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Chapter III

Contents

CHAPTER III

Schistosomiasis Japonica

Frederik B. Bang, M.D., and F. Tremaine Billings, Jr., M.D.

INTRODUCTION ON LEYTE

Life Cycle of the Parasite

Schistosomiasis japonica, a disease due to a parasitic worm, Schistosoma japonicum, is found in large areas of China, in a few foci in Japan, and on four of the larger islands of the Philippines. A strain, apparently of low pathogenicity for man, is present on Formosa, and there is at least one small focus in the Celebes. When the cercariae (larval forms) escape from infected snails into fresh water, as in ricefields, swamps, or ponds, they seek a susceptible host and either penetrate this host or die in from 24 to 48 hours. If the water drains into a river, the cercariae may be swept down the stream and in its course find their susceptible host. After burrowing through the skin, and migrating through the bloodstream and the lungs, they lodge at a later stage of development in the liver. By crawling down the portal venous system, they arrive at the branches of the vessels leading from the large intestine or rectum. After fertilization of the female by the male which carries her in a groove of his body, the female deposits clumps of eggs within the terminal branches of the vessels or in the liver. The embryo develops to a miracidium inside the eggshell. If this egg works its way through the intestinal mucosa, it is extruded in the feces and the miracidium hatches. The miracidium penetrates susceptible snails (if available) and in several weeks develops into a cystlike stage which has within it many cercariae. Thus, an increase in eggs takes place in the definitive host (man, dog, or other appropriate animal), and an increase in the cercariae occurs within the snail.1

Recognition, Incidence, Epidemiology

Before World War II, American experience with acute schistosomiasis japonica was limited. Most knowledge of the disease had been derived from

1(1) Faust, E. C., and Meleney, H. E.: Studies on Schistosomiasis Japonica. Am. J. Hyg. Monographic Series, No. 3, 1924. (2) Faust, E. C.: Schistosomiasis Japonica: Its Development and Recognition. Ann. Int. Med. 25: 585-600, October 1946. (3) War Department Technical Bulletin (TB MED) 167, June 1945.


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chronic infections in native populations living in endemic areas and from occasional acute outbreaks among small numbers of foreigners visiting or resident in these areas.2

When the campaign to recapture the Philippine Islands was planned, it was known that schistosomiasis japonica was endemic in the eastern part of Leyte Island, but its intensity and potential danger were not generally realized. A number of preventive and educational measures were undertaken, as described in detail elsewhere,3 and, among the officers of many of the hospital units that followed up the invasion, there was some academic discussion of the disease and the possibility of encountering it. Nevertheless, the picture left in the minds of many was hazy.

It is not surprising, therefore, that schistosomiasis japonica burst very suddenly upon a relatively uninformed Medical Department early in the Leyte campaign, in December 1944. The invasion of Leyte had occurred on 20 October 1944. During the invasion, many soldiers had frequent contact with fresh water. Combat troops, patrols, and engineers occupied in building bridges and airports and in repairing roads were frequently in freshwater swamps and streams for short or long periods of time. The value of protective clothing was not appreciated. The troops were inadequately informed concerning the dangers of contact with fresh water, and, when actual fighting died down, many soldiers bathed, washed clothes and vehicles, and swam in infested waters.

Late in November and during December, U.S. soldiers were admitted to hospitals with symptoms that were sometimes suspected as being due to schistosomiasis, but for the most part the disease was not recognized. Ova of S. japonicum were first found in stools of a soldier on Leyte Island, on 30 December 1944, by Lt. Walter L. Barksdale, SnC, who was on detached service with the 36th Evacuation Hospital from the 19th Medical General Laboratory, Hollandia, New Guinea. The patient was under the care of Capt. David P. Gage, MC, on temporary duty with the 36th Evacuation Hospital from the 49th General Hospital, who had suspected the diagnosis and had encouraged a search for the ova. It is of interest that on 28 December 1944 in the 132d General Hospital on Biak Island the diagnosis of schistosomiasis had also been made from a liver biopsy by Capt. Morris Goldberg, MC. The patient was a soldier who had been evacuated from Leyte with unexplained fever and marked enlargement and tenderness of the liver.

On Leyte during the last week in December 1944, at least 16 patients who were subsequently found to have schistosomiasis were admitted to hospitals. Most of these patients came from two organizations-the 51st Portable Surgical Hospital and the 50th Engineer Combat Battalion. During the months of January and February 1945, slightly more than 300 additional

2Egan, C. H.: Outbreak of Schistosomiasis Japonica. J. Roy. Nav. M. Serv. 22: 6-18, January 1936.
3Ferguson, M. S., Graham, O. H., Bang, F. B., and Hairston, N. G.: Studies on Schistosomiasis Japonica. V. Protection Experiments Against Schistosomiasis Japonica. Am. J. Hyg. 44: 367-378, November 1946.


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cases of schistosomiasis were diagnosed in hospitals on Leyte.4 These soldiers were from all types of units but combat troops, engineers, and artillerymen predominated.

The occurrence of schistosomiasis in the 50th Engineer Combat Battalion provided a unique opportunity, which was taken by Lt. Col. Ralph R. Sullivan, MC, and Capt. Malcolm S. Ferguson, SnC,5 to study the epidemiology of the disease. This battalion, numbering 534 soldiers, was employed to a large extent in building bridges, but the occupations and opportunities for exposure varied from company to company and among the different platoons. The incidence of cases in the battalion was thoroughly investigated and correlated with the battalion's job roster to determine the amount of exposure to fresh surface water of the individual companies, platoons, and personnel. A paragraph of this paper may be quoted here:

The attack rate for the battalion was 19.6 percent (102 cases as of 31 May 1945) which may be compared with an estimated XXIV Corps rate of 0.73 percent. The rates increase to 27 and 33 percent respectively as B and C companies, engaged in bridge construction, are considered separately. Moreover, the attack rate increases to the range of 41-53 percent as attention is focused on the specific platoons engaged in bridge construction. Finally as the rates are computed for the water-exposed bridge-workers themselves, these range from 71-89 percent in the various platoons of B and C Companies. Actually in dealing with the water-exposed bridge-workers it becomes a matter of trying to explain why 100 percent of them were not infected. Since a number were unfortunately not hospitalized or were not diagnosed because typical ova could not be demonstrated, the possibility of 100 percent infection in this group cannot be eliminated.

Another interesting, circumscribed episode of infection occurred among men of the 51st Portable Surgical Hospital. On 16 November 1945, nine members of this unit, including two medical officers, left their bivouac at Dulag for Abuyog to obtain medical supplies. As a bridge over a stream later recognized as infested with cercariae of S. japonicum was under construction, they could proceed no further and decided upon a swim. It is worthy of note that the medical officers commented before entering the water on the possibility of contracting schistosomiasis but only jokingly, and they decided to risk it. The stream in question is slow moving, and these officers were under the impression that the danger in moving water was minimal. Two officers and six enlisted men went in for approximately 30 minutes; one enlisted man did not enter the water. In the eight who were in the water, symptoms of schistosomiasis developed 4 to 5 weeks later; the one who remained on the bank escaped. No other cases of schistosomiasis developed among personnel of the 51st Portable Surgical Hospital. No snails (Oncomelania quadrasi) were found in this area, but higher up the stream snails were found.

Another noncombat unit, in which many became infected with S. japonicum, was the 118th General Hospital, Tolosa, Leyte. Although the

4Essential Technical Medical Data, U.S. Army Forces, Far East, for January and February 1945.
5Sullivan, R. R., and Ferguson, M. S.: Studies on Schistosomiasis Japonica. III. An Epidemiological Study of Schistosomiasis Japonica. Am. J. Hyg. 44: 324-347, November 1946.


94

medical officers of this unit were aware of the existence of schistosomiasis on Leyte, they had no idea of the very real danger of infection from streams in the immediate vicinity of the hospital. Surveys of the area in question had been made for snails, and when none were found an unjustified feeling of confidence in the freedom of the water from cercariae pervaded the unit. The stream is one which runs between Tanuan to the north and Tolosa to the south. Of a medical detachment consisting of approximately 500 enlisted men, 164 admitted contact with this fresh water or with swamps draining into it. By 30 April 1945, 75 of these men had been found to have schistosomiasis by the demonstration of ova in their stools. Others may have been found to have the disease at a later date, or may have remained undiagnosed.

Hospital admissions on Leyte Island, for the period January-May 1945, due to schistosomiasis were listed as follows:6

 

Number of cases

January

69

February

305

March

313

April

197

May

78


Total

962


A breakdown of a random 575 of these cases shows the occurrence by various types of units to be as follows:

Unit:

Number of cases:

Infantry

189

Engineer

203

Field Artillery

54

Antiaircraft

61

Cavalry and reconnaissance

10

Medical

12

Quartermaster

4

Signal

15

Tank

10

Ordnance

12

Chemical

4

Special Service

1


By February 1946, a total of approximately 1,300 cases of schistosomiasis japonica had been diagnosed in American troops infected on Leyte Island. Comparatively few cases were diagnosed on Leyte after the last of May 1945, but other cases were found, as follows:

1. Among units that had been exposed to infested water and had moved on to more advanced bases before the onset of symptoms. An example7 of this is a survey of an engineer battalion, moved from Leyte to Okinawa, in

6Essential Technical Medical Data, U.S. Army Forces, Pacific, for July 1945.
7Essential Technical Medical Data, U.S. Army Forces, Pacific, for September 1945. Appendix E thereto.


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which 19 of 206 men examined were found to have ova of S. japonicum in their feces. Of these patients, 12 gave a history of symptoms. They had all been away from Leyte approximately 4 months at the time of the survey.

2. Among soldiers evacuated from Leyte through medical channels for diseases other than schistosomiasis.

3. Among personnel who had been infected immediately before returning home on rotation and whose symptoms first occurred either in transit or in the United States.

Disposition of Patients Infected on Leyte

As has been indicated, the theater was not fully prepared to handle efficiently a sudden outbreak of acute schistosomiasis japonica among American troops on Leyte. At first, the criteria for diagnosis, the method of treatment, and the final disposition of these cases were somewhat haphazard and were decided for the most part by individual hospitals. Some patients with schistosomiasis were evacuated as soon as the diagnosis was made. Others were treated and then evacuated, while still others were treated and held for observation.

Finally, a disposition policy, based on suggestions from the Surgeon General's Office, was announced,8 as follows:

Seriously ill cases and those with present evidence of involvement of the central nervous system should be evacuated to the United States without delay. Other patients who after a course of treatment have persistent clinical signs or positive laboratory findings should also be evacuated. Mild cases which appear to have been cured and have regained their previous state of health may be returned to duty where they can be given periodic examinations of their general conditions and of the blood and stool specimens in accordance with instructions contained in letter from Headquarters, USAFFE, 5 March 1945, FEMD 710, Subject: Aftercare of Patients with Schistosomiasis Japonica.

The Surgeon General, in a letter to the Theater Surgeon, USAFFE (U.S. Army Forces, Far East), dated 26 March 1945, had suggested that all patients in whom a diagnosis of schistosomiasis japonica had been made be evacuated to the United States, after a course of treatment, for further observation and treatment in the centers designated for the care of tropical diseases-Moore General Hospital, Swannanoa, N.C., and Harmon General Hospital, Longview, Tex. This stand was taken by The Surgeon General because it was known that followup of these patients was both important and time consuming (by many months) and that treatment in many cases would have to be repeated. It was thought that the number of patients who would have to be evacuated for this cause was not large enough to affect the military strength significantly.

The theater surgeon replied to this letter by endorsement, dated 14 April 1945, reiterating the policy of retaining in the theater mild cases for followup. Many difficulties, however, were encountered both in administra-

8Technical Memorandum No. 5, Office of the Theater Surgeon, U.S. Army Forces, Far East, 31 Mar. 1945.


96

tion and in clinical evaluation to determine which patients to keep and which to send home. For this reason, in a letter to section and base surgeons dated at Headquarters, USAFWESPAC (U.S. Army Forces, Western Pacific), 18 July 1945, the theater surgeon directed that all patients with a diagnosis of schistosomiasis japonica be evacuated to the Zone of Interior. It was emphasized in this letter that the period of treatment and observation in the theater should not exceed 120 days and that any soldiers with schistosomiasis, who had already been sent to limited duty under previously existing directives, should be rehospitalized and evacuated to the United States.

Actually, after February 1945, very few patients ill with schistosomiasis were seen.9 The majority admitted to hospitals thereafter had mild or asymptomatic cases, diagnosed by routine examinations of stools during unit surveys or during hospitalization for other causes.

Postscript from Mindanao

In the early part of December 1945, it was brought to the attention of the Office of The Surgeon General, by the Walter Reed General Hospital, Washington, D.C., that the chief of the Tropical Disease Section at that hospital, Capt. Joseph H. Burchenal, MC, had made a definite diagnosis of schistosomiasis japonica in five soldiers whose only possible common source of infection had been at the Davao Penal Colony, 51 kilometers north-northeast of Davao, Mindanao, Philippine Islands. Actual exposure to infection was believed to have occurred in the Mactan ricefields, 8 kilometers east of the penal colony. These soldiers had been prisoners of war, following the surrender of the Philippine Islands to the Japanese. Some 600 soldiers and sailors were reported by officers imprisoned there to have survived to return to the United States. Of these, it was possible to follow up approximately 50, all of whom were given thorough tests for schistosomiasis, including examinations of the stools. The diagnosis was made in approximately 30 of them. It is possible that other individuals among these 600 men had schistosomiasis which remained undiagnosed.

THE DISEASE PICTURE

The course of schistosomiasis japonica in all three of its stages has been discussed in textbooks of tropical medicine. A full description of the early manifestations of the disease is justified here, however, by the extensive experience with American troops infected during the Leyte campaign, affording an unusual opportunity to make numerous observations on the early phase of the disease. Hitherto, the repeatedly infected, chronically ill populations of endemic regions were the principal subjects available for

9See footnote 6, p. 94.


97

large-scale study, with, on occasion, much smaller groups of Americans and Europeans exposed to the same environment.10

As the three stages into which it is customary to divide the course of the disease are continuous, the clinical phenomena attributed to them usually overlap. The first stage includes the period from the penetration of the body by the cercariae to the settling of the paired worms in the mesenteric venules. The second stage is initiated when eggs are deposited by the female worms in the small vessels of the intestinal wall, the liver, or occasionally elsewhere. Allergic manifestations are common at this time. The third stage is characterized by proliferation and repair of damaged tissue and by continued heavy deposition of eggs. The present review will be largely concerned with the second stage, when the acute manifestations occur.

It should be reemphasized that this division into stages is purely for the sake of convenience. Experience with American troops with acute schistosomiasis japonica on Leyte showed that, in clinically severe and moderately severe cases, the onset of symptoms was directly associated with the maturation of worms and the deposition of ova. In some clinically mild cases, the onset of symptoms was noted shortly after the ova had been found in the stools and, in some cases, diagnosed only by the demonstration of ova in the stools, maturation of worms and deposition of ova caused no symptoms.11 It seems probable that the severity of symptoms is a measure of the severity of the infection.

Billings and his associates, in their clinical study of 337 cases of acute schistosomiasis japonica in American troops, including a detailed analysis of 75 of them, discussed at length the interval of time between exposure to infection and the occurrence of symptoms. In 12 cases in which the exact time of the only exposure to infection was known, symptoms first occurred from 26 to 58 days after exposure, an average of 42 days. In the remaining 63 cases, it was more difficult to estimate this latent period because the time of exposure varied from several days to several weeks, and penetration of the skin by cercariae could have occurred on any one or all of the days on which the individual was in contact with fresh water. However, even when contact with infested water covered a period up to 14 days, the latent period was fairly uniform. In 14 of the 75 cases analyzed in detail, there was a close correlation between the onset of symptoms and the appearance of ova in the stools, and there was definite indication that the infection was asymptomatic during the period of development of the schistosomes.

10See footnote 1 (1) and (2), p. 91.
11Billings, F. T., Winkenwerder, W. L., and Hunninen, A. V.: Studies on Acute Schistosomiasis in Philippine Islands; Clinical Study of 337 Cases With Preliminary Report on Results of Treatment With Fuadin in 110 Cases. Bull. Johns Hopkins Hosp. 78: 21-56, January 1946.


98

SYMPTOMS, PHYSICAL FINDINGS, AND EARLY COURSE

The manifestations and early course of the acute phase of the disease as it appeared among American troops who took part in the invasion of Leyte Island are described in the study by Billings and his associates and in several other papers.12

Symptoms

"Swimmers' itch," symptomatically the first possible indication, occurs very soon after exposure to water infested with cercariae. Its incidence is apparently highly variable. On Leyte, three groups13 of patients were carefully questioned about itching immediately after contact with fresh water, and the incidence varied as follows: 1 in 42, 4 in 41, and 9 in 75. Thus, it occurred in 8.8 percent of these 158 patients. The extensive recent work on swimmers' itch, which is due to schistosomes, usually in newly infected men in whom sensitization plays a large role, should be related to these data.

Following an asymptomatic latent period during which the parasite developed to adulthood, the onset of symptoms was usually abrupt with headache, chills, feverishness, cough, urticaria, aches, and anorexia of varying severity. In some cases, the onset was insidious, and the symptoms in some of these remained mild throughout the symptomatic phase and in others were intensified after several days. In a few instances, the onset was not only abrupt but severe or fulminating in character. Lastly, the disease sometimes had an asymptomatic course; such cases were detected through group surveys. On the basis of the intensity and severity of symptoms and the height of the temperature and the duration of the fever, the series of 337 cases cited (p. 97) were divided into four groups, as follows: Severe, 21 cases; moderately severe, 123 cases; mild, 168 cases; and asymptomatic, 25 cases. The incidence of the chief symptoms as shown in table 13, however, is based on 75 cases subjected to detailed analysis. It should be stated that this classification is made on clinical grounds only, and it is not known whether the severity of symptoms is necessarily correlated with the degree of infection.

Moderately severe cases.-Since these cases present the most common symptomatology, they are discussed first. The symptoms usually began suddenly with fever, chills, headache, generalized aches and pains, soreness and stiffness of the neck, discomfort in the upper part of the abdomen accompanied by anorexia, urticaria, and an irritating dry hacking cough, all or

12(1) Thomas, H. M., and Gage, D. P.: Symptomatology of Early Schistosomiasis Japonica. Bull. U.S. Army M. Dept. 4: 197-202, August 1945. (2) Johnson, A. S., Jr., and Berry, M. G.: Asiatic Schistosomiasis; Clinical Features, Sigmoidoscopic Picture and Treatment of Early Infections. War Med. 8: 156-162, September 1945. (3) Thomas, H. M., Bracken, M. M., and Bang, F. B.: Clinical and Pathological Picture of Early Acute Schistosomiasis Japonica. Tr. A. Am. Physicians 59: 75-81, 1946.
13See footnote 11, p. 97, and footnote 12 (1) and (2).


99

some of which lasted from 1 to 8 weeks. The clinical course of schistosomiasis, acute, moderately severe, is shown in figures 33 and 34.

TABLE 13.-Incidence of symptoms in 75 patients with acute schistosomiasis japonica

Symptoms

Patients affected


Number

Percent

Fever

75

100.0

Headache

69

92.0

Weight loss

69

92.0

Malaise

67

89.3

Anorexia

66

88.0

Pain in upper quadrant of abdomen

60

80.0

Stiff neck

57

67.0

Abdominal cramps

52

65.0

Cough

48

64.0

Generalized aches, backaches, and arthralgia

45

60.0

Urticaria and angioneurotic edema

39

52.0

Chills

37

49.0

Diarrhea

21

28.0

Constipation

18

24.0

Pain in chest

17

22.0

Itching (after exposure to infested water)

9

12.0

Testicular aching

9

12.0

Neurologic complications

7

9.3

Nausea and vomiting

6

8.0

Asthma

6

8.0


In 14 cases, 8 of which presented the shorter latent periods, the acute febrile illness, considered as ushering in the symptomatic phase of the disease, subsided partially or entirely in from 2 to 8 days; thereafter, the symptoms persisted in mild form, or remained completely in abeyance for a week or two, and then recurred, gradually or sharply. This initial acute illness often suggested dengue, atypical forms of which occurred on Leyte. Typical skin eruptions of dengue were never noted in these cases, however, in which the acute febrile period may represent the host reaction to the initial dissemination of the ova of S. japonicum.

The first chief complaints in many cases were fever, chills, headache, cough, and urticaria with or without angioneurotic edema; in several cases, the first manifestations were limited to this type of skin lesion. Later, within a few days to 2 weeks, the urticaria and cough subsided in most cases, but pain or discomfort in the upper quadrants of the abdomen, anorexia, loss of weight, headache, fatigue toward evening, stiff neck, and varied myalgic and arthralgic pains persisted, though fluctuating from day to day.

The febrile stage lasted from 1 to 8 weeks; the fever was remittent and of the saw-toothed type, with the temperature rising sharply to 102 to


100

FIGURE 33.-Clinical course of schistosomiasis japonica, acute, moderately severe, in 20-year-old white male. This patient was admitted to hospital on 25 January 1945. Trivalent antimony compounds, at that time, were being given in amounts inadequate for most effective treatment. Patient, asymptomatic on 1 March 1945, subsequently relapsed.


101

FIGURE 34.-Clinical course of schistosomiasis japonica, acute, moderately severe, in 22-year-old white male. This patient was admitted to hospital on 6 January 1945. Treated with small amounts of Fuadin, the patient made rapid progress and felt well when evacuated on 18 February 1945.


102

104 F. in the evening and, with rare exceptions, returning to normal or below normal in the morning. Likewise, there was diurnal variation in the intensity of symptoms; the majority of patients felt better or "tolerably" well in the morning but worse in the afternoon and evening, when all symptoms were characteristically intensified.

Urticaria or angioneurotic edema, which was noted in 52 percent of the patients, varied from an occasional small and fleeting wheal to lesions of tremendous size. The lesions were indolent and persistent. They were not strikingly responsive to adrenalin. Swelling of the posterior half of the tongue was noted in one patient, but edema of the fauces and larynx was not seen.

A very common symptom was soreness and stiffness of the neck. In this series of 75 patients, 57 had this complaint and in some it was striking. Usually, it developed suddenly and lasted from 24 to 48 hours, then subsided only to recur in several days' time. In one patient, the head was held rigid, incapable of any movement, for a period of 2 weeks. Lateral rotation was especially restricted and, less commonly, flexion. This symptom is probably not due to involvement of the meninges, but is more likely myalgic in origin, as soreness of the trapezius and sternocleidomastoid muscles was elicited on palpation. Meningitis was occasionally suspected, but examinations of the spinal fluid revealed no abnormalities.

In association with anorexia and discomfort in the upper quadrants of the abdomen, abdominal cramps were frequent, but diarrhea occurred in only 21 patients (28 percent), and then it was not clear whether it was due to the disease or to an intercurrent infection, as attacks of diarrhea were fairly common among persons on Leyte. More frequently, the bowel movements were normal or were constipated, sometimes severely so as the disease progressed. Blood in the stools was found rarely and only in the occult form. Anorexia and loss of weight, which in cases of long standing may amount to as much as 40 pounds, were prominent features.

A nonproductive cough was sometimes accompanied by moist rales or scattered areas of consolidation, especially at the bases of the lungs, or by diffuse signs characteristic of acute asthmatic bronchitis, which occasionally dominated the clinical picture at first. In some cases of the latter type, the true nature of the disease was not suspected until more characteristic symptoms appeared.

Alopecia, which was noted by Hunt14 in several of a series of 18 patients who contracted the disease on the adjacent island of Samar, was not seen in this series. Lesions of the skin in which ova of S. japonicum were demonstrated (fig. 35) were reported in one case of the disease among American troops on Leyte.15

14Hunt, A. R.: Schistosomiasis in Naval Personnel, a Report of 16 Cases. U.S. Nav. M. Bull. 45: 407-419, September 1945.
15Fishbon, H. M.: Case in Which Eggs of Schistosoma japonicum Were Demonstrated in Multiple Lesions. Am. J. Trop. Med. 26: 319-326, May 1946.


103

Mild cases.-The symptoms and physical findings in this form of the disease were often minimal. In many cases, patients complained toward evening of occasional cough, slight feverishness, malaise, headache, fatigability, and anorexia. Occasionally, they had mild discomfort in the upper quadrants of the abdomen, transitory scattered aches and pains, and at times they complained of a "crick" in the neck. They did not seek medical attention for days or even weeks, but attributed their symptoms merely to the unaccustomed tropical environment. When a patient reported to sick call in the morning, as a rule his temperature was normal and he felt well, so that the infection was easily overlooked. In fact, such vague and variable symptoms led to the diagnosis of psychoneurosis in several patients before schistosomiasis was discovered.

FIGURE 35.-Schistosome dermatitis-papular eruption on back.

Physical examination in many cases of this type revealed loss of weight, enlargement of the posterior cervical lymph nodes, tenderness in the epigastrium and right upper quadrant of the abdomen, and a slightly en-


104

FIGURE 36.-Clinical course of schistosomiasis japonica, mild, in 29-year-old white male. This patient was admitted to hospital on 12 January 1945 and was evacuated on 18 February 1945. Treated with small amounts of Fuadin, the patient improved rapidly.


105

FIGURE 37.-Clinical course of schistosomiasis japonica, acute, severe, with involvement of the central nervous system, in a 21-year-old white male. This patient was admitted to hospital on 3 February 1945 and treated with Fuadin and tartar emetic to 21 February. Two months later, eosinophilia was still found, but repeated stool examinations were negative, and peripheral neurologic signs were minimal. Patient was evacuated to the Zone of Interior on 11 April 1945.


106

larged liver. The spleen was seldom palpable. Figure 36 illustrates such a mild case with a short episode of low grade fever and minimal abnormal physical findings.

Severe cases.-In 21 of the series of 337 patients, the symptoms and the clinical course were sufficiently severe to justify this classification. Figure 37 illustrates the clinical course of the disease in one patient of this group. The patients were often prostrated and semicomatose; the temperature was high and spiking; and the headaches, generalized aches and pains, cough, and anorexia were severe. Enlargement and tenderness of the liver were more pronounced, and the spleen was uniformly enlarged. In a few patients in this series, mild anemia was observed. Several in the group of severe cases had neurologic manifestations which are described later (p. 108).

Asymptomatic cases.-In 25 patients of the 337 studied, the disease developed without symptoms; no such cases were included among the 75 studied in detail. Schistosomiasis was suspected in this group because of known exposure to infested water or because of the discovery of eosinophilia, either during a routine survey of military units in which other members were known to have schistosomiasis or during hospitalization for another disease. The incidence of this type of the disease among troops who were stationed in endemic areas was impossible to estimate and could only be determined by extensive surveys of such units.

Physical Findings

Table 14 presents a list of the most frequent physical findings in the 75 cases of acute schistosomiasis japonica studied in detail. The discussion will be limited to the patients with schistosomiasis of moderate severity. These patients usually appeared thin, the degree depending, however, on the duration of symptoms. They were sallow and appeared chronically rather than acutely ill. In the absence of urticaria, the skin was normal. Enlargement of the posterior cervical lymph nodes, and less often a mild general enlargement of all the lymph nodes, was found. The mucous membranes in some patients were pale. The eyes, ears, nose, mouth, and throat were normal. Since cough was a frequent complaint, one might have expected changes in the lungs, but in most patients abnormal pulmonary signs were not elicited. Only five patients in this series had objective pulmonary changes. These were seen in roentgenograms as scattered areas of infiltration and patchy consolidation at the base of one or the other lung. In most instances, the abnormal findings disappeared after 1 or 2 weeks. In one severe case observed on Leyte, typical miliary seeding (pseudotubercles) of the lungs was demonstrated roentgenographically.

The heart and blood pressure were normal; the pulse varied directly with the temperature. The abdomen was usually flat but occasionally some-


107

TABLE 14.-Incidence of important physical findings in 75 patients with acute schistosomiasisjaponica

Physical findings

Patients affected

Number

Percent

Enlargement or tenderness of liver

69

92

Tenderness of epigastric region

63

84

Enlargement of spleen

51

67

Enlargement of posterior cervical lymph nodes

27

36

General enlargement of lymph nodes

25

33

Objective pulmonary changes

5

6

Objective neurologic changes

3

4


what distended. There was often mild generalized tenderness, usually limited to the upper quadrants of the abdomen and especially to the midepigastrium where tenderness to palpation and percussion was sometimes exquisite. The liver was tender and palpably enlarged in 92 percent of the 75 patients. It extended as much as 5 cm. below the costal margin in some instances, but in many patients the enlargement was demonstrable only as a widening of the area of dullness. Even in these patients, there was tenderness to deep palpation below the right costal margin and to percussion over the lower costal area. The spleen was enlarged 67 percent. It occasionally extended as much as 4 cm. below the costal margin, but in many instances enlargement was indicated only by increased dullness over the splenic area. The spleen was slightly or not at all tender. Although testicular pain was complained of by several patients, the genitalia appeared normal.

Sigmoidoscopic Examination

The important sigmoidoscopic studies by Johnson and Berry16 of patients with acute schistosomiasis japonica are a significant contribution to observation of the disease. They examined the lower part of the large intestine of 63 patients. The following excerpt from their report describes their findings:

* * * characteristic multiple, firm, yellow nodules, 1 to 3 mm. in diameter, occurring in clusters of from 3 to 25 were seen beneath the mucosa. They were most abundant at the rectosigmoid junction, but were also present above in the lower sigmoid. In many cases the nodules were found 4 to 5 cm. below the rectosigmoid junction. There was no ulceration, and definite relationship to the visible blood vessels was not apparent. The mucosa showed no inflammatory or vascular changes. On biopsy of these lesions many ova were present in the tissue removed. All were beneath the mucosa. Some were not as mature as the ova seen in stool examination but could be identified easily.

16See footnote 12 (2), p. 98.


108

Following these observations, the examination of the lower part of the large intestine by means of a sigmoidoscope became a routine procedure in all hospitals caring for patients with schistosomiasis japonica and in the tropical disease centers in the United States. This examination was especially valuable as an aid to definite diagnosis of the disease in cases in which difficulty was encountered in finding ova in the stools. It was also particularly helpful as an aid to determining whether treatment of the disease had been effective. The appearance of characteristic nodules in the intestinal mucosa after a course of treatment was completed was highly suggestive of the persistence of live worms in the portal system. A biopsy of such a nodule in which ova with live miracidia could be demonstrated furnished proof that a cure had not been obtained, and further treatment was instituted.

Later observations enlarged on the findings of Johnson and Berry. At the 118th General Hospital, small ulcerations were demonstrated, scrapings of which yielded ova. At Harmon General Hospital, 300 patients were examined by proctoscope.17 In only three were lesions demonstrated. These were described as "single, flat, oval, moderately indurated granulomata, 0.5 to 2.0 cm. in their longest diameter. These were 7, 10, and 15 cm., respectively, from the anus. They were well demarcated and the low grade inflammatory appearance did not extend to the surrounding normal mucosa." These lesions were described as bleeding easily with the traumata of the proctoscope, and ova were demonstrated in biopsies of them. In 46 sigmoidoscopic examinations at Moore General Hospital,18 33 patients were found "abnormal," but only 1 had a polyp and 1 a small nodule, both containing ova of S. japonicum.

Neurologic Manifestations

During the period from the invasion of Leyte on 20 October 1944 to March 1946, groups of U.S. Army medical officers reported 33 new cases of schistosomiasis japonica of the central nervous system among Americans who were on that island.19 These and other cases are fully summarized in a review of a large number of patients with neurologic signs and symptoms by Kane and Most.20 It is possible that other cases of this type appeared

17Mason, P. K., Daniels, W. B., Paddock, F. K., and Gordon, H. H.: Schistosomiasis Japonica; Diagnosis and Treatment in American Soldiers. New England J. Med. 235: 179-182, 8 Aug. 1946.
18Most, H., Kane, C. A., Lavietes, P. H., Schroeder, E. F., Behm, A., Blum, L., Katzin, B., and Hayman, J. M., Jr.: Schistosomiasis Japonica in American Military Personnel: Clinical Studies of 600 Cases During the First Year After Infection. Am. J. Trop. Med. 30: 239-299, March 1950.
19(1) See footnote 11, p. 97, and footnote 12 (1), p. 98. (2) Tillman, A. J. B.: Cerebral Manifestations of Schistosomiasis Japonica. Bull. U.S. Army M. Dept. 4: 492, November 1945. (3) Carroll, D. G.: Cerebral Involvement in Schistosomiasis Japonica. Bull. Johns Hopkins Hosp. 78: 219-234, April 1946. (4) Cutler, J. G.: Schistosomiasis of the Central Nervous System. J. Nerv. & Ment. Dis. 104: 425-431. October 1945. (5) Watson, C. W., Murphy, F., and Little, S. C.: Schistosomiasis of the Brain Due to Schistosoma japonicum; Report of Case. Arch. Neurol. & Psychiat. 57: 199-210, February 1947.
20Kane, C. A., and Most, H.: Schistosomiasis of the Central Nervous System; Experiences in World War II and Review of the Literature. Arch. Neurol. & Psychiat. 59: 141-183, February 1948.


109

from time to time as later manifestations of the disease, but certainly they were few, and it may be said that, among almost 1,300 cases of the disease diagnosed, neurologic involvement occurred in approximately 2.5 percent.

Nevertheless, further details and observations relating to the neurologic picture associated with schistosomiasis japonica as it appeared among American troops seem worthy of consideration and discussion. Data from the review of this subject by Kane and Most and from the studies of Billings and his associates have been drawn upon heavily in the preparation of this discussion and description.

Previous workers have well established the fact that the neurologic manifestations are probably due to the presence of ova of S. japonicum in the substance of the central nervous system.21 No new light has been thrown on the subject of how these ova arrive there. Although Shimidzu refers to the fact that a second Japanese investigator, Fujinami, found worms in the cerebral veins of monkeys exposed to a very heavy concentration of cercariae, no reports have been found in which worms have been observed in operative or autopsy material from human brains. This does not preclude the possibility that adult forms may be present in cerebral blood vessels at some distance from the main pathological process incited by the ova. Although some ova may filter through the liver-lung barrier from the portal system and reach the central nervous system, it is difficult to explain the occurrence of "nests" of eggs within the brain by the deposition of eggs in areas other than the cerebral veins. It should be emphasized that the discovery of adult worms in thrombosed veins at post mortem is difficult if the veins are full of blood.

Many of the gross and microscopic findings from localization of these ova in the central nervous system had been described before the experience with the disease in American troops in World War II. Suffice it to say that the ova have now been demonstrated in practically all areas of the brain but seem to have been found in greater abundance in the pia-arachnoid, the cortex, the subcortex, the basal ganglia, the internal capsules, and the chorioid plexuses of the lateral ventricles.

With such a wide distribution of the ova, it is not surprising that, when the central nervous system is involved, the neurologic symptoms and other manifestations are protean.

Clinically, a striking feature of the complication is the suddenness of the onset regardless of whether the neurologic signs and symptoms occur in association with the first acute stage of the disease or as a later manifestation. Kane and Most, analyzing 18 neurologic cases, found that the average interval from the time of first potential exposure to the onset of neurologic manifestations was 14 weeks with a range of from 6 to 36 weeks. The average interval from the time of appearance of the first recognized general

21(1) See footnote 1(1), p. 91. (2) Shimidzu, K.: Ein Operationsfall von Schistosomiasis cerebi. Arch. f. klin. Chir. 182: 401-407, 1935.


110

systemic symptoms to the occurrence of signs and symptoms referable to the central nervous system was 5.3 weeks with a range of from 3 days to 24 weeks. The neurologic manifestations were the presenting features of the disease in two of their cases.

The intervals from first exposure to manifest involvement of the central nervous system were as follows:

Time interval (weeks):

Number of cases

0-5

0

6-10

9

11-15

3

16-20

1

21-25

4

26

1


It is thus apparent that neurologic complications of schistosomiasis may appear as late as 6 months after exposure to the disease, and there is no reason to believe that they may not appear even later, depending on the location of the ova in the brain, the number present, and the rate of development and repression of the inflammatory process.

In addition to the usual indications of infection with S. japonicum, patients with involvement of the nervous system may exhibit a variety of other symptoms. Kane and Most tabulated the significant symptoms occurring in their cases of neurologic schistosomiasis (table 15) and discuss the significance of the most outstanding. Although headache was experienced by all the patients on whom they report, they found that for the most part it was either transitory or intermittent in character and of little value in localizing the lesion. In a few of their patients, it was a severe and persistent complaint, and, in three out of four patients on whom an operation was eventually performed for a brain lesion the headache was located over the area where the pathological process was found.

There were disturbances of the sensorium at some time during the course of illness in all of the 18 patients. This varied from momentary periods of confusion resembling petit mal attacks to prolonged periods of unconsciousness lasting hours, especially in those with convulsive seizures. Disorientation and confusion was a striking feature and in six patients lasted as long as 2 weeks. Many of this group of patients were listless and apathetic for several weeks but four showed marked restlessness, at times bordering mania. Of the four patients operated upon, all experienced convulsions of one type or another with coma lasting up to 12 hours. All types of seizures were noted-sensory, motor (Jacksonian, tonic-clonic, adversive, atypical), and psychomotor-and these were associated with a variety of transient sequelae-motor aphasia, cranial nerve and visual field defects, alexia, micropsia, plus pyramidal tract defects usually consisting of hemiparesis or hemiplegia.


111

TABLE 15.-Incidence of symptoms in 18 patients with schistosomiasis japonica, involving the central nervous system

Symptoms

Patients affected


Number

Percent

Headache

18

100

Disturbance of sensorium

18

100

Weakness of extremities

18

100

Incontinence

10

55

Visual disturbance

10

55

Speech disturbance

10

55

Apraxia

9

50

Ataxia

7

38

Sensory disturbance

4

22

Tinnitus

3

17

Vertigo

2

11

Deafness

1

5


Visual disturbances were found in 10 of the 18 patients. These disturbances represented cortical involvement of the higher centers of sight, and visual field defects were noted in a few patients who were found at operation to have granulomatous tumors.

Disturbance of the higher speech centers was noted in 10 of the 18 patients. These were usually transitory in nature and varied from slight inability to use the right words or slurring to true motor aphasia.

Weakness in one or more extremity was observed in all 18 patients. The onset of this phenomenon was usually sudden, and the type of paralysis consisted in the different cases of hemiplegia, quadraplegia, hemiparesis, or paralysis of one extremity. In some patients, the paralysis was flaccid; in others, spastic; and, in one, it was mixed, the patient having spastic paralysis of the upper extremities and flaccid paralysis of the lower extremities.

Kane and Most conclude on the basis of the neurologic findings that in practically all their cases there was diffuse encephalitis and involvement of the pyramidal tracts. In several of them, the nuclei of some of the cranial nerves seemed to be involved, and in others there appeared to be changes in the cerebellum. In those patients on whom operations for brain tumor were performed, lesions were chiefly found in the left parietotemporal or occipital lobes.

LABORATORY FINDINGS

Stool Examinations

Final diagnosis of schistosomiasis japonica depended on the demonstration of the characteristic ova of the parasite either in the stools or in the


112

tissues of the patient. In the great majority of cases seen during the outbreak among American troops on Leyte, ova were found in the stools before a diagnosis was definitely made and treatment begun. It was the general policy both overseas and in the hospitals in the United States to withhold treatment until ova had been demonstrated, except in severe cases requiring immediate treatment. This was considered a sound policy because other parasitic infections were extremely prevalent, and sometimes mimicked acute schistosomiasis. It was thought that in almost every case of schistosomiasis, ova could be demonstrated if enough stools were examined by trained personnel and if routine proctoscopic examinations were made.

The following difficulties were, however, encountered in the demonstration of ova, especially during earlier days of the outbreak:

1. In many cases, especially the mild ones, ova were present in the stool in relatively few numbers. However, in some mild cases, ova were demonstrated in the first stool examined, while in occasional severe cases as many as 15 to 20 stool specimens were examined before ova were found.

2. Many laboratory officers were not familiar with the appearance of the ova of S. japonicum in all its stages of development, and confusion arose between identification of vegetable cells and maturing and degenerating ova. Vogel22 had described the ova of S. japonicum in all stages. In addition, a manual based on a series of studies in locally infected dogs was written and illustrated by Lt. N. G. Hairston, reproduced locally, and distributed by the Office of the Surgeon, USAFFE. These publications were of great assistance in the training of laboratory officers. Where immature ova were present in a stool, mature ova could also be found, and it was safer and less likely to be confusing to base a definite diagnosis of the disease on mature ova containing miracidia.

3. The technique used to find ova in stools was tedious and necessitated painstaking and thorough adherence to procedure. Many laboratory officers were not familiar with the best technique, and faced with hundreds of suspected cases the problem of careful stool examinations on all of them was in many instances overwhelming. Varied techniques were employed reflecting the diversity of training and differences of opinion among laboratory officers as to the most efficient method.

It soon became clear that, in addition to the direct examination of any bloody mucous that might be present in the stool, some method of concentrating the eggs from a larger portion of the stool was worthwhile, and a number of techniques were compared. A method originally described by Hunninen23 was frequently used. Baroody and Most24 at the Moore General Hospital concluded that among a variety of techniques, including acid ether,

22Vogel, H.: Ueber Entwicklung, Lebensdauer und Tod der Eier von Bilharzia japonica im Wirtsgewebe. Deutsche tropenmed. Ztschr. 46: 57-69, 1 Feb. 1942; 81-89, 15 Feb. 1942.
23See footnote 11, p. 97.
24Baroody, B. J., and Most, H.: Relative Efficiency of Water Centrifugal Sedimentation and Other Methods of Stool Examination for Diagnosis of Schistosomiasis Japonica. J. Lab. & Clin. Med. 31: 815-823, July 1946.


113

zinc sulphate, brine flotation, and niter centrifugal sedimentation, the last was the best. It has the advantage of simplicity for field usage. However, in general diagnostic laboratories, other techniques have subsequently replaced it, and for the relative advantages of each the standard texts such as the "Clinical Parasitology" by Craig and Faust may be consulted.

Hematological Findings

Leukocytes and eosinophils.-It had been known for some time that leukocytosis and eosinophilia are characteristic of acute schistosomiasis japonica. This was confirmed in the clinical studies of the disease as it occurred among American troops.

In addition, it was found that there was a tendency for the counts to rise as the acute phase of the disease progressed. There appeared to be no constantly direct relationship between the degree of leukocytosis and eosinophilia and the severity of symptoms; rather the counts often fluctuated irregularly from day to day and from week to week. Many mild or asymptomatic cases were found to have leukocytes and eosinophils that remained within normal numerical limits throughout observation of the acute phase.

As intensive treatment was instituted and the acute phase subsided, there was definite evidence that the number of leukocytes and eosinophils declined. At both Moore25 and Harmon26 General Hospitals, it was observed that, in the later stages of the disease, the degree of leukocytosis and eosinophilia could in general be used as an indication of whether treatment had been successful. Occasional eosinophilia could not be taken to mean failure of treatment, but persistent eosinophilia was a useful warning indicating that repeated careful search of the stools might reveal the ova of S. japonicum. In the final analysis, however, the presence or absence of ova in the stool was the only reliable criterion for evaluation of treatment.

Erythrocytes.-Mild anemia occurred rarely in the acute cases of schistosomiasis japonica seen among American troops. By the time these soldiers reached hospitals in the Zone of Interior, the erythrocytes were normal in number.

Roentgenographic Findings

Significant findings by roentgenogram were limited to the chest. In clinical reports27 dealing with the acute phase of the disease, it was mentioned that signs of scattered pulmonary infiltrations were demonstrable at the time of physical examination. Abnormalities were visible in roent-

25See footnote 18, p. 108.
26(1) Mason, P. K., Daniels, W. B., Paddock, F. K., and Gordon, H. H.: Latent Phases of Asiatic Schistosomiasis. Arch. Int. Med. 78: 662-678, December 1946. (2) See footnote 17, p. 108.
27See footnote 12 (2) and (3), p. 98, and footnote 22, p. 112.


114

genograms of the lungs28 and occurred five times in 75 cases analyzed in detail by Billings and his associates. For the most part, these abnormal findings were present for only a short time, a matter of 1 or 2 weeks, and only in the severe or moderately severe cases.

Tests of Liver Function

Since many of the eggs of S. japonicum are scattered into the liver after they have been deposited in the small vessels of the portal system, it would have been of interest to know the effect of this seeding upon that organ. Unfortunately, however, no studies were reported relating to hepatic function in the acute phase of the disease. On the other hand, Lippincott and his associates,29 at Harmon General Hospital, studied the hepatic function of patients with schistosomiasis japonica who had been evacuated to the United States after the acute phase. In this study, they used several tests including determinations of Bromsulphalein (sulfobromophthalein) retention, galactose tolerance, hippuric acid excretion, icterus index, serum bilirubin, formol-gel reaction, and urinary urobilinogen in serial dilutions. They found that diminution of hepatic function was minimal and were inclined to attribute the abnormal findings to the antimony used in treatment.

Spinal Fluid Examinations

Lumbar punctures and examinations of the spinal fluid were carried out only in those cases in which the central nervous system was apparently damaged. In the acute stage overseas, abnormal findings were limited to an increased cellular content of the fluid in a few cases. In by far the greatest number of examinations, the spinal fluid was normal. The amounts of globulin and protein and the patterns of colloidal gold curves were not reported. There was an increase in the protein and globulin content of the spinal fluid in a few of the neurologic cases studied in the United States, and a midzonal type of reaction to colloidal gold was observed in a very few cases.30

PICTURE OF THE DISEASE IN PATIENTS EVACUATED TO ZONE OF INTERIOR

Following diagnosis and preliminary treatment in oversea hospitals, patients with schistosomiasis japonica were evacuated to the Zone of In-

28Weinberg, H. B., and Tillinghast, A. J.: Pulmonary Manifestations of Schistosomiasis Caused by Schistosoma japonicum. Am. J. Trop. Med. 26: 801-809, November 1946.
29Lippincott, S. W., Paddock, F. K., Rhees, M. C., Hesselbrok, W. B., and Ellerbrook, L. D.: Tests of Liver Function in Schistosomiasis Japonica, With Particular Reference to Antimony Treatment and With Report of 2 Autopsies. Arch. Int. Med. 79: 62-76, January 1947.
30See footnote 21 (2), p. 109.


115

terior. On reaching the United States, they were sent to one or the other of two centers for the study of tropical diseases in the Army, Moore General Hospital or Harmon General Hospital. Each hospital received approximately 600-650 patients with this diagnosis. Three very complete reports of the disease as observed following the acute stage, in the so-called latent stage, at these hospitals were prepared for publication by Most and his associates (p. 108) and by Mason and his associates (pp. 108 and 113). From Harmon General Hospital, a thorough evaluation of the clinical status at the time of initial examination and during followup of 300 patients31 diagnosed and treated overseas was reported. These patients appear to be a representative cross section of all those received at the two tropical disease centers, although it should be noted that they were probably as a group more severely infected than those patients received from overseas at a later date, who not only had less severe acute manifestations of the disease but had been treated more extensively before evacuation to the Zone of Interior. Suffice it to say that these 300 patients received at Harmon General Hospital were in strikingly good physical condition. None were acutely ill, although 255 (85 percent) had a combination of residual complaints of relatively mild degree, such as abdominal discomfort (155), weakness (75), and headache, myalgia, and nervousness (186); positive stools were obtained in 76 (30 percent) of the 255 patients. Of 46 (15 percent) patients with no complaints, positive stools were obtained in 17 (38 percent). The liver and spleen were palpable in 32 and 4 patients, respectively. All patients had lost weight. The general condition of the 300 patients was such that for only 6 did furlough have to be delayed beyond the initial 2-week period of evaluation. All of these had neurologic complications.

The abdominal complaints present in 155 of the 300 soldiers were limited to the upper quadrants of the abdomen and varied from an indefinite awareness of soreness to intermittent mild to moderate cramping pain in the region of either the epigastrium or the liver.

It is interesting to note, in the same report from Harmon General Hospital, the observation that, although moderate and marked leukocytosis was a common feature of the acute phase of the disease, in the latent phase after evacuation to the Zone of Interior positive stools were no more common in those with leukocytosis than in those with normal numbers of white blood cells. Marked eosinophilia was also more characteristic of the acute than of the latent phase, although there seemed to be some correlation between the level of the eosinophilia and the likelihood of finding ova in the stool.

Proctoscopic examinations of these 300 patients resulted in the demonstration of lesions due to schistosomiasis in only 3. This is in striking contrast to the high incidence of lesions of the lower bowel in the acute phase.

Involvement of the central nervous system was manifested as often in the latent phase seen in the Zone of Interior as in the acute phase of the

31See footnote 26 (1), p. 113.


116

disease observed overseas. This may be accounted for by the fact that very few of the neurologic complications cleared up before evacuation to the United States, and in addition several cases were reported in which signs referable to the central nervous system developed as a late manifestation (p. 110). The general prognosis for patients with schistosomiasis japonica of the central nervous system does not seem to be favorable as far as complete recovery is concerned, though marked improvement of function has been observed in most cases.

TREATMENT AND RESULTS

Methods

Before experience with schistosomiasis japonica in American troops, no opportunity had presented itself to study various methods of treatment of this disease in large numbers of acutely infected individuals. Observations had for the most part been limited to patients chronically infected and reinfected, living in endemic areas where adequate followup studies were impossible, and one could not be sure of the duration of the disease before treatment nor of the amount of reinfection occurring during and after treatment. In a few isolated instances where small numbers of individuals were infected by brief exposure to infested water, adequate followup studies on the efficacy of the treatment employed were not reported. The epidemic of schistosomiasis on Leyte brought the Army Medical Department face to face with the challenging problem of determining what the best method of treatment was. If the known methods of therapy were not effective, new ones would have to be evolved.

The drugs accepted as most useful in treating this infection before World War II were the trivalent antimony compounds, Fuadin (stibophen) and tartar emetic, which contain 13.6 percent and 36 percent antimony, respectively. Emetine and Anthiomaline (lithium antimony and thiomalate) were quickly shown to be ineffective. The data to be presented deal with the use of Fuadin and tartar emetic.

Before the epidemic on Leyte, little was known by the Army Medical Corps about the toxicity to man of large amounts of trivalent antimony or about its parasiticidal properties against S. japonicum. It was used carefully and, as it turned out later, too sparingly in the beginning. No complete studies are available regarding the results of treatment overseas, for the most part with amounts of antimony now known to be much less than adequate for a complete cure. It is significant, however, that of 300 patients diagnosed as being infected with S. japonicum in oversea hospitals, in the large majority on the basis of positive stool examinations, only 31 percent were found to have positive stools on arrival at Harmon General Hospital. At Moore General Hospital, closer to 45 percent of such patients had stools


117

positive for the ova. All of these patients had been treated overseas, and it is safe to say that, inadequate as their treatment now seems, it must have been effective in some instances. Table 16 presents a summary of most of the treatment schedules used, especially in the United States, with results of treatment.

TABLE 16.-Treatment schedule and results of treatment of patients infected with S. japonicum, using increasing amounts of trivalent antimony compounds

Treatment schedule1

Trivalent antimony compound

Gram of antimony

Number of patients treated

Treatment failures

Where treated


Faudin (6.4 percent solution)

Tarter emetic (0.5 percent solution)

Number

Percent

 


Cc.

Cc.

 

 

 

 

 

1

40

---

0.35

165

255

33

Overseas.

2

65

---

.57

44

38

85

Harmon General Hospital.

3

65

---

.57

15

15

100

Harmon General Hospital followed at Moore General Hospital.

4

70

---

.61

44

34

77

Moore General Hospital.

5

100

---

.87

32

8

32

Do.

6

105

---

.91

15

6

40

Harmon General Hospital followed at Moore General Hospital.

7

---

290

.52

51

26

51

Moore General Hospital.

8

---

320

.58

59

11

19

Harmon General Hospital.

9

---

320

.58

18

100

55

Harmon General Hospital followed at Moore General Hospital.

10

---

360

.65

100

20

20

Moore General Hospital.

11

---

416

.75

44

3

7

Do.

12

---

416

.75

41

7

17

Harmon General Hospital followed at Moore General Hospital.

1See text (p. 118) for discussion.
2Only observed from 4 to 28 weeks after treatment.

Winkenwerder and his associates,32 while still on Leyte, reported results of treatment of 184 patients with comparatively small amounts of Fuadin. These results are not conclusive because the followup period was not long enough, but the data serve to emphasize that this method of treatment in the early days of the epidemic was not effective. One-third of the patients suffered a relapse before evacuation to the United States interrupted observations. These unsatisfactory results with the doses of trivalent

32Winkenwerder, W. L., Hunninen, A. V., Harrison, T., Billings, F. T., Carroll, D. G., and Maier, J.: Studies on Schistosomiasis Japonica; Analysis of 364 Cases of Acute Schistosomiasis With Report of Results of Treatment With Fuadin in 184 Cases. Bull. Johns Hopkins Hosp. 79: 406-435, December 1946.


118

antimony recommended in the early days of the epidemic were confirmed at the Army tropical disease centers. A final report on 72 cases treated with tartar emetic was published by Carroll and Hunninen.33

It soon became apparent that if the trivalent antimony compounds were to be effective at all, they would have to be given in larger doses. Consequently, several methods of treatment were used, employing one or the other of the two drugs, Fuadin and tartar emetic, and gradually increasing the amounts administered to each patient as more and more was learned of the individual's tolerance to the drug and the parasite's resistance to its effects.

The following were treatment schedules used (see table 16):

1. Fuadin (6.4 percent solution) intramuscular injections on alternate days of 1.5 and 3.5 cc., then 5.0 cc. for 7 doses to a total of 40 cc. in 17 days.

2 and 3. Fuadin (6.4 percent solution) intramuscular injections on 5 successive days of 1.5, 3.5, 5.0, 5.0, and 5.0 cc., then on alternate days 5.0 cc. for 9 doses to a total of 65 cc. in 23 days.

4. Fuadin (6.4 percent solution) intramuscular injections on 3 successive days of 1.5, 3.5, and 5.0 cc., then on alternate days 5.0 cc. for 12 doses to a total of 70 cc. in 27 days.

5. Fuadin (6.4 percent solution) daily intramuscular injections of 2, 4, 6 cc., then 8 cc. for 11 doses to a total of 100 cc. in 14 days.

6. Fuadin (6.4 percent solution) intramuscular injections on alternate days of 5.0 cc. to a total of 105 cc.

7. Tartar emetic (0.5 percent solution) intravenous injections on alternate days of 5, 10, and 15 cc., then 20 cc. for 13 doses to a total of 290 cc. in 31 days.

8 and 9. Tartar emetic (0.5 percent solution) intravenous injections on alternate days of 8, 12, 16, and 20 cc., then 24 cc. for 11 doses to a total of 320 cc. in 29 days.

10. Tartar emetic (0.5 percent solution) intravenous injections on alternate days of 10 and 20 cc., then 30 cc. for 11 doses to a total of 360 cc. in 25 days.

11 and 12. Tartar emetic (0.5 percent solution) intravenous injections on alternate days of 8, 12, 16, 20, and 24 cc., then 28 cc. for 12 doses to a total of 416 cc. in 33 days.

Some interesting considerations as to the results of treatment are suggested by table 17. In the first place, as has been indicated, the observations on patients treated by the first method were terminated too soon by evacuation to the United States, and more than 33 percent undoubtedly relapsed. This conclusion is based on the fact that a much higher percentage of patients relapsed at the tropical disease centers even though they received 65-70 cc. of Fuadin.

33Carroll, D. G., and Hunninen, A. V.: Studies on Schistosomiasis Japonica in Philippine Islands; Clinical Study of 72 Cases Treated With Tartar Emetic. Bull. Johns Hopkins Hosp. 82: 366-372, March 1948.


119

In the second place, it can be definitely stated that tartar emetic is a more effective drug in the treatment of schistosomiasis japonica than is Fuadin under the conditions described here. This conclusion is based on the fact that, by methods 2 and 3 and 8 and 9, approximately the same amount of antimony is administered to the patients yet a higher percentage suffered a relapse in the group receiving Fuadin than in the group taking tartar emetic. There is some discrepancy in the results of treatment by methods 8 and 9, although these methods are identical. This may be accounted for by the fact that the patients under method 8 were treated and followed at Harmon General Hospital, while those under method 9 were treated at Harmon General Hospital and followed at Moore General Hospital. All stools at Moore General Hospital were examined by the concentration method, whereas many at Harmon General Hospital were examined by direct smear alone.

Thirdly, it is of great interest to note that the most effective schedule of treatment was the one that employed the largest amounts of tartar emetic; that is, 416 cc. or 0.75 gm. of antimony. The use of Fuadin, even when as much as 0.91 gm. of antimony was administered, was not so effective. However, relative toxicities are not known.

TABLE 17.-Incidence of minor toxic symptoms of trivalent antimony compounds in patients with schistosomiasis japonica

Trivalent antimony compound

Number of patients treated

Cough

Nausea

Vomiting

Joint and muscle pain

Occasional

Frequent

Occasional

Frequent

Tartar emetic:

 

Percent

Percent

Percent

Percent

Percent

Percent

     Fresh (320 cc.)

36

69

33

17

6

81

---

    

Commercial (320 cc.)

33

58

30

15

6

52

3

    

Fresh (416 cc.)

17

76

24

18

6

24

65

    

Commercial (416 cc.)

16

81

19

13

---

13

81

Fuadin:

 

 

 

 

 

 

 

 

 

    

First course (65 cc.)

33

---

---

---

---

6

3

    

Second course (55 cc.)

25

---

---

4

4

28

28

    

Sixth course (105 cc.)

15

---

---

---

---

---

100


Results of Treatment; Relapses

It was the experience of all observers that trivalent antimony, whether as Fuadin or tartar emetic, even in the early insufficient doses altered the course of the disease as was indicated by subsidence of symptoms, return of the temperature to normal or more nearly so, decrease in the number of leukocytes and eosinophils, and disappearance of ova from the stools, at least temporarily.


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Relapses, when they occurred, were detected in all but very rare cases only by the reappearance of ova in the stools. In a few instances, clinical signs and symptoms recurred, and more frequently the eosinophils again increased in number. In relapses, ova reappeared in the stools in from 4 to 11 weeks after cessation of therapy. Both Moore and Harmon General Hospitals arbitrarily set a 3-month followup period as sufficient time to allow for the reappearance of ova. This time limit was fixed after many patients had been followed without relapse for much longer periods of time. It is possible that further followup of these patients by the Veterans' Administration will indicate that relapse can occur months after the completion of a course of treatment. Numerous very careful and very exhaustive examinations of concentrated specimens of stool are necessary before it can be stated that a patient has been cured of this disease.

Toxicity of Fuadin and Tartar Emetic

A striking fact that has been emphasized by the administration of large amounts of trivalent antimony, either as Fuadin or tartar emetic, to large numbers of patients is that neither of these drugs is as toxic as it was once thought to be. At Harmon General Hospital, 2,100 injections of 0.5 percent solution of tartar emetic in 5 percent glucose and saline were given to 102 patients and the toxic manifestations summarized.34 There were no serious reactions. Table 17 presents the types of reactions that were encountered while using tartar emetic and Fuadin. Transient electrocardiographic changes persisting several days after termination of a course of treatment have been described by Tarr35 at Moore General Hospital and by Schroeder and his associates36 at Harmon General Hospital. The latter analyzed 315 electrocardiograms of 100 patients during various stages of treatment with Fuadin and tartar emetic. They observed increase in the amplitude of P waves in 11 percent of the patients; fusion of ST segment and T waves, in 45 percent; in 99 percent, varying degrees of decrease in amplitude of T waves in all leads resulting in deep inversion in many cases; and in 27 percent, prolongation of the QT interval. They concluded that, since in all cases the changes were transient, they were probably not indicative of cardiac damage nor of serious impairment of cardiac function.

SUMMARY

Approximately 1,300 cases of acute schistosomiasis japonica resulting from exposure to the parasites on Leyte, Philippine Islands, were diagnosed

34See footnote 26 (1), p. 113.
35Tarr, L.: Effect of Antimony Compounds, Fuadin and Tartar Emetic, on Electrocardiogram; Preliminary Report. Bull. U.S. Army M. Dept. 5: 336-339, March 1946.
36Schroeder, E. F., Rose, F. A., and Most, H.: Effect of Antimony on the Electrocardiogram. Am. J.M. Sc. 212: 697-706, December 1946.


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and treated by members of the U.S. Army Medical Department. An opportunity was taken for careful study of the disease in its early stages, and advances were made in methods of diagnosis and treatment.

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