphus death rate was only 9.1 percent. In past epidemics, the fatality rate hasbeen as high as 70 percent. The disease is relatively mild in children, but ittends to be severe with a high mortality in old people.

Deaths are rare in the first week of illness. In severely ill untreatedpatients, evidence of increasing involvement of the central nervous system oftenappears during the second week of disease. They may become deeply stuporous,comatose, and die. Convulsions presage a fatal outcome. Other patients developsigns of renal insufficiency, and still others present the picture of peripheralvascular collapse during the second week. There is a striking correlationbetween clinical severity and the development of azotemia with elevated bloodurea nitrogen and creatinine levels. These changes appear to be caused primarilyby extrarenal factors, such as greatly increased protein breakdown, dehydration,and hypotension, rather than by a true diffuse renal lesion. Azotemia wasdetected in every fatal case of the Cairo series, although not every patient whoexhibits this change will die. Survivors showed no evidence of renal impairmentwhen tested several months after the acute episode.

The appearance of peripheral circulatory failure is usually indicative ofimpending death. The extremities become cold and cyanotic, the blood pressuredrops to low levels, and the pulse becomes rapid. The basis for this peripheralvascular failure is unknown, but extensive involvement of the capillaries,injury to the vasomotor centers of the brain, and severe myocarditis areprobably important contributing factors. Electrocardiographic findings in typhusfever are nonspecific and consist of low voltage, inverted T waves, depressionof ST segments, and an increase in PR interval.

The most important complications are bacterial pneumonia, multiple skinabscesses, and parotitis. Although gangrenous involvement of the extremities hasbeen associated with a number of typhus epidemics, it was rarely observed inWorld War II outbreaks, except at Belsen.

Immunity and relapse-Immunity is good inuntreated subjects who recover from epidemic typhus fever. Delayed relapses dooccur, however, and constitute Brill's disease. Relapses are common in patientswho receive rickettsiostatic therapy during the first few days of illness, butuncommon if treatment is initiated after the eruption has appeared.

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Therapy.-During World War II, PABA was foundto have antirickettsial properties and was effective in the treatment ofepidemic typhus fever in patients who had as well as in those who had not beenvaccinated. Thoroughly studied, it was brought to the position of a safe andpromising drug for clinical use.

Prophylaxis-Effective protectionof the troops was accomplished by the use of a potent vaccine and its productionin adequate quantities, and by improved methods of louse control.

ENDEMIC (MURINE) TYPHUS

Although the studies on murine typhus during World War II were relativelylimited in comparison with those undertaken in connection with epidemic typhusfever and scrub typhus, there was accumulated nevertheless sufficientinformation upon which to base the following summary description of the disease.

Clinical picture-The incubation period fromactual exposure to the onset of acute illness ranges from 8 to 16 days. Woodwardnoted that headache, backache, and arthralgia are frequently experienced duringthe fourth to sixth day after exposure. For a day or so prior to the onset ofillness, prodromal symptoms such as nausea and general malaise are common. Thedisease then begins with chills or chilly sensations, headache, and fever.Nausea and vomiting frequently occur during this early period. Generalized achesand muscular weakness may be pronounced.

The clinical features of murine typhus resemble those of epidemic typhusexcept that in the average case the disease is less severe than in the majorityof cases of epidemic typhus. In endemic typhus, the patient's temperatureincreases in stepwise fashion for 3 or 4 days until it reaches its maximumlevel, and then usually ranges between 103^? and 104^? F.until defervescence occurs. The total febrile course averages 12 days, but maybe a few days longer or shorter. Defervescence is by lysis over 2 or 3 days. Arash is observed in about 80 percent of cases, typically appearing on the fifthday 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. Occurringin all degrees of intensity, it usually persists for about 5 days, but may beephemeral 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, andlethargy. Transient partial deafness occurs at times. As in epidemic typhus,some involvement of the respiratory tract is common. A dry, hacking coughdevelops, usually in the second week, and crackling rales may be heard in thebase of the lungs. These are believed to be manifestations of interstitialpneumonitis of rickettsial origin.

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The pulse rate is increased and is usually regular. Minorelectrocardiographic changes of nonspecific nature may be detected for a briefperiod. Persistent hypotension is not uncommon, especially during the secondweek of acute illness, and is attributed to a combination of factors includingextensive vasculitis of the capillaries of the skin and other organs andinvolvement of the brain with injury to vasomotor centers. Clinical signs ofmyocardial 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. Moderatealbuminuria is not uncommon. Azotemia may develop in severe cases and isbelieved to be largely due to extrarenal factors.

Diagnosis-An illness characterized by an abruptonset with headache, chills or chilly sensations, fever, malaise, prostration,nonproductive cough, and later the appearance of a rash should suggest typhusfever among the diagnostic possibilities. Epidemiological considerations andcharacteristics of the rash may aid in arriving at a tentative clinicaldiagnosis, but final differentiation rests upon the use of appropriatelaboratory tests. These include complement fixation with purified rickettsialantigens, Weil-Felix Proteus OX-19 agglutination, rickettsialagglutination, and isolation of the strain by animal inoculation. The last isnot practical for routine use, but the serological tests are adequate and morepractical. They should be performed on two or more sera obtained from thepatient during the acute illness and convalescence to show a diagnostic changein antibody titer. In endemic typhus, titers will be considerably higher withendemic than with epidemic antigen in the complement fixation test. The samerelationship obtains in rickettsial agglutination. A significant rise in OX-19agglutination titer may be helpful, but it does not differentiate betweenendemic typhus, epidemic typhus, and Rocky Mountain spotted fever. Sera frompatients who have previously received epidemic typhus vaccine, and latercontracted murine typhus, exhibit much more cross-reaction in complementfixation tests than do sera from nonvaccinated persons. The complement fixationtest, therefore, does not differentiate the two forms of typhus in thesepatients, but the rickettsial agglutination test, according to availableevidence, retains specificity in such cases.

Natural course-The usual course in adults isuncomplicated, with subsidence of fever toward the end of the second week,followed by an uneventful convalescence. The disease is readily tolerated bychildren, but less well by elderly persons. The mortality is 1 to 2 percent.Complications are infrequent and usually consist of secondary infections whichgive rise to parotitis, otitis media, or bacterial pneumonia.

Immunity-After an attack ofmurine typhus, immunity is apparently of long duration. Recrudescence, in amanner analogous to Brill's disease, has not been reported.

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Therapy.-Treatment is the sameas for epidemic typhus fever. Smith⁹⁹andcivilian workers¹⁰⁰ independently demonstratedthe beneficial effect of large doses of PABA in the management of murine typhus.

Prophylaxis-Control measures are directed atreducing the rat populations that serve as the reservoir of the disease and therat ectoparasites that serve as the vectors. Rat control measures includegeneral sanitation, rat poisoning, and ratproofing of buildings. The principalmethod of ectoparasite control is by DDT dusting of ratruns and harborages.¹⁰¹

Prophylactic vaccination, although possible, is not usually practical in viewof the sporadic occurrence of cases.

EPILOGUE

The preventive, clinical, and laboratory events concernedwith the typhus fevers during World War II represent a brilliant chapter in thehistory of medicine. Many contributions were outside the scope of this reviewand are detailed elsewhere.¹⁰² No historicalsummary of typhus would be complete, however, without acknowledgment of the keenstimulation and wise guidance provided by Brig. Gen. Stanhope Bayne-Jones andBrig. Gen. Leon A. Fox, Director and Field Director, respectively, of the UnitedStates of America Typhus Commission. The U.S. Army Medical Department can bejustly proud of the contributions made by its members under the leadership ofthese 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.
¹⁰⁰Levy, M. D., and Arnold, W. T.: Para-Aminobenzoic Acid in the Treatment of Endemic Typhus Fever. Texas State J. Med. 42: 314-316, September 1946.
¹⁰¹See footnote 85, p. 205.
¹⁰²See footnote 4, p. 144.

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