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

HISTORY OF THE OFFICE OF MEDICAL HISTORY

AMEDD BIOGRAPHIES

AMEDD CORPS HISTORY

BOOKS AND DOCUMENTS

HISTORICAL ART WORK & IMAGES

MEDICAL MEMOIRS

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

ORGANIZATIONAL HISTORIES

THE SURGEONS GENERAL

ANNUAL REPORTS OF THE SURGEON GENERAL

AMEDD UNIT PATCHES AND LINEAGE

THE AMEDD HISTORIAN NEWSLETTER

Chapter VI

Contents

CHAPTER VI

Scrub Typhus

Chris J. D. Zarafonetis, M.D., and Myles P. Baker, M.D.

Scrub (or miteborne) typhus is an acute febrile disease caused by infection with Rickettsia tsutsugamushi. Clinically, it resembles other rickettsial diseases with an abrupt onset characterized by chilly sensations or rigors, followed by fever, headache, malaise, and later a rash. The differential diagnosis may be established early by finding the primary sore or eschar at the site of infection, often with associated satellite or generalized lymphadenopathy; at a later stage, some cases may be distinguished serologically. Scrub typhus is also called tsutsugamushi disease, tropical typhus, rural typhus, Japanese river fever, and Kedani fever.1

The earliest description of the malady in the Japanese literature was written by Hakuju Hashimoto in 1810, while the first English report was made by Palm in 1878. Mites were suspected as the probable vectors as early as 1879. The field mouse, Microtus montebelli, was implicated as an important natural reservoir of infection in 1918.

During the 20 years before World War II, careful research work, notably in Malaya and Sumatra, had indicated that tsutsugamushi disease was not limited to Northwestern Japan, Formosa, and the Pescadores Islands, where the Japanese had by 1931 definitely established its rickettsial etiology. The clinical picture, pathology, and epidemiology were shown to be fundamentally the same in Sumatran mite fever, in the scrub typhus of Malaya, the endemic typhus of New Guinea, the coastal fever of North Queensland, Australia, and in cases reported from Burma and Indochina. The common pattern could be traced in spite of wide variations in mortality and frequent failures to find the primary eschar. Prior to the experience of World War II, however, the only species of mite proved by animal experiments to be the vector of tsutsugamushi disease was the trombiculid mite identified by Japanese workers. Other mites had been highly suspected in Sumatra and Malaya, but conclusive proof had not been furnished. Similarly, the principal reservoir host of the trombiculid mite had not been incriminated elsewhere than in Japan and Malaya. Definitive work on the mite-rat complex, in New Guinea and Burma, remained to be done.

This identification of scrub typhus, as it was commonly called in the Armed Forces, with tsutsugamushi disease of the Japanese removes it from the list of strictly tropical diseases, for Japan can scarcely be considered

1Blake, F. G., Maxcy, K. F., Sadusk, J. F., Jr., Kohls, G. M., and Bell, E.J.: Studies on Tsutsugamushi Disease (Scrub Typhus, Mite-Borne Typhus) in New Guinea and Adjacent Islands; Epidemiology, Clinical Observations and Etiology in the Dobodura Area. Am. J. Hyg. 41: 243-373, May 1945.


112

within the tropics. It was, in fact, little known outside Japan as late as 1942. Its distribution is known to us now only as indicated by the accident of human infection with R. tsutsugamushi. With the advent of large-scale jungle warfare, scrub typhus became an important medical problem to troops in the Far East. Indeed, approximately 6,000 cases were to appear in U.S. Forces alone during the campaigns that followed the outbreak of war with Japan.

As military operations progressed in the Southwest Pacific and in Burma, U.S. Armed Forces passed into and through areas hitherto scarcely studied as to prevalent diseases and lived there under field conditions very unlike the customary sheltered life of the white planter of prewar years. One immediate result was a wider appreciation of the geographic area of distribution of this disease. Until then, such places as Bougainville and Goodenough Islands, the Schouten Islands, and Netherlands New Guinea, or Luzon and Mindoro Islands in the Philippines, had not been reported as sites of scrub typhus. Medical officers became acquainted at first hand with the clinical picture and pathology of the disease and had opportunity to compare it with other rickettsial infections, notably epidemic typhus. Opportunity was afforded for thorough study of its epidemiological and entomological aspects in the field and laboratory and for the institution of preventive measures.

CLINICAL EXPERIENCE

Southwest Pacific Area

In this region, Gunther had by 1940 collected 105 cases of a disease which he labeled "endemic typhus," chiefly from the Wau area in the mountains south of the Markham Valley in northeast New Guinea.2 The clinical picture was described by him at length, the similarity to tsutsugamushi disease emphasized. Diagnostic agglutinations with Proteus OX-K were reported. The patients were white men who had been clearing jungle areas. Scattered cases were reported from New Britain Island and the coastline of northeast New Guinea west of Finschhafen. The disease was, then, well known when American and Australian Armed Forces moved into New Guinea in the spring of 1942.

THE FIRST PHASE: ORIENTATION (1942)

The first cases.-Typhus fever was first recognized among our troops in the Southwest Pacific as an isolated case, reported from northern Queensland in March 1942. Eight cases were reported from the Port Moresby area of Papua late in September 1942, and subsequently, a few cases appeared in the Milne Bay area at the eastern extremity of Papua.3 During the summer

2Gunther, C. E. M.: A Survey of Endemic Typhus in New Guinea. Med. J. Australia 2: 564-573, 30 Nov. 1940.
3Essential Technical Medical Data, Southwest Pacific Area, for February 1944.


113

and early autumn of 1942, combat operations in Papua were primarily the assignment of Australian forces. At the close of the year, Lt. Col. S. W. Williams, of the 2/9th Australian General Hospital at Port Moresby, was able to report a preliminary study of 300 cases of scrub typhus.4 Within 10 miles of Port Moresby, the disease was rare, considering the large number of troops concentrated there; all but a handful of these cases developed under combat conditions along the Moresby-Buna track, the so-called Kokoda Trail. This early Australian experience tallied closely with the prewar description of the clinical picture given by Gunther. Emphasis was laid on the following points:

Among the first hundred patients there was only one death; among the second hundred, exposed to the hardships of living conditions while following the Japanese retreat over the Owen Stanley Range, there were three deaths. In cases observed during December 1942, chiefly from the Buna-Gona combat area, the mortality was "nearly 10 percent." These soldiers, too, were spent by weeks of campaigning in the mountains and fighting around Buna.

Early diagnosis was not found a simple matter. Eschars were noted in only 60 percent of the cases. As experience was to show, they should be sought in covered parts of the body. Similarly, the rash was observed in about 60 percent only. Generalized lymph node enlargement was the most useful diagnostic sign in distinguishing the disease, in the early stages, from malaria. Even so, the diagnosis, in absence of eschar and rash, might well remain in doubt until the appearance of blood agglutinins for Proteus OX-K on about the 9th or 10th day of fever. It was noted that patients with scrub typhus fever may appear deceptively well during the first week, only to develop serious pulmonary, circulatory, and neurological symptoms in the second week of fever.

American troops were soon presenting examples of those diagnostic problems that proved to be scrub typhus. The majority of men who were to engage in combat in the Buna-Gona area were flown over "The Hump" of the Owen Stanleys, were set down at Dobodura airstrips, and went into battle late in November 1942. Patients with scrub typhus began to appear in December in Port Moresby hospitals, evacuated thereto by air. In January 1943, there was a sharp rise in the number of reported cases of scrub typhus in the Southwest Pacific Area (table 12). The case fatality rate for 1943 was 5.5 percent per 100 cases. In 1944, over 4,000 cases of scrub typhus were reported with a case fatality rate of 3.8 percent. During the first 8 months of 1945, the number of cases was less than those reported for the same period in 1943, with a case fatality rate of 5.4 percent. Owing to the exigencies of the military situation, soldiers convalescing from scrub typhus were evacuated to general hospitals on the Australian mainland, with the result that any compilation of case material was rendered impracticable. Medical officers in hos-

4Williams, S. W.: Scrub Typhus in Papua. Preliminary Report. A Description Founded on Observation of 300 Cases by the Medical Staff of an Australian General Hospital, 5 Jan. 1943. [Official record.]


114

TABLE 12.-Number of cases and deaths due to scrub typhus in the Southwest Pacific Area, U.S. Army, January 1943 to August 1945

[Preliminary data based on unit summary reports]


Period

Cases

Deaths

1943

 

 

January

92

4

February

62

1

March

45

5

April

55

2

May

64

0

June

79

5

July

83

6

August

81

3

September

95

5

October

93

4

November

67

3

December

119

13


Total

935

51

1944

 

 

January

75

9

February

104

16

March

184

8

April

75

12

May

130

4

June

212

15

July

647

9

August

1,759

32

September

757

38

October

251

10

November

113

6

December

89

6


Total

4,396

165

1945

 

 

January

100

5

February

66

2

March

45

4

April

32

2

May

15

2

June

43

2

July

20

1

August

11

0


Total

332

18


Grand total

5,663

234


115

pitals of the Advance Base, becoming familiar with clinical features of the textbook picture of the disease, cultivated a high index of suspicion of scrub typhus in the case classified as fever of undetermined origin with no evidence of malaria, no leukocytosis, no clinical response to Atabrine (quinacrine hydrochloride) or quinine, and with generalized lymph node enlargement. Eschars were more carefully sought for, and ulcers, without a scab, were found in the groins and axilla (fig. 8). By the time that agglutinins for Proteus OX-K appeared in the blood, the temperature curve had become diagnostically characteristic in cases without other diagnostic signs. One temperature chart (often making up the bulk of the record evacuated with the convalescent) could be superimposed on another, so alike were they.

FIGURE 8.-"Ulcer" eschar on right axilla in tsutsugamushi fever of 15th day of illness, 363d Station Hospital, Dobodura area, Papua.

In one series of cases,5 the temperature was usually 99 to 102 F. on the first day of illness. There was a rise in temperature within 24 hours to 100 to 103 F., and during the days that followed the 4-hourly chart showed a swinging temperature with daily remissions from 99 to 104 F. throughout the illness, subsiding by lysis on the 14th to 17th days. In the more severe cases, for the first 3 to 5 days a remittent type of fever was seen, followed by a sustained fever up to 105 F. until recovery or death. In some fatal cases a remittent fever ranging from 99 to 106 F. was recorded. A temperature which did not rise above 103 F. was seen in a few fatal cases.

The first necropsies-Inexperience with the disease and lack of any specific treatment lent particular interest to the pathologist's findings in the first

5Williams, S. W., Sinclair, A. J. M., and Jackson, A. V.: Mite-Borne (Scrub) Typhus in Papua and the Mandated Territory of New Guinea; Report of 626 Cases. Med. J. Australia 2: 525-539, 18 Nov. 1944.


116

seven necropsies performed in December 1942 and January 1943 at Port Moresby by Capt. (later Maj.) Austin J. Corbett, MC.6 He reported three groups of findings, as follows:

1. An acute diffuse myocarditis, with perivascular and interstitial infiltration with plasma cells, macrophages, and lymphocytes, as a constant and characteristic finding. Damage to the myocardial fibers varied in degree. Arteriolar walls showed thickening, degeneration, and intramural round-cell infiltration.

2. In the lungs, alveolar septa were infiltrated with mononuclear cells in a perivascular arrangement, and the vascular endothelium within the septa was swollen and fragmented.

3. In the brain, perivascular proliferation of glial cells and infiltration with lymphocytes were observed; the endothelium of smaller blood vessels was swollen, and several vessels showed intramural round-cell infiltration.

Cardiac findings and prognosis-The finding of a diffuse myocardial lesion at autopsy, and the occasional finding of gallop rhythm and "soft" heart sounds on physical examination of the precariously balanced patient in the second and third weeks of fever, gave rise to much concern about the convalescent's prognosis. In the rear hospitals, in Australia, convalescents were examined carefully for evidence of residual cardiac damage and insufficiency and were found to have none. Pending the accumulation of enough data to support a general policy of sending all but the most hard-hit cases back to duty, the majority of convalescents were returned to duty following maximum hospitalization benefit.

THE SECOND PHASE: INVESTIGATIONS (1943)

A second phase in U.S. Army experience with scrub typhus began in the summer of 1943. The occurrence of cases from month to month, without seasonal incidence, was unremitting among combat and service troops, which were increasing in number as the bases were developed along the north coast of New Guinea to Finschhafen. The New Guinea hospitals had become more stabilized, facilitating the study of cases. This period saw clinical and epidemiological studies carried out by a group of investigators, headed by Dr. Francis G. Blake, working under the auspices of the United States of America Typhus Commission, and it saw also the development of preventive measures to protect troops from scrub typhus.

Clinical study-It will be noted in table 12 that cases were diagnosed without letup during the spring and summer of 1943. Base B, which included Dobodura and Oro Bay, Papua, became a hive of activity with ever-increasing numbers of troops moving into camp areas in the base. Between 1 August and 1 December 1943, 248 patients with scrub typhus were admitted to Base B hospitals. The mortality in these cases was 2.4 percent. From a study of a group of 20 cases, most of them at the 363d Station Hospital, Dr. Blake and

6Corbett, A. J.: Scrub Typhus. Bull. U.S. Army M. Dept. No. 70, pp. 34-54, November 1943.


117

his collaborators constructed an exemplary word picture of the disease, as follows:7

The characteristic early symptoms and physical signs of mite typhus at onset and during the first 5 to 7 days of the disease are headache, apathy and generalized malaise, fever, relative bradycardia, anorexia, conjunctival congestion, lymphadenitis, often regional, and eschar. Although the diagnosis may be suspected from the general symptoms and physical signs together with a normal or low leukocyte count, only the presence of a typical eschar is sufficiently pathognomonic to establish the diagnosis at this stage of the disease. Consequently, the whole body surface should be scrutinized in detail with adequate light for, unless this is done, the eschar may be easily overlooked if it is located in the less readily accessible areas.

Commonly, between the fifth and eighth days a characteristic macular or maculopapular rash appears on the trunk and may later spread to the extremities. It should be borne in mind, however, that although the development of a rash tends to confirm the suspected diagnosis, rashes sufficiently similar to that of mite typhus to cause confusion may at times occur in dengue and other infections.

The subsequent course of tsutsugamushi disease after the first week may be relatively mild, with no recognizable evidence of the more serious aspects of the disease, and with a total febrile period of 12 to 14 days; or moderately severe with signs of pneumonitis and encephalitis and recovery by lysis early in the third week; or severe to extremely severe with febrile course of approximately 3 weeks' duration. Symptoms and signs of more severe pneumonitis and encephalitis are constant. Evidence of peripheral circulatory collapse are common and signs of myocarditis may appear. Hepatitis and nephritis sometimes complicate the picture. Thromboses and cerebral or gastrointestinal hemorrhage may take place. Death is not infrequent in these severe cases, particularly in older individuals, but the majority recover by lysis during the latter half of the third week.

Laboratory studies have confirmed the already known fact that the Weil-Felix test becomes positive for Proteus OX-K about the 12th to 14th day of the disease in the majority of cases but that not all patients develop agglutinins for this organism in a diagnostic titer of 1 in 160 or higher. Rickettsia orientalis (tsutsugamushi) may readily be recovered from the blood of patients during the acute stage of the disease by the intraperitoneal inoculation of 0.2 to 0.3 ml. of blood into white mice. Both of these laboratory procedures, if positive, establish the diagnosis, but a negative Weil-Felix test for Proteus OX-K does not exclude miteborne typhus.

The total leukocyte count, usually within the normal range during the first week but sometimes showing a leukopenia, tends to increase during the second week. In cases progressing favorably, this leukocytosis is commonly due in large part to a progressive increase in the absolute number of lymphocytes.

Limited observations on the blood chemistry of the miteborne typhus of New Guinea have shown that hypochloremia, a moderate but not critical reduction in serum albumin, a rise in serum globulin, and a diminution in plasma fibrinogen tend to occur during the height of the disease.

The treatment of mite typhus consists primarily of complete bed rest, good nursing care, adequate diet, fluid and salt intake, and the judicious and selective use of symptomatic drug, supportive, and oxygen therapy only when specifically indicated. Penicillin is ineffective.

Blake and his coworkers particularly emphasized the localization above thigh level of the eschar, or primary ulceration, present in all 20 of their cases. This is in contradistinction to the bites of mites causing scrub itch, on the

7See footnote 1, p. 111.


118

ankles and shins. This observation tallied with that of the Australians at Port-Moresby (65 percent on arms, axilla, neck, and trunk). They emphasized further (1) the absence of signs of right-sided heart failure, (2) the picture of a true rickettsial pneumonitis, with which physical signs and findings at autopsy are in keeping, and (3) the relation of cyanosis and pulmonary congestion to pneumonitis, rather than to myocardial insufficiency.

During the spring and summer of 1943, Australian patients were held at the general hospitals in Port Moresby, as American patients were not, making possible certain observations on 626 cases8 that added to the clinical picture.

Significantly, as regards course, a few cases were recognized in ambulatory patients not sick enough to go off duty, but later showing agglutinins to Proteus OX-K of 1:125 or higher (taken as a minimum diagnostic titer in this series). No relapse of fever attributable to the rickettsial infection was observed. Among symptoms, macules were noted on the soft palate, in association with the typical rash over the body.

In the severe cases, cardiovascular abnormalities such as faint systolic murmurs, tic-tac sounds, gallop rhythm, tachycardia, hypotension, and pulsus alternans were occasionally observed. Measurements of venous pressure and electrocardiographic study did not speak for myocardial insufficiency or clinically demonstrable myocarditis. Hearts examined microscopically in patients dying in the sixth week of complications not referable to circulatory apparatus showed no infiltration or fibrosis.

Cyanosis and increased respiratory rate accompanied the development of abnormal physical signs in the lungs, which did not include those of consolidation unless there was secondary infection, atelectasis, or infarction. Pulmonary infarction was a late complication to be reckoned with.

In the severely ill, mental symptoms uniformly appeared from about the 6th to the 10th day; apathy was more common than restless irritability and insomnia. Nerve deafness was present in 90 cases, and could be expected to be transient, lasting only a week. Paresis of the shoulder girdle muscles and sensory changes in arms and legs were observed during convalescence. Tremors of the hands appearing in the difficult second week were rare but striking, in one instance simulating the tremor of parkinsonism. Examinations of cerebrospinal fluid (60) revealed an increase in pressure (about 160 mm.) in less than half the individuals tapped; increase in lymphocyte count was infrequent (7 cases).

Mortality continued to vary much during the period of investigation; it rose from 1 to 2 percent in the first 200 cases to 25 percent in the next 150 cases, comprising soldiers exhausted by weeks of jungle combat, and handicapped by slow evacuation. For the next 276 cases, mortality was 7.2 percent. This varying mortality gives a fairer picture than the overall figure for 626 cases, 9.7 percent.

If, prior to evacuation, the soldier was seriously ill by the sixth day, or had already had 6 days of fever, it was thought wiser, if possible, to treat him "where he lies," rather than subject him to evacuation. Most patients were treated in convalescence in the expectancy that they would be fit to return to duty within 12 weeks from onset of their illness.

Lipman, Casey, Byron, and Evans reported a study of 200 patients observed at the 362d Station Hospital in Base B between February 1943 and February 1944.9 The clinical picture in their cases conformed with Blake's. Their extensive experience permitted observation of complications that should

8See footnote 5, p. 115.
9Lipman, B. L., Casey, A. V., Byron, R. A., and Evans, E. C.: Scrub Typhus; Results of a Study of the Cases of Two Hundred Patients Admitted To and Treated At a Station Hospital Between Feb. 9, 1943, and Feb. 4, 1944. War Med. 6: 304-315, November 1944.


119

be borne in mind; that is, pleural effusion, 5 percent; peripheral neuritis, ulnar, 5 percent; thrombophlebitis, 5 percent; and pulmonary and splenic infarction, each 2.5 percent. The mortality in their 200 cases was 10 percent. They emphasize the point made by the Australians at Port Moresby, that combat troops who will or must disregard early symptoms of scrub typhus are those with whom it goes hard. The older age group tolerated the onslaught of scrub typhus less well than did those younger. Six of the thirteen officers in this series died; four of the six were over 35 years of age. In therapy, these authors recommend the following: (1) A lumbar puncture for relief of meningismus and cerebral symptoms associated with an elevated spinal fluid pressure, (2) treatment of incipient and established peripheral vascular failure with oxygen and intravenous plasma, and (3) penicillin for secondary bronchopneumonia complicating the rickettsial pneumonitis.

Irons and Armbrust, at the 3d Medical Laboratory in Base B, extended their observations on the Weil-Felix reaction to a series of 74 cases of scrub typhus.10

Of this series, 86 percent developed blood agglutinins for Proteus OX-K. Controls with other febrile diseases gave negative reactions. In general, however, the incidence, maximum titer, and duration of the reaction were inversely proportional to the severity of the disease. Only 2 of the 7 fatal cases showed a positive Weil-Felix reaction during their clinical course; the maximum titer was 1:80. Patients with less than 18 days of fever were more likely to develop a titer of 1:160 or over than were those with longer febrile periods. The initial Weil-Felix reaction occurred at approximately the 17th day of the disease, after the peak in severity of clinical manifestations, or during obvious clinical improvement.

Accordingly, the authors concluded that the Weil-Felix reaction is of no value in prognosis. For diagnosis, no absolute level could be given, but a rise and fall in serial tests proved helpful in some cases. That a negative reaction does not exclude scrub typhus was indicated by isolation of the causative micro-organism in some cases with no OX-K titer.

Epidemiological study-In addition to delineating the clinical features of scrub typhus, Blake and his coworkers clarified the epidemiological background of the disease, as follows:

An analysis of the occurrence of cases among American forces in an advanced base area near Buna on the northeast coast of New Guinea indicated that, although the disease was contracted in widely scattered localities, some were more dangerous than others. It also indicated that the exposure to infection was associated with activities which brought men into intimate contact with field conditions, such is those which prevail in bivouacs or in establishing camps. During the period of this study in the Dobodura area, the environments in which human infections were known to have originated were kunai grass fields, in which natural conditions were undisturbed at the time of occupation. From the time distribution of onset of cases of the disease it was clear that maximum risk was experienced during the first week or two following arrival of a unit in a new area. This

10Irons, E. N., and Armbrust, C. A.. Jr.: Relation of the Weil-Felix Reaction to the Clinical Course of Tsutsugamushi Disease. Bull. U.S. Army M. Dept. 5: 85-95, January 1946.


120

risk decreased progressively so that after the fourth or fifth week the incidence became sporadic or ceased entirely, and the site could be occupied with impunity thereafter. 

Decline in the attack rate could not be explained as due to the accumulation of immune individuals. It therefore was probably due to decreased exposure to bites of some species of larval mites that served as vectors. Decrease in exposure was correlated with progressive changes produced by development and use of the campsite. Evidently, the conditions thus created were unfavorable to continued activity and survival of the vector species.

In attempting to identify this vector species, collections of larval mites were made not only in localities where cases had originated and extensive environmental changes taken place, but also in localities where the environment appeared to be similar but where the natural conditions remained undisturbed.

*   *   *   *   *   *   *

* * * the observations made are consistent with the hypothesis that either Trombicula fletcheri or Trombicula walchi, or both, may serve as vectors in this area. Furthermore, by mouse inoculation, R. orientalis was recovered from two pools of mites (T. fletcheri) collected from two bandicoots. Brain tissue from these same animals, injected into white mice failed to produce a rickettsial infection. In view of this negative result and the fact that generation-to-generation transfer of R. orientalis occurs in mites, the evidence does not incriminate the bandicoot as a reservoir host.

This concept of bivouacs and the establishment of campsites as the background of scrub typhus was entirely in keeping with U.S. Army experience during 1943, elsewhere than at Dobodura. On 5 September 1943, the 503d Parachute Infantry Regiment jumped in the Markham Valley terrain which included much open grassy country with kunai grass prevailing. The regiment remained in jungle combat for about 12 days. By October, 37 cases of scrub typhus had appeared.11 For the next 5 to 6 months, cases continued to occur as areas were developed around the Nadzab airstrips northwest of Lae in northeast New Guinea.

Outbreaks-In November 1943, an epidemic of scrub typhus broke out on Goodenough Island, north of Papua, chiefly in a hospital area situated in kunai grass. For the first few nights after arrival in the area, personnel lived under conditions prevailing in the field. This was a serious outbreak. Seventy-five cases occurred on the island over the subsequent 4 months, most of them in December. The mortality, 25 percent, was uniquely high and cannot be adequately explained with the knowledge at hand. The patients were not in combat and were not exhausted when stricken. With each successive beachhead taken, cases of scrub typhus developed. The landing at Cape Gloucester in the Bismarck Archipelago was made in December 1943. At the 30th Evacuation Hospital, 104 cases were reported in February with 5 deaths; in March, there were 51 cases with 8 deaths. The mortality was 8.3 percent for these New Britain cases, more in keeping with the Dobodura series.12 It is well to note, however, that in the first 3 months of 1944 the 363d Station Hospital at Dobodura had 60 cases of scrub typhus, of which 9 ended fatally, a mortality of 15 percent, in contrast to an average of 7.1 percent for the

11See footnote 3, p. 112.
12Quarterly Report, Surgeon, 30th Evacuation Hospital (Semimobile), Southwest Pacific Area, 1 Jan.-31 Mar. 1944.


121

Dobodura region.13 Eight of the deaths occurred in the first 35 cases admitted after transfer from the combat areas several hundred miles to the west. The patient sick with scrub typhus did not tolerate evacuation well.

Following the landing at Saidor in northeast New Guinea in January 1944, 61 cases developed in March, 59 of them among troops on patrols or bivouacked in a combat area. At Aitape, on the northwest coast, the same story held true: Landings on 22 April and 33 cases of scrub typhus in May, 52 in June, and continued incidence in July and August. Headquarters, 32d Infantry Division, proffered the comments that the cases developed in fairly well identified areas, or in troops on patrol, that withdrawal from the perimeter to cleared areas caused a dwindling of cases, and that uncleared kunai grass and low sites where kunai grass and underbrush are mingled are dangerous. At Hollandia in Netherlands New Guinea, there were scattered cases; 43 of the 140 reported for the Sixth U.S. Army in June originated there. It is worthy of note that the new staging area for the 32d Division at Hollandia was burned over before troops were allowed to move into it in September. During the ensuing month, there were no cases reported from this area. An engineer aviation battalion that moved into Hollandia late in April reported 24 cases with 7 deaths in May and June, "due to sleeping in kunai grass, since no tents or cots were available the first month." The small Wakde Task Force that captured this island with its important airstrip in May reported a few cases in the third and fourth weeks of June.14

It is to be noted that task force units were becoming familiar with the type of terrain to be avoided and the dangers of sleeping on or near the ground in uncleared areas likely to harbor infected mites. Meanwhile, active measures for personnel protection of the soldier were in preparation.

THE THIRD PHASE: PEAK OF INCIDENCE AND CONTROL MEASURES (1944)

The subsequent epidemics at Owi and Biak (in the Schouten Islands) and at Sansapor (in Netherlands New Guinea) mark a third period in Army experience with scrub typhus, in which (1) the disease first assumed proportions serious from a military point of view, (2) new ecological types of foci appeared, and (3) procedures, long-planned, were directed at energetic control of the epidemics.

Outbreaks-Cases first developed on Owi, a small island off the southern shore of Biak, about 10 to 14 days after arrival of units of the Army Air Forces early in June. During July and early August, as much as one-fourth to one-third of the effective personnel of two air force squadrons on Owi were hospitalized for scrub typhus. On nearby Biak, there were 107

13Kohls, G.M., Armbrust, C. A., Irons, E. N., and Philip, C. B.: Studies of Tsutsugamushi Disease ( Scrub Typhus, Mite-Borne Typhus) in New Guinea and Adjacent Islands; Further Observations on Epidemiology and Etiology. Am. J. Hyg. 41: 374-396, May 1945.
14(1) Quarterly Report, Surgeon, Sixth U.S. Army, Southwest Pacific Area, 1 Apr.-30 June 1944. (2) Quarterly Report, 32d Infantry Division, plus attached units, Southwest Pacific Area, 1 July-30 Sept. 1944. (3) Quarterly Report, 1913th Engineer Aviation Battalion, Southwest Pacific Area, 1 Jan.-31 Mar. 1944.


122

cases in the 186th Infantry within 41 days of D-day, 32 of them from one company engaged in patrol in the island hills.15 Certain units were unable to function effectively until replacements were secured. Owi and Biak are coralline, with bare ridges and porous outcrops, very little swampy land, no kunai flats, and few open grassy areas. Even where there is little topsoil, as on Owi, dense underbrush, ferns, and many immense rotting logs provide cover and moisture for mites. With New Guinea experience as precedent, scrub typhus was not expected in this type of terrain. The first cases were relatively mild, eschars were infrequent, and these fevers of undetermined origin were not directly recognized as scrub typhus. They were thought on Owi to be dengue fever until typical cases of scrub typhus appeared, and Culex mosquitoes were found to be scarce. The risk on Owi lay in the slowness in clearing of campsites. A contributing factor was the necessity for using all available bulldozers for the construction of airstrips. Men leaving clothes on rotting logs, when swimming in the ocean, may also have contributed. On Biak, severe fighting in uncleared areas, seeking cover in thick underbrush, and patrolling, all contributed to exposure to the infected mites.

Members of the U.S.A. Typhus Commission arrived at Owi soon after scrub typhus was recognized, and encouraged the speedy clearing of campsites and sanding of tent floors, together with impregnation of clothing. Emulsions of dimethyl phthalate were made available and all personnel were equipped with treated clothing within 2 weeks of arrival of the repellent.16 The fall in incidence in the various units expressed the sum of the effect of control measures. On Biak, similarly, the 41st Infantry Division was in impregnated clothing by the second week in August and camp areas were cleared. The scrub typhus rate fell appreciably in the latter part of August.17 The absorbingly interesting story of the development and institution of preventive measures against scrub typhus are recounted in another volume in the history of the Medical Department in World War II.18

The Owi-Biak outbreak included at least 1,080 cases, which passed through the 92d Evacuation Hospital. The mortality, 0.7 percent, was low, and many cases were milder than had been the experience in Papua.19 No ill effects were noted from the air evacuation to Nadzab or Finschhafen of convalescents 5 days or more after defervescence.

The Sansapor task force landed at the western extremity of New Guinea

15Essential Technical Medical Data, U.S. Army, Services of Supply, Southwest Pacific Area, for September 1944.
16Letter, Lt. Col. Cornelius B. Philip, SnC, to Surgeon, U.S. Army Forces in the Far East, 5 Aug. 1944, subject: Scrub Typhus on Owi and Biak Islands.
17Monthly Sanitary Report, 41st Infantry Division, Office of Surgeon, Southwest Pacific Area, October 1944.
18Philip, Cornelius B.: Scrub Typhus and Scrub Itch. In Medical Department, United States Army. Preventive Medicine in World War II. Volume VII. Communicable Diseases : Arthropodborne Diseases Other Than Malaria. [In preparation.]
19Quarterly Report, Surgeon, 92d Evacuation Hospital (Semimobile), Southwest Pacific Area, 1 July-30 Sept. 1944.


123

on 30 July 1944.20 On 6 August, the first case of scrub typhus developed, an unusually short incubation period. The outbreak was explosive (135 cases by D+13) and a cause of serious depletion in strength. In one battalion, 17 percent (125 cases) were stricken. Impregnated clothing appeared to be definitely protective, when used. In all, about 931 cases (data are incomplete) were reported in the course of 53 days at Sansapor, with a mortality of 3.4 percent. Attempt was made to avoid a long 1,200-mile air evacuation until patients were afebrile. This led to much congestion at the one functioning evacuation hospital but was doubtless the better part of wisdom in view of the earlier experience in the Cape Gloucester and Aitape operations. At Sansapor, it was noted that areas of infection were found particularly in abandoned plantations or native gardens filled with a rank growth of grass. These areas, as at Owi-Biak, represented a different type of focus from those seen theretofore, and apparently in this instance a highly infected type, to judge from the high incidence of eschars and the recovery of R. tsutsugamushi from white mice injected with material from each of three lots of rat mites.

Convalescence and disposition-The base hospitals to which the New Guinea cases were evacuated continued, over the course of the 20 months from January 1943 to August 1944, to determine the disposition of convalescent cases. Many ambulatory convalescents complained on admission of rapid heart rate and shortwindedness on slight exertion. Some litter cases were slow to mobilize themselves. At the 105th General Hospital in Australia, Levine carried out observations on 130 convalescents and found no evidence, by physical examination, electrocardiogram, roentgen examination, or by measurements of vital capacity or venous pressure, of persistent myocardial damage.21

Exercise tolerance tests gave mediocre results, which could be contributed to, commonly, by a prevalent anxiety state. Patients whose heart rates were rapid prior to a road march returned from a 5-mile march with normal heart rates. Such a functional test appeared more reliable than a "Schneider index" determination. Of this series of 130 patients, 117 were returned to full duty.

A critical evaluation by Howell of the 233d Station Hospital, at Nadzab, of electrocardiograms in 190 convalescents from scrub typhus (92 percent within 1 to 4 weeks after subsidence of fever) and 10 acute cases revealed no significantly abnormal electrocardiographic patterns.22 There were minor deviations from normal, to be sure, and these were all too often exaggerated in importance by the unwary observer. But they were no more frequent than

20(1) See footnote 13, p. 121. (2) Quarterly Report, Surgeon, Headquarters, Sixth U.S. Army, Southwest Pacific Area, 1 July-30 Sept. 1944.
21Levine, H. D.: Cardiac Complications of Tsutsugamushi Fever (Scrub Typhus); An Investigation of Their Persistency. War Med. 7: 76-81, February 1945.
22Howell, W. L.: Absence of Electrocardiographic Changes in Tsutsugamushi Fever (Scrub Typhus). Report of 200 Consecutive Cases. Arch. Int. Med. 76: 217-218, October 1945.


124

have been found in a series of tracings from approximately 500 healthy young adults.

In the summer of 1944, at the instigation of Col. Bruce P. Webster, MC, then Surgeon, Base E, a reconditioning program for scrub typhus convalescents was set up at the 90th Station Hospital. Three hundred and twelve unselected and successive patients were classified on admission with regard to their capacity for exercise.23 Only 8 percent were considered to be, properly, bed cases. These patients had been evacuated chiefly from Owi-Biak, Sansapor, and Aitape. They had averaged 4 weeks prior hospitalization. In rare cases, there was residual hypesthesia and deafness. Tachycardia, tremors of the hands, and giddiness were frequent. At the completion of a purposeful, graded reconditioning program, 303, or 97 percent, were returned to full duty, after an average of 1 month in this hospital. These patients were symptom free on discharge, the majority with weight regained. Nine patients were evacuated to the rear because of associated disabilities, not referable directly to scrub typhus.

This policy of returning the scrub typhus convalescent to duty was thus supported as experience with the disease increased in 1944. Few such soldiers were subsequently evacuated for inability "to stand the gaff" of field duty. Technical Memorandum No. 10, Headquarters, United States Army Forces in the Far East, dated 29 August 1944, declared it official policy (1) that in patients who have safely reached convalescence from scrub typhus, complete recovery is to be expected, (2) that permanent physical defects resulting from the disease are exceptional, (3) that physical reconditioning, with unequivocal reassurance that there is no residual heart damage, will expedite recovery of stamina, and (4) that patients who require a month or more of full physical reconditioning should be transferred for that purpose to the newly established training center at Oro Bay.

The concept of the part that the myocardial lesion plays in scrub typhus had thus changed materially from that which prevailed early in 1943 when the first cases were observed, precariously ill, and at post mortem. Berry, Johnson, and Warshauer,24 reporting experience with 85 cases and 110 convalescents in two New Guinea station hospitals between 20 December 1943 and 20 June 1944, drew the following conclusions:

1. Clinically, there is no severe irreversible myocardial damage.

2. Peripheral vascular collapse in the severely ill patient poses the therapeutic problem, not myocardial failure; the clinical picture is analogous to that of shock and should be treated accordingly.

3. Circulatory symptoms in convalescence are no more pronounced than after any severe infection.

23Romeo, B. J.: Convalescence From Scrub Typhus. Bull. U.S. Army M. Dept. 6: 167-173, August 1946.
24Berry, M. G., Johnson, A. S., Jr., and Warshauer, S. E.: Tsutsugamushi Fever; Clinical Observation in One Hundred and Ninety-five Cases. War Med. 7: 71-75, February 1945.


125

4. The patient should not be given the impression that he has any heart disease.

The soundness of this policy was borne out by the report25 from one general hospital in the Zone of Interior that examination of such patients as were returned from overseas with the diagnosis of myocarditis following scrub typhus fever definitely indicated their disability to be that of neurocirculatory asthenia.

Settle, Pinkerton, and Corbett26 reviewed the pathological changes from 55 fatal cases of scrub typhus occurring in American troops in Papua, Netherlands New Guinea, and adjacent islands. They reassert that generalized acute vasculitis was a constant finding. But they note that although myocarditis was present in all cases, it was severe in only about half the patients, more commonly in those dying relatively early, between the 9th and 12th days of illness. They suggest that in these severe cases myocardial failure may contribute to fatality; yet they elect to emphasize the generalized vascular lesions and the concept that patients with rickettsial vasculitis may die of peripheral circulatory collapse. They draw attention to a similar conclusion of Woodward and Bland27 from their cases of epidemic louseborne typhus in the Mediterranean Theater of Operations, U.S. Army.

IN THE PHILIPPINES (1945)

In the Philippine Islands, scrub typhus appeared sporadically during U.S. Army operations28 but never to the degree of military importance it had assumed at Owi and Biak, and might have done at Sansapor had enemy resistance been more taxing. Scrub typhus had not been identified in the Philippines prior to World War II. Toward the close of the Leyte campaign, late in 1944, 3 cases were reported from the northern end of the island. Fifty-one cases were reported from Samar, where units of the Army did extensive patrol duty after the invasion of nearby Leyte. On Mindoro, experience with scrub typhus followed the typical course: Invasion in December 1944, the first case admitted to hospital 12 days after the initial landing, and the bulk of the 100 cases reported in January and early February. Sporadic cases continued for the next 3 months.

On Luzon, rare cases were identified from the mountainous country east of Manila during the fighting in February 1945. Diagnosis was based on the finding of classical eschars and a positive Weil-Felix reaction with the OX-K strain of Proteus. A cluster of three cases appeared early in May in one in-

25Benjamin, J. E., Porter, R. R., and Dreisbach, R. H.: Sudden Death in Patient Supposed To Have Myocarditis Following ScrubTyphus. Bull U. S. Army M. Dept. 4: 235-238, August 1945.
26Settle, E. B., Pinkerton, H., and Corbett, A. J.: A Pathologic Study of Tsutsugamushi Disease (Scrub Typhus) With Notes on Clinicopathologic Correlation. J. Lab. & Clin. Med. 30: 639-661, August 1945.
27Woodward, T. E., and Bland, E. F.: Clinical Observations in Typhus Fever, With Special Reference to the Cardiovascular System. J.A.M.A. 126: 287-293, 30 Sept. 1944.
28Essential Technical Medical Data, U.S. Army Forces, Pacific (for Western Pacific Area), May and June 1945.


126

fantry regiment engaged in battle in the mountains west of Baguio. A rising titer of OX-K agglutination was present in all three cases. All had a typical rash and clinical course, and one had an eschar. Beginning on 9 May 1945, cases of scrub typhus were recognized in a regiment engaged in a beachhead landing in the Bicol Peninsula in the southern end of Luzon. Six cases developed in the course of a week and four more in the following fortnight. Eschars were present in only 2 of the 10 cases, but clinical course, rash, and rising OX-K titers were diagnostic. During the combat of Negros in late April and May 1945, six cases appeared in two infantry units, all with eschars.

These reported data on approximately 180 cases are inevitably incomplete, for they do not include patients evacuated from Luzon for other medical reasons who developed scrub typhus en route to or after arrival at New Guinea base hospitals. Statistical reports on Southwest Pacific Area scrub typhus for 1945 include 258 cases up to 1 June (table 12) with a mortality of 5.8 percent. There was nothing unusual in the clinical picture of the cases in the Philippine Islands. Plasma and blood transfusions were used more frequently than in New Guinea days, to forestall or alleviate peripheral circulatory collapse. The number of cases so treated, however, did not permit any comparative study. In the focal areas of infection studied, as on Mindoro and Negros, cogon grass was prevalent. This was probably not so near Baguio. Bearing in mind the Owi-Biak experience, the U.S.A. Typhus Commission warned that any environment harboring rats infested with Trombiculae that will accept man as a casual host can be a potential source of human infection.

The Philippine experience with scrub typhus made it clear that when man exposes himself to field conditions wherein he may become an accidental host, scrub typhus will appear sporadically, and unpredictably, in hitherto unreported districts.

South Pacific Area

Before the war, scrub typhus had not been recognized in the Solomon Islands. The first case was identified on Bougainville in December 1943. Nine more cases developed in January 1944. All had been exposed in a bivouac area on the bank of the Laruma River. Sporadic cases, 11 in number, each after exposure in the same area, developed in the course of the next 6 months. In all but two of these cases, agglutinins for Proteus OX-K developed in a titer of 1:160 or higher.

An interesting outbreak of mild scrub typhus developed on Bougainville in a Fijian force of 750 who were bivouacked in a meadow of coarse grass between riverbank and jungle at the former site of a native village.29 From 14 to 22 days later, 49 patients were in hospital with a fever that averaged 11 days' duration. An eschar typical of scrub typhus was found in all cases, and was above the legs in 32 (65 percent) of them. Generalized lymph node

29Anderson, W. L., and Wing, W. M.: Tsutsugamushi Disease (Scrub Typhus); A Clinical Study of 49 Cases. War Med. 8: 163-166, September 1945.


127

enlargement was constant; the eruption was present in 45 percent (22 patients). Bradycardia was the rule. Tachypnea was not observed. In these Fijians, in whom malaria could be excluded, the splenic enlargement was made out in the course of the second week in approximately 40 percent. Proteus OX-K agglutinins were present in 24 cases, or about 50 percent; only 5 had titers of 1: 1,200 or over; 19 ranged from 1: 50 to 1: 200. Two weeks later, another patrol of the same strength wearing clothing impregnated with dimethyl phthalate bivouacked in the same area with no resultant cases of scrub typhus. Two months later, an unprotected patrol went into the same area. After they came out, 23 cases of scrub typhus appeared. The available evidence suggests that this was a localized focus of mild scrub typhus.

India-Burma Theater

Before the outbreak of hostilities in 1941, there had been considerable interest in Indian Army Medical Services in cases diagnosed as "fevers of the typhus group." It had become clear that there were two types in the Simla hill country: (1) The murine or flea typhus case, developing agglutinins for Proteus OX-19, occurred under urban conditions, such as the bazaar sections of the cantonments, and (2) scrub or mite typhus, with agglutinins for Proteus OX-Kingsbury strain, occurred sporadically or in explosive focal outbreaks in units living under field conditions, particularly in scrub jungle. Attempts to establish the presence of rickettsial infection in a larval mite had not been made, nor had it been possible to isolate a strain of OX-K typhus in a wild rat. The rodent reservoirs of mite typhus in India were not established. The disease had been known to exist in Burma since 1932.

The late months of 1943 marked a period of orientation in this disease for U.S. Army medical officers. During November, a group of 22 febrile patients were admitted to the 20th General Hospital at Ledo, Assam.30 The fever was intense, associated with generalized lymphadenopathy, mild conjunctivitis, and on occasion a nonpetechial rash, appearing on the fifth to eighth day. Small ulcers or crusted papules were found and thought to mark the bite of the infecting insect. The fever lasted 8 to 20 days. The first Weil-Felix reactions were negative, save for a few agglutinations of OX-K in low titer. However, these patients, mostly Chinese troops in active training for jungle warfare, were considered likely cases of scrub (mite) typhus. In Shingbwiyang, Burma, on the Stilwell Road, 50 cases, entirely similar, had appeared in November. By 1 February 1944, 352 cases had been reported, 35 of them Americans, the remainder Chinese, all from units living under field conditions along the Stilwell Road. Two centers of infection where troops had been in training were incriminated, one of them the center of the jungle training area of the 22d Chinese Division, the other a campsite much fre-

30Letter, Maj. D. S. Pepper, MC, Assistant Chief, Medical Service, 20th General Hospital, to Surgeon, Base Section 3, China-Burma-India Theater, 9 Dec. 1943, subject: Report on Investigation of "C.B.I. Fever."


128

quented by Chinese troops. All American soldiers with scrub typhus had been living in the jungle. By December, the clinical picture had taken on a definite and characteristic pattern, in every way conforming to the picture of scrub typhus already familiar in the Southwest Pacific Area and to the descriptions of tsutsugamushi fever in Japan. Eschar, rash, fever curve, circulatory symptoms and signs, pneumonitis, and encephalitic manifestations were observed. Agglutinations in high titer for Proteus OX-K were found.

It was noted that the focal areas from which most of these Chinese cases came were not occupied by an appreciable number of troops until October 1943. During each of the last 2 weeks of November, there were 40 cases, and this rate rose to 60 per week through December. Incidence dropped off sharply in early January, following rather closely the movement of troops out of the area.

Earlier, in the autumn of 1943, a British unit in the India-Burma theater had 121 cases in an outbreak that began 9 days after moving into an area for training exercises.31 The epidemic subsided directly after the area was left, with cases continuing in the unit for about 2 weeks. The description of their cases was in all respects similar to the Chinese and American groups. 

Captured Japanese reports revealed that the enemy in Burma was encountering the same disease, which they called eruptive fever. They recognized similarity to tsutsugamushi fever but did not find the eschar frequently enough to warrant making this diagnosis in Burma. Their mortality rate is not given save in the comment-"very low." This incidence among the Japanese is all the more interesting in the light of our repeatedly negative reports about scrub typhus in enemy troops in New Guinea.

The subsequent story of scrub typhus among American troops in Burma is described in a comprehensive report by Sayen, Pond, Forrester, and Wood from the 20th General Hospital.32 Up to July 1945, there were 726 cases reported from the India-Burma theater in U.S. Army personnel with 52 deaths, a mortality of 7.2 percent. Among U.S. Army troops, 535 cases were carefully studied at the 20th General Hospital; 472 of these Americans were acutely ill on admission. There were 27 deaths, giving a mortality of 5.7 percent.

Sayen and his coworkers point out that a more intelligent understanding of the severity of scrub typhus is gained from grouping their cases according to the circumstances surrounding the successive outbreaks. Among 113 American soldiers from Services of Supply units installed along the Ledo Road who developed the disease sporadically, the mortality was approximately 4 percent. Among 105 patients who were evacuated by air from active jungle combat in the mountains north of Myitkyina, Burma, from March to May 1944, the mortality was 16 percent. This group, exhausted by the stress of

31Blumgart, Herman L., and Pike, George M.: History of Internal Medicine in India-Burma Theater. Chapter on Scrub Typhus, inclosure 5 thereto. [Official record.]
32Sayen, J. J., Pond, H. S., Forrester, J. S., and Wood, F. C.: Scrub Typhus in Assam and Burma; A Clinical Study of 616 Cases. Medicine 25: 155-214, May 1946.


129

fighting, and stricken with scrub typhus, was in an area from which evacuation was difficult. The mortality of only approximately 1.5 percent among 177 cases evacuated in the autumn of 1944 from troops undergoing jungle training north of Myitkyina must be related to speedy hospitalization in the forward area, and early evacuation to a general hospital. This group was in far better physical condition than the combat troops of the second group. In a fourth group of 77 cases, evacuated from combat south of Bhamo, Burma, in January and February 1945, the fatality rate rose again to 7 percent. Evacuation for this group was as difficult as for the Myitkyina combat group, marching after onset of fever again being unavoidable. The patient's pretyphus state of health and quality of early care were vital in prognosis.

The typical march of symptoms developed in all of these cases. Effort on the part of Sayen and his coworkers to classify the cases according to severity warrants quotation, as follows:

In the average case of scrub typhus, during the first week there were no signs by which the probable outcome could be determined. Occasionally a high fever at this time indicated a severe course. During the second and third weeks, however, certain phenomena appeared which justified placing the patient in "severe" or "grave" groups with respective mortalities of approximately 25 and 50 percent. However, until the disease was definitely on the decline one could not be sure that these features would not appear. Consequently, the diagnosis of "mild" or "moderate" scrub typhus, which carried practically no mortality, was not justified until defervescence was established. * * *

A case of scrub typhus was assigned to the "severe" group on the basis of any one of the following:

(1) An alarming increase of the general evidences of illness in the second week.

(2) More than the usual amount of fever: Over a week of peaks to 104, or 105 for more than 2 days.

(3) Frank clinical signs of dysfunction of an important organ:

(a) Signs of "typhus pneumonitis": Respirations 36 per minute for 2 days; cyanosis of the skin.

(b) Signs of meningoencephalitis: Severe delirium; meningismus.

(c) Signs of nephritis: Azotemia over 50 mgm. percent, isosthenuria, heavy albuminuria and cylindruria.

(d) Marked enlargement of the heart or sharp T-wave inversion in the electrocardiogram.

(e) Pitting edema with or without ascites. 

(f) Multiple hemorrhagic phenomena.

The appearance of any of these phenomena indicated that statistically the patient's chances of survival had been reduced from 19 in 20 to about 3 in 4.

A severe case of scrub typhus was considered in the "grave" group on the basis of one of the following findings:

(1) A steady increase of illness during the third week. 

(2) Very high fever: 105 for 5 days or 106 for 2 days.

(3) Signs of severe dysfunction of more than one vital organ, or evidence of severe inflammation of the central nervous system and the lungs. Of these, the most common were the following:

(a) Extensive pneumonitis: Persistent cyanosis out of oxygen [tent]; respiratory rate 50 per minute for 2 days, or over 36 per minute for a week.

(b) Encephalitis: Malignant restlessness, Cheyne-Stokes respiration, a convulsion, coma.


130

(c) Severe nephritis: Anuria.

(d) Tachycardia exceeding 130 per minute.

The appearance of these phenomena indicated that, statistically, the patients' chances for survival were 25 to 50 percent. We have never seen a patient recover whose cyanosis was unrelieved by oxygen or who had persistent hyperpnoea, pulmonary edema, or coma lasting 24 hours.

In their discussion of the classical signs, laboratory findings, and treatment of scrub typhus, Sayen and his coworkers bring out the following interesting points that tally with or supplement findings recorded in the Southwest Pacific Area.

1. The finding of an ulcer or papule that later became a typical mite ulcer 1 to 14 days prior to onset of symptoms was not uncommon. The presence (60 percent of 200 cases) or character of the eschar or ulcer had no relation to the severity of the disease, or to the OX-K titer. In only 27 percent was the primary lesion on the thighs or below.

2. Increasing generalized enlargement with, usually, tenderness of the lymph nodes was an early development in all but 6 of the 200 patients, and was, in fact, the most constant of the main diagnostic clinical signs.

3. The eruption (71 percent of cases) involved the trunk always, the face in 15 percent. Generally of 4 to 9 days' duration, it might outlast the fever. A few rashes were florid or purpuric. There was no relation of the rash to the severity of the disease.

4. Ophthalmoscopic examination revealed engorgement of retinal veins in 67 percent of cases in the first and second weeks, progressing to bilateral edema of the retina and optic nerve head in 36 percent, with retinal hemorrhage and exudate in a few instances. Retinopathy of this sort was absent in other febrile disease, and was actually helpful in the early diagnosis of atypical cases, later confirmed by the OX-K agglutination reaction.33

5. Bronchial rales, changing in location, appeared in "mild" and "moderate" cases, did not of themselves indicate a rickettsial pneumonitis.

6. Brief periods of gallop rhythm were not evidence of a prognostically important degree of interstitial myocarditis.

7. Agglutination titers for Proteus OX-K of 1: 100 were not seen except in scrub typhus. About half of a series of 200 cases failed to have this "diagnostic" titer. It was helpful diagnostically in isolated atypical cases. In epidemics, a "clinical" diagnosis was generally made before agglutination became positive (about the 14th day, on an average).

8. Cerebral malaria was the disease of chief importance to exclude in differential diagnosis of the case without conclusive signs of scrub typhus. 

9. Roentgen examination of the chest in scrub typhus cases often failed to indicate the extent and severity of the rickettsial pneumonitis. Intermittent dyspnea at rest, then persistent tachypnea, and cyanosis relieved initially by oxygen comprised a march of signs more valuable than physical findings in

33For a further discussion of the ocular manifestations of scrub typhus (new and original work) see Medical Department, United States Army. Surgery in World War II. Ophthalmology and Otolaryngology. Washington: U.S. Government Printing Office, 1957, pp. 141-144.-J. B. C., Jr.


131

the chest or roentgen examination in establishing the presence of pneumonitis.

10. Cardiac enlargement, sharp T-wave inversion with or without RS-T elevation (11 percent of 61 cases suspected of cardiac complication), and persistent gallop rhythm were not found to be necessarily evidence of ill omen. Dangerous rickettsial myocarditis could not be diagnosed, prior to final collapse, save by inference of precedent. No patient with T-wave inversion died; three cases who had tracings before death showed no electrocardiographic abnormality.

11. Spinal fluids in 27 patients with signs of meningeal irritation were under increased pressure (average 230 mm. of water). Ten had increase in cells, generally lymphocytes; three had a polynuclear pleocytosis with negative cultures. Spinal fluid protein levels were elevated (68 to 156 mg. percent, in four cases).

12. Convulsions occurred in 12 patients, of whom 3 were not considered dangerously ill until the convulsive seizure.

13. Spontaneous diuresis late in the febrile course, or at the onset of convalescence, was observed in 38 percent of 200 cases; the largest diureses were seen in the sicker patients with edema (10 percent of face, hands, shins, and feet), and with ascites. It constituted a reassuring prognostic sign.

14. Hypochloremia was little modified by parenteral saline therapy. Return to normal blood chloride levels occurred in convalescence, regardless of therapy.

15. In convalescence, thrombophlebitis and pulmonary embolism were occasional complications. Pleurisy developed in 10 percent of 200 cases; effusions, if present, were small, sterile; fever lasted only 4 days, and evidence of pleurisy was generally gone in a week.

16. In treatment.-(1) The mildest appearing case in the first week should be prepared by absolute bed rest for an unpredictably severe ordeal in the second week. (2) An adequate number of experienced nurses is of vital importance to see that small frequent feedings are taken, fluids pushed (minimum of 3 liters daily), and severely ill patients protected. (3) Salt administration can be overdone; it may aggravate edema. (4) Oxygen should be given by mask preferably; when given by nasal catheter, it did not, in the average case, relieve cyanosis. (5) Rectal paraldehyde, 30 cc. in oil, was the best sedative for "malignant restlessness," and might make it possible for the cyanotic patient to tolerate oxygen by mask, and prevent exhausting exertion. (6) Digitalis was not used. (7) Penicillin was of no avail save in the presence of a complicating bronchopneumonia. (8) The concept of peripheral circulatory collapse was not raised; intravenous plasma was not used with this in mind. (9) Intravenous fluids were given when indicated, carefully, and without untoward incident.

As experience with scrub typhus increased, confidence grew in the convalescent's ability to cope with the demands of duty. Patients with mild and


132

moderate cases (less than 3 weeks of fever) were informed soon after defervescence that they were returning to their units and were gradually reconditioned for discharge about 3 to 4 months from the onset of illness. Patients who had been gravely ill were evacuated to the Zone of Interior. The severe cases were appraised individually. Of the last 300 cases, 82 percent were returned to full duty. No evidence of residual myocardial damage was detected during reconditioning.

PATHOLOGY

Although a number of reports34 dealt with the pathology of scrub typhus, the most comprehensive study was performed at the Army Institute of Pathology (now the Armed Forces Institute of Pathology), Washington, D.C., by Maj. Arthur C. Allen, MC, and Dr. Sophie Spitz.35 These workers undertook to study the lesions not only of scrub typhus, but also of louseborne typhus, Rocky Mountain spotted fever, and Q fever in order to determine whether the various rickettsial diseases could be differentiated histologically. After careful study of the histological preparations and protocols of 78 cases of scrub typhus, 24 cases of epidemic typhus, 12 cases of Rocky Mountain spotted fever, and lung sections from 2 cases of Q fever, the authors made the following observations:

l. The primary lesion, or eschar, is considered to be provoked by the combined action of the secretion of the larval mite and the inoculated rickettsiae. It is suggested that the absence of the eschar in certain instances of scrub typhus may be due to variations in cutaneous immunity.

2. Interstitial pneumonitis of a marked degree is common in scrub typhus in contrast with epidemic typhus and Rocky Mountain spotted fever. The histologic picture of the interstitial pneumonitis of scrub typhus is indistinguishable from that of Q fever, rheumatic fever, toxoplasmosis, and viral pneumonia.

3. It is concluded that the amount of hepatic damage as noted histologically does not warrant the presumption that hypoproteinemia is due to hepatic insufficiency.

4. Early, acute, diffuse glomerulonephritis is common in scrub typhus, epidemic typhus, and Rocky Mountain spotted fever. The indirect role of the rickettsiae in the pathogenesis of the glomerulonephritis is indicated.

5. The focal encephalitis or nodule of scrub typhus is qualitatively similar to that of epidemic typhus and is in contrast to the "microinfarct" of Rocky Mountain spotted fever. The nodules of scrub typhus and epidemic typhus are practically limited to the gray matter, whereas the encephalitis of spotted fever involves the white matter preponderantly.

6. Contrary to the generally held impression, there is a sparsity of histologically evident vascular damage in scrub typhus. Arteritis is exceedingly slight in scrub typhus in contrast with epidemic typhus and Rocky Mountain spotted fever. Accordingly, it is suggested that the designation "diffuse vasculitis" when applied to scrub typhus represents an oversimplification not justified by the morphologic evidence.

7. It is concluded that the peripheral circulatory failure in patients with rickettsial diseases is a complex phenomenon which cannot be explained solely on the basis of

34See footnotes 5, p. 115; and 26, p. 125.
35Allen, 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.


133

morphologic damage of vessels. The contributory role of the adrenal gland in the circulatory failure is suggested.

8. The evidence of lymphoblastic origin for the cells characterizing the interstitial infiltrate is presented. The identification of the large "basophilic macrophage" with the "acute splenic tumor cell" is suggested and the evidence pointing toward the association of these cells with an allergic response is given.

Finally, Allen and Spitz proposed a much broader pathological concept of the rickettsioses than that generally held at the time of their studies, as follows:

From the pathologic point of view, the rickettsioses have long been regarded as a form of diffuse vascular disease. Surely, this impression is almost inescapable after a study of epidemic typhus and spotted fever. However, the histology of scrub typhus may perhaps warrant a change in the direction of emphasis. Although focal, more or less bland thrombophlebitis in scrub typhus is not uncommon, actual arteritis occurs rarely, and, in our series, was never of the fibrinoid variety seen in louse-borne or tickborne typhus. Moreover, the arteritis of scrub typhus does not seem to be a lesion sui generis, but, rather, appears to be secondary to an extension of the periarterial infiltrate into the wall. This interpretation was made previously by Kouwenaar. Yet, notwithstanding the disparity in the histologic evidences of vascular damage, there are basic clinical, etiologic, and, in many respects, immunologic similarities between scrub typhus and the other rickettsioses. Therefore, perhaps, a re-evaluation of the significance of the pathologic changes is in order. A close analogy to this problem is found in a nonrickettsial disease-acute disseminated lupus erythematosus (Libman-Sacks disease). The prominence of the degeneration of vessels in many organs led initially to the concept that this entity was a diffuse vascular disease. However, further studies prompted a broader concept; namely, that disseminated lupus erythematosus was in effect a disturbance of collagen, be it of a vessel, a cardiac valve, or a serous membrane. Moreover, the histologic and clinical pictures were such as to suggest a hyperergic reaction. The analogy may be extended by reference to periarteritis nodosa and to the arteritis that follows administration of sulfonamides. In other words, in the over-all view of the pathologist, the more remote, possibly hyperergic effects of the rickettsiae-the effects of the adrenal gland, on the glomeruli, and on the production of interstitial inflammation-assume more importance than the direct damage wrought by the localization of the rickettsiae.

LABORATORY AIDS IN DIAGNOSIS

The Weil-Felix reaction-In 1929, Fletcher, Lesslar, and Lewthwaite,36 while studying two forms of tropical typhus, discovered a serological difference which proved to be of considerable diagnostic value. They found that sera obtained from cases of rural typhus agglutinated in high dilution suspensions of the Kingsbury (K) strain of Proteus, in contrast to sera in urban typhus cases, which agglutinated the Proteus OX-19 micro-organisms. Subsequent studies showed the rural form to be the miteborne scrub typhus and the urban form to be murine (fleaborne) typhus.

During World War II, the Weil-Felix reaction was extensively employed in the laboratories of U.S. Army medical installations. Observations at the Virus and Rickettsial Diseases Laboratory, Army Medical Center, Washing-

36Fletcher, W., Lesslar, J. E., and Lewthwaite, R.: The Aetiology of the Tsutsugamushi Disease and Tropical Typhus in the Federated Malay States. Tr. Roy. Soc. Trop. Med. & Hyg. 23: 57-70, June 1929.


134

ton, D.C., clearly indicated the Proteus OX-K agglutination was not elicited by sera from other rickettsial diseases, and was, therefore, a valuable diagnostic aid for scrub typhus.37

Meanwhile, Zarafonetis,38 working in the Cairo laboratory of the U.S.A. Typhus Commission, carried out a series of studies in typhus-vaccinated individuals to determine what serological effects may result from vaccination alone. Only one instance of OX-K agglutination was found, and there was no change in titer following booster vaccination. He concluded that typhus vaccination did not cause an increase in OX-K antibodies.

Proteus OX-K agglutination tests were also performed on serial blood specimens from 104 acutely febrile patients who had been previously vaccinated with Cox-type epidemic typhus vaccine. No anamnestic reactions were detected in these studies.

The final phase of these observations was concerned with the serological findings in typhus fever patients who developed their illness despite prior vaccination with Cox-type epidemic typhus vaccine.39 Again, such patients were found not to develop agglutinins for suspensions of Proteus OX-K.

Thus, there appeared to be no need to modify the previously held interpretation of rising OX-K titers, that this finding was essentially specific for scrub typhus. However, in tests on sera from 51 cases of louseborne relapsing fever, Zarafonetis, Ingraham, and Berry40 found that all patients had Proteus OX-K titers of 1: 40 or more in at least one serum specimen. The titers ranged from 1: 40 to 1: 2,560. These workers suggested, therefore, that "since there is considerable overlapping in the geographic distribution of tsutsugamushi disease and louseborne relapsing fever, it becomes necessary to interpret Weil-Felix OX-K results with caution, particularly when atypical cases of either disease are in question."

Complement fixation tests-At the outset and well into World War II, the Weil-Felix Proteus OX-K agglutination test was the only available serological test of value in the diagnosis of scrub typhus. It was fortunate that this nonrickettsial antigen appeared to be specific for scrub typhus with the single exception of louseborne relapsing fever that has been noted. In view of important progress in the development of specific rickettsial antigens for use in complement fixation and agglutination tests for other rickettsial diseases, it was anticipated that similarly successful results would follow with

37Plotz, 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.]
38(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.
39Zarafonetis, 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.
40Zarafonetis, C. J. D., Ingraham, H. S., and Berry, J. F.: Weil-Felix and Typhus Complement-Fixation Tests in Relapsing Fever, With Special Reference to B. proteus OX-K Agglutination. J. Immunol. 52: 189-199, March 1946.


135

scrub typhus antigens. Bengtson,41 at the National Institute of Health, U.S. Public Health Service, was the first to prepare satisfactory complement fixing antigens from infected eggs by a technique similar to that used for epidemic typhus. Additional experience, however, revealed that there were significant antigenic differences between various strains of R. tsutsugamushi. Because of these differences, diagnostic complement fixation tests on human sera require the use of several antigens prepared from different strains of R. tsutsugamushi. Thus, while the complement fixation test became available for scrub typhus, its use was limited essentially to research laboratories during World War II.

Isolation and identification of strains -Diagnosis of scrub typhus by isolation of strains is, of course, absolute in contrast to the presumptive nature of serological tests. Isolation of strains is also desirable for laboratory comparison of immunity relationships between strains, for possible vaccine production, and for the preparation of antigens for serological tests. In addition, strains may be used in the laboratory evaluation of chemotherapeutic agents proposed for the treatment of scrub typhus. To these ends, therefore, strain isolations were carried out by several groups of workers in World War II and returned to adequately equipped laboratories for pertinent study.42

Prior to these efforts, attempts to isolate and serially transmit tsutsugamushi disease in laboratory animals gave negative results in the hands of many investigators. Japanese workers had been successful with rabbits, using intraocular injections. Mice were later found to be readily susceptible but were, unfortunately, not available for use in the field laboratories. Guinea pigs were susceptible to many tsutsugamushi strains, but apparently not to others. This was the situation in January 1944, when the Imphal, Ceylon, and Calcutta strains of scrub typhus were received in the Cairo, Egypt, laboratory of the U.S.A. Typhus Commission. These strains had been maintained at the district laboratory in Calcutta and at the Haffkine Institute in Bombay, India, by British workers and were forwarded to Brig. Gen. Leon A. Fox, Field Director, U.S.A. Typhus Commission, by Lt. Col. M. H. P. Sayers, RAMC. The strains were received in rabbits, infected intraocularly, and were maintained for several passages in rabbits. The infectivity of these strains for two desert rodents, namely, Gerbillus pyramidum and Gerbillus gerbillus, was then tested.43 They were found to be highly susceptible to infection with R. tsutsugamushi and were, therefore, a suitable substitute in the absence of a supply of white mice. Since these rodents were plentiful, it

41Bengtson, I.A.: Complement Fixation in Tsutsugamushi Disease (Scrub Typhus). Pub. Health Rep. 61: 895-900, 14 June 1946.
42(1) See footnote 1, p. 111; and 13, p. 121. (2) Philip, C. B., Woodward, T. E., and Sullivan, R. R.: Tsutsugamushi Disease (Scrub or Mite-Borne Typhus) in the Philippine Islands During American Reoccupation in 1944-45. Am. J. Trop. Med. 26: 229-242, March 1946. (3) Letter, Lt. Col. M. H. P. Sayers, R.A.M.C., Assistant Director of Pathology, 14th Army, Calcutta, India, to Brig. Gen. L. A. Fox, U.S.A. Typhus Commission, Cairo, Egypt, 4 Jan. 1944.
43Zarafonetis, C. J. D.: The Susceptibility of the Rodents, Gerbillus pyramidum and Gerbillus gerbillus, to Experimental Tsutsugamushi Infection (Scrub Typhus). Proc. Soc. Exper. Biol. & Med. 59: 113-116, June 1945.


136

was possible to accelerate a number of studies in scrub typhus at the U.S.A. Typhus Commission laboratories at Myitkyina as well as in Cairo.

Growth of the etiological agent of scrub typhus in the yolk sac of developing chick embryos was accomplished by a number of workers.44 This was an important method of experimental vaccine and antigen production.

SPECIFIC TREATMENT

The treatment of scrub typhus includes both general and specific measures. The general supportive measures consist of nursing care, diet, maintenance of fluid and electrolyte balance, and the management of complicating diseases or conditions. These aspects of therapy have been adequately indicated in the reports that have been cited.45 Here, consideration will be limited to specific measures, such as the use of immune serum, antibiotics, and chemotherapy.

Serotherapy-Hyperimmune rabbit serum was found to reduce the mortality of experimental scrub typhus in mice.46 Human convalescent serum, however, was without effect on the clinical course of scrub typhus even when given during the first week of illness.47 Since there are wide differences in the antigenic pattern of various strains of R. tsutsugamushi,48 it may be that only homologous antiserum would be effective therapeutically.

Antibiotics-Although penicillin and streptomycin proved to be valuable for certain complicating bacterial infections, these antibiotics had no significant specific effect on the etiological agent of scrub typhus. Since the war, the newer broad-spectrum antibiotics have been used with signal success in rickettsial infections.

Chemotherapy-In a report to the Division of Medical Sciences, National Research Council, dated 26 December 1942, Drs. John C. Snyder, J. Maier, and C. Russell Anderson, first demonstrated an antirickettsial effect of PABA (para-aminobenzoic acid) in mice experimentally infected with murine (fleaborne) typhus. This led to extensive clinical and laboratory studies and to experimental trials of PABA in animals infected with R. tsutsugamushi. Gerbilles proved to be of great value in this connection. Snyder and Zarafonetis,49 and Murray with these authors50 demonstrated conclusively that,

44(1) See footnote 39, p. 134. (2) Bengtson, I. A.: Apparent Serological Heterogeneity Among Strains of Tsutsugamushi Disease (Scrub Typhus). Pub. Health Rep. 60: 1483-1488, 14 Dec. 1945. (3) Lewthwaite, R., and O'Connor J. L.: Prophylactic Vaccine Against the Tsutsugamushi Disease. Second Report on an Attempt to Prepare a Vaccine From Hens' Eggs Experimentally Infected. Virus Laboratory, Commonwealth Serum Laboratories, Melbourne, Australia, 1943.
45See footnotes 1, p. 111; 9, p. 118; and 32, p. 128.
46Topping, N. H.: Tsutsugamushi Disease (Scrub Typhus); The Effects of Immune Rabbit Serum in Experimentally Infected Mice. Pub. Health Rep. 60: 1215-1220, 12 Oct. 1945.
47(1) See footnote 9, p. 118. (2) Hay, C. P.: Scrub Typhus at Port "X." J. Roy. Nav. M. Serv. 30: 127-135, July 1944.
48See footnote 44 (2).
49Snyder, J. C., and Zarafonetis, C. J. D.: Effects of Para-Aminobenzoic Acid in Experimental Tsutsugamushi Disease (Scrub Typhus). Proc. Soc. Exper. Biol. & Med. 60: 115-117, October 1945. 
50Murray, E. S., Zarafonetis, C. J. D., and Snyder, J. C. : Further Report on Effect of Para-Aminobenzoic Acid in Experimental Tsutsugamushi Disease (Scrub Typhus). Proc. Soc. Exper. Biol. & Med. 60: 80-84, October 1945.


137

properly administered, PABA significantly reduced the mortality of experimental scrub typhus in gerbilles. PABA was effective against strains of R. tsutsugamushi that had come from widely separated regions including India, Ceylon, and New Guinea. On the basis of their observations, these workers strongly recommended a clinical trial of PABA therapy in human beings.

Such an opportunity presented itself to Tierney,51 of the Cairo Unit of the U.S.A. Typhus Commission, in 1945. Working at the 20th General Hospital, in Ledo, Tierney carried out a controlled study on 18 patients with scrub typhus. He administered sufficiently large doses to obtain adequate blood concentrations of PABA and found that the treated patients had fewer complications and shorter fever than a comparable group of untreated subjects.

Although there are now improved means of administering large doses of PABA,52 and PABA has itself been supplanted by the newer antibiotics as the treatment of choice in scrub typhus, these early studies were of great significance to those concerned with the scrub typhus problem. Lack of an effective vaccine, the insidious vector, the widespread distribution, and a significant mortality rate, all made scrub typhus an important medical problem affecting morale in the field. Furthermore, several prominent investigators succumbed to infections acquired during the course of laboratory investigations with R. tsutsugamushi. The search for an effective therapeutic agent for scrub typhus during World War II was stimulated by an awareness of these factors.

Immunization-Information regarding the degree and duration of immunity following an attack of scrub typhus was fragmentary, even at the close of World War II. From the available data, it appeared that a strong and lasting immunity was induced by the disease, and considerable support was added to this belief by animal studies in several laboratories.53 Indeed, these observations indicated that animals experimentally infected with one strain of R. tsutsugamushi are resistant for some months, at least, to inoculation with both homologous and heterologous strains. Studies in progress at the end of hostilities, however, revealed that a number of strains of R. tsutsugamushi had important antigenic differences as judged from cross-neutralization tests54 and toxic neutralization tests,55 as well as from study of the com-

51Tierney, N. A.: Effect of Para-Aminobenzoic Acid in Tsutsugamushi Disease. J.A.M.A. 131: 280-285, 25 May 1946.
52Zarafonetis, C. J. D.: Clinical Use of Para-Aminobenzoic Acid. Texas J. Med. 49: 666-672, September 1953.
53(1) See footnotes 1, p. 111; and 13, p. 121. (2) Bell, E. J., and Plotz, H.: Infection and Immunity Following the Intracutaneous Inoculation of Scrub Typhus. Proc. Soc. Exper. Biol. & Med. 59: 143-144, June 1945. (3) Zarafonetis, C. J. D., Snyder, J. C., and Murray, E. S.: Immunity Following Para-Aminobenzoic Acid Therapy in Experimental Tsutsugamushi Disease (Scrub Typhus). Proc. Soc. Exper. Biol. & Med. 61: 240-242, March 1946.
54Bell, E. J., Bennett, B. L., and Whitman, L.: Antigenic Differences Between Strains of Scrub Typhus as Demonstrated by Cross-Neutralization Tests. Proc. Soc. Exper. Biol. & Med. 62: 134-137, June 1946.
55Smadel, J. E., Jackson, E. B., Bennett, B. L., and Rights, F. L.: A Toxic Substance Associated With the Gilliam Strain of R. orientalis. Proc. Soc. Exper. Biol. & Med. 62: 138-140, June 1946.


138

plement fixation antigen.56 From the observations and from efforts to produce an effective vaccine, it became evident that much remained to be learned regarding the immune response to the various scrub typhus strains.

Vaccine studies-In view of the apparent immunity conferred by an attack of scrub typhus in man and confirmed in the animal work just noted, it was hoped that a satisfactory vaccine could be developed for scrub typhus as had been done for epidemic typhus. Several laboratories turned their attention to this problem. Fulton57 at the National Institute for Medical Research in London prepared vaccines from the lungs of infected mice and cotton rats. He found some protection was afforded by intraperitoneal vaccination to intraperitoneal challenge. Similar observations were made by Smadel, Rights, and Jackson58 at the Virus Division of the 1st Medical General Laboratory, 814th Hospital Center, Paris, France, and by Plotz, Bennett, and Reagan59 at the Medical Department Professional Service Schools, Washington. D.C. The subcutaneous administration of these vaccines induced no resistance to infection.

Vaccine suspensions were also prepared from infected yolk sacs of developing chick embryos.60 However, these preparations failed to confer immunity in a wide series of tests. It appears that the ether-extraction method, which was so valuable in the production of epidemic typhus vaccine, had some inexplicably deleterious effect when applied to suspensions of R. tsutsugamushi.

POSTWAR STUDIES

Immunity-In the period immediately following the war, important work was done on unsettled problems bearing on prophylaxis and treatment. In studies conducted by Smadel and his associates at the Army Medical Department Research and Graduate School, Washington, D.C.,61 it was found, briefly that in human volunteers immunity to the homologous strain of R. tsutsugamushi persisted for at least 1 year, and in some for longer periods. In contrast, resistance to heterologous strains of R. tsutsugamushi was of a transient nature. Even within a month after inoculation with one strain, an appreciable number of persons became ill following injection with a heterologous strain. By the end of a year, all were again susceptible to heterologous

56See footnote 44 (2), p. 136.
57Fulton, F.: Methods For the Study of Mite Typhus-A Progress Report. National Inst. Med. Res., Hampstead, London, 21 June 1944.
58Smadel, J. E., Rights, F. L., and Jackson, E. B.: Scrub Typhus Vaccines Prepared From Formalinized Suspensions of Tissues of White and Cotton Rats. Report dated 19 June 1945, Headquarters, First Medical General Laboratory, 814th Hospital Center, U.S. Army.
59Plotz, H., Bennett, B. L., and Reagan, R. L.: Preparation of an Inactivated Tissue Culture Scrub Typhus Vaccine. Proc. Soc. Exper. Biol. & Med. 61: 313-317, March 1946. 
60See footnotes 44 (3), p. 136; and 59.
61(1) Smadel, J. E., Ley, H. L., Jr., Diercks, F. H., and Traub, R.: Immunity in Scrub Typhus; Resistance to Induced Reinfection. Arch. Path. 50: 847-861, December 1950. (2) Smadel, J. E., Ley, H. L., Jr., Diercks, F. H., Paterson, P. Y., Wisseman, C. L., Jr., and Traub, R.: Immunization Against Scrub Typhus; Duration of Immunity in Volunteers Following Combined Living Vaccine and Chemoprophylaxis. Am. J. Trop. Med. 1: 87-99, January 1952.


139

infection. During the period of waning immunity, the disease which resulted from the heterologous strain was modified from the classical picture. Indeed, the illness observed in tests shortly after recovery was so mild that it would probably not have been recognized as scrub typhus if rickettsemia had not been demonstrated. On the other hand, the disease which resulted when the individuals were tested after 1 year generally presented the typical picture of scrub typhus.

Of further interest is the observation that only about 40 percent of the subjects who developed illness following reinoculation with scrub typhus after 1 year displayed a significant (fourfold) rise in titer of Proteus OX-K agglutinins.

Treatment-In postwar studies, dramatic results in treatment of scrub typhus and other rickettsial infections were achieved with broad-spectrum antibiotics, such as Chloromycetin (chloramphenicol), Aureomycin (chlortetracycline), and Terramycin (oxytetracycline).62 A program making use of these for chemoprophylaxis under special circumstances would not prevent infection but would prevent clinical illness. Field trials suggest that, if prophylactic medication is continued for 4 weeks or longer after exposure, it is unlikely that signs of scrub typhus will appear after the drug is discontinued.63

Vaccines are still (1957) in the experimental stage, but, in view of the immunity factors discussed, it is not anticipated that effective protection will be afforded in this manner.

SUMMARY

During World War II, scrub typhus was found to be endemic in foci distributed throughout a large triangular region of Asia and the Pacific which lies between Japan, India, and Australia. Outbreaks are more common in types of terrain that provide suitable cover for reservoir hosts as well as moisture conditions favorable to the growth and activity of the vector mites. Wild mice and rats and jungle tree squirrels are known to be naturally infected with R. tsutsugamushi. Larval mites of the genus Trombicula transmit the disease from animal to animal or from animal to man. Since infection of the mites can be transovarially acquired, the vector also serves as an important natural reservoir of scrub typhus.

62(1) Smadel, J. E., Woodward, T. E., Ley, H. L., Jr., and Lewthwaite, R.: Chloramphenicol (Chloromycetin) in the Treatment of Tsutsugamushi Disease (Scrub Typhus). J. Clin. Investigation 28: 1196-1215, September (pt. 2) 1949. (2) Smadel, J. E., Jackson, E. B., and Ley, H. L., Jr.: Terramycin as a Rickettsiostatic Agent and Its Usefulness in Patients With Scrub Typhus. Ann. New York Acad. Sc. 53: 375-384. 15 Sept. 1950. (3) Prezyna, A. P., Teh-Ling, C., Tsu-Lin, W., Dougherty, W. J., and Bond, H. B.: Treatment of Scrub Typhus in the Pescadores Islands With Chloramphenicol, Aureomycin, and Terramycin. Am. J. Trop. Med. 3: 608-614, July 1954.
63Smadel, J. E., Traub, R., Frick, L. P., Diercks, F. H., and Bailey, C. A.: Chloramphenicol (Chloromycetin) in the Chemoprophylaxis of Scrub Typhus (Tsutsugamushi Disease). III. Suppression of Overt Disease by Prophylactic Regimens of Four-Week Duration. Am. J. Hyg. 51: 216-228, March 1950.


140

The desert rodents, G. pyramidum and G. gerbillus, were shown to be susceptible to infection with scrub typhus and were valuable experimental animals in studies on this disease during World War II.

Clinical picture-After an incubation period of from 6 to 18 days, the illness begins abruptly with chilly sensations or rigors, followed by fever, headache, malaise, and anorexia. The face is flushed, and there is conjunctival injection. A primary lesion or eschar is present in nearly all cases at the time of onset. It may have been present for as long as 5 days earlier, and usually persists throughout the active phase of the disease. The eschar represents the site of infection by the mite. Occasional patients exhibit more than one eschar. This lesion may be up to 1.0 cm. in diameter and consists of a central tough black scab surrounded by a slightly elevated dull red areola (fig. 9). In moist areas of the body, such as the axilla, groin, and scrotum, the scab is often lacking, and the lesion appears as a shallow punched-out ulcer. It is neither painful nor pruritic. There is often regional or generalized lymphadenitis. The spleen may become palpable. The fever rises in stepwise fashion, reaching 102 to 105 F. by the end of the first week. It usually remains elevated until the third week at which time it subsides by lysis. As the disease passes into its second week, the general symptoms are increased except in mild cases.

On about the fifth to the eighth day, a dull red macular eruption appears first on the trunk (fig. 10) and later spreads to the arms, legs, and face. It varies in intensity and extent and lasts from 1 to 10 days. Nonproductive cough is common, and in severe cases, bronchitis and pneumonia may appear. Roentgen examination of the chest may reveal changes similar to those of primary atypical pneumonia. Indeed, pathological studies suggest that these findings represent a rickettsial pneumonitis. Hypotension, tachycardia, and cyanosis may occur at the height of the disease and are attributed more to peripheral vascular collapse than to heart failure.

The clinical features presented by the scrub typhus patient reflect the histopathology of the disease, which is basically a disseminated, focal vasculitis and perivasculitis especially of the vessels of the skin, lungs, heart, and brain.

Leukocyte counts are usually within normal limits, but a moderate leukocytosis may develop during the second week of illness.

Diagnosis-The typical case of scrub typhus is readily diagnosed on the clinical findings. Prior to the appearance of the cutaneous eruption, however, early diagnosis depends upon finding an eschar, since dengue, relapsing fever, malaria, infectious hepatitis, typhoid fever, epidemic typhus, and murine typhus exhibit many of the same clinical features.

The diagnosis may be confirmed by serological tests. A significant rise in titer in the Weil-Felix Proteus OX-K agglutination test differentiates scrub typhus from other rickettsial infections. However, patients with relapsing fever also develop OX-K agglutinins. Complement fixation tests


141

FIGURE 9.-Eschar on ankle in tsutsugamushi disease.

FIGURE 10.-The rash of tsutsugamushi disease is a faint macular one, frequently transient in nature.


142

with purified suspensions of R. tsutsugamushi may be useful in the diagnosis, but the sera must be tested with antigens prepared from several different strains of the micro-organism. This is necessary because there are important antigenic differences between various strains. Although recovery and identification of the micro-organism proves the diagnosis, it is not feasible for routine use.

Natural course-After the first week, the subsequent course of scrub typhus may be relatively mild, with a total febrile period of 12 to 14 days, or it may be moderately severe with signs of encephalitis and pneumonitis and fever up to 3 weeks. In severe cases, patients are febrile for about 3 weeks, have signs of pneumonitis, encephalitis, and often of circulatory collapse and myocarditis. Thromboses and cerebral or gastrointestinal hemorrhage may occur. Death is not infrequent in severe cases. However, the mortality of untreated cases varies from 1 to 25 percent or more in different series. The death rate rises sharply after the age of 40. There is evidence that the course of scrub typhus is likely to be more severe in men who have been under the strains of combat or have lacked early treatment.

Recovery from scrub typhus is ultimately complete. Many patients, however, have a prolonged convalescence and present a picture of neurocirculatory asthenia with sleeplessness, tremulousness, lack of ability to concentrate, easy fatigability, excessive sweating, palpitation, dyspnea, and sense of intrathoracic pressure.

Relapse is rare in cases that have run their natural course.

Following an attack of scrub typhus, immunity to the homologous strain appears to persist for at least a year. Resistance to heterologous strains of R. tsutsugamushi, however, is transient.

Therapy-The patient should be placed at bed rest, avoid overexertion, and receive frequent small feedings and adequate fluid intake. Specific therapy should be instituted as early as possible. Scrub typhus during World War II was found responsive to high doses of PABA (best administered as a 10-percent chilled aqueous solution of the sodium or, preferably, the potassium salt);64 since World War II, chemotherapy has been successful.

Prophylaxis-Prevention of scrub typhus in areas where it is endemic is difficult, at best, and may be impossible under combat conditions. When feasible, preventive measures should include appropriate clearing and oiling of campsites to change the ecology of the area so that it is unfavorable to rodents and mites. Impregnation of clothing with dimethyl phthalate, or with an emulsion of benzyl benzoate and dibutyl phthalate, affords considerable individual protection as mites which come in contact with treated cloth are killed. In view of the immunity factors that have been referred to, it is not anticipated that effective protection will be afforded by the development of a vaccine.

64See footnote 52, p. 137.

RETURN TO TABLE OF CONTENTS