CHAPTER III
Schistosomiasis Japonica
Frederik B. Bang, M.D., andF. Tremaine Billings, Jr., M.D.
INTRODUCTION ON LEYTE
Life Cycle of the Parasite
Schistosomiasis japonica, a disease due to a parasitic worm, Schistosomajaponicum, is found in large areas of China, in a few foci in Japan, and onfour of the larger islands of the Philippines. A strain, apparently of lowpathogenicity for man, is present on Formosa, and there is at least one smallfocus in the Celebes. When the cercariae (larval forms) escape from infectedsnails into fresh water, as in ricefields, swamps, or ponds, they seek asusceptible 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 andin its course find their susceptible host. After burrowing through the skin, andmigrating through the bloodstream and the lungs, they lodge at a later stage ofdevelopment in the liver. By crawling down the portal venous system, they arriveat the branches of the vessels leading from the large intestine or rectum. Afterfertilization of the female by the male which carries her in a groove of hisbody, the female deposits clumps of eggs within the terminal branches of thevessels or in the liver. The embryo develops to a miracidium inside theeggshell. If this egg works its way through the intestinal mucosa, it isextruded in the feces and the miracidium hatches. The miracidium penetratessusceptible snails (if available) and in several weeks develops into a cystlikestage which has within it many cercariae. Thus, an increase in eggs takes placein the definitive host (man, dog, or other appropriate animal), and an increasein the cercariae occurs within the snail.1
Recognition, Incidence, Epidemiology
Before World War II, American experience with acuteschistosomiasis japonica was limited. Most knowledge of the disease had beenderived 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 endemicareas and from occasional acute outbreaks among small numbers of foreignersvisiting or resident in these areas.2
When the campaign to recapture the Philippine Islands wasplanned, it was known that schistosomiasis japonica was endemic in the easternpart of Leyte Island, but its intensity and potential danger were not generallyrealized. A number of preventive and educational measures were undertaken, asdescribed in detail elsewhere,3 and, among theofficers of many of the hospital units that followed up the invasion, there wassome 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 schistosomiasisjaponica burst very suddenly upon a relatively uninformed Medical Departmentearly in the Leyte campaign, in December 1944. The invasion of Leyte hadoccurred on 20 October 1944. During the invasion, many soldiers had frequentcontact with fresh water. Combat troops, patrols, and engineers occupied inbuilding bridges and airports and in repairing roads were frequently infreshwater swamps and streams for short or long periods of time. The value ofprotective clothing was not appreciated. The troops were inadequately informedconcerning the dangers of contact with fresh water, and, when actual fightingdied down, many soldiers bathed, washed clothes and vehicles, and swam ininfested waters.
Late in November and during December, U.S. soldiers wereadmitted to hospitals with symptoms that were sometimes suspected as being dueto schistosomiasis, but for the most part the disease was not recognized. Ova ofS. japonicum were first found in stools of a soldier on Leyte Island, on30 December 1944, by Lt. Walter L. Barksdale, SnC, who was on detached servicewith 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 GeneralHospital, who had suspected the diagnosis and had encouraged a search for theova. It is of interest that on 28 December 1944 in the 132d General Hospital onBiak Island the diagnosis of schistosomiasis had also been made from a liverbiopsy by Capt. Morris Goldberg, MC. The patient was a soldier who had beenevacuated from Leyte with unexplained fever and marked enlargement andtenderness of the liver.
On Leyte during the last week in December 1944, at least 16patients who were subsequently found to have schistosomiasis were admitted tohospitals. Most of these patients came from two organizations-the 51stPortable Surgical Hospital and the 50th Engineer Combat Battalion. During themonths 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 onLeyte.4 These soldiers were from alltypes of units but combat troops, engineers, and artillerymen predominated.
The occurrence of schistosomiasis in the 50th Engineer CombatBattalion provided a unique opportunity, which was taken by Lt. Col. Ralph R.Sullivan, MC, and Capt. Malcolm S. Ferguson, SnC,5to study the epidemiology of the disease. This battalion, numbering 534soldiers, was employed to a large extent in building bridges, but theoccupations and opportunities for exposure varied from company to company andamong the different platoons. The incidence of cases in the battalion wasthoroughly investigated and correlated with the battalion's job roster todetermine the amount of exposure to fresh surface water of the individualcompanies, platoons, and personnel. A paragraph of this paper may be quotedhere:
The attack rate for the battalion was 19.6percent (102 cases as of 31 May 1945) which may be compared with an estimatedXXIV Corps rate of 0.73 percent. The rates increase to 27 and 33 percentrespectively as B and C companies, engaged in bridge construction, areconsidered separately. Moreover, the attack rate increases to the range of 41-53percent as attention is focused on the specific platoons engaged in bridgeconstruction. Finally as the rates are computed for the water-exposedbridge-workers themselves, these range from 71-89 percent in the variousplatoons of B and C Companies. Actually in dealing with the water-exposedbridge-workers it becomes a matter of trying to explain why 100 percent of themwere not infected. Since a number were unfortunately not hospitalized or werenot diagnosed because typical ova could not be demonstrated, the possibility of100 percent infection in this group cannot be eliminated.
Another interesting, circumscribed episode of infectionoccurred among men of the 51st Portable Surgical Hospital. On 16 November 1945,nine members of this unit, including two medical officers, left their bivouac atDulag for Abuyog to obtain medical supplies. As a bridge over a stream laterrecognized as infested with cercariae of S. japonicum was underconstruction, they could proceed no further and decided upon a swim. It isworthy of note that the medical officers commented before entering the water onthe possibility of contracting schistosomiasis but only jokingly, and theydecided to risk it. The stream in question is slow moving, and these officerswere under the impression that the danger in moving water was minimal. Twoofficers and six enlisted men went in for approximately 30 minutes; one enlistedman did not enter the water. In the eight who were in the water, symptoms ofschistosomiasis developed 4 to 5 weeks later; the one who remained on the bankescaped. No other cases of schistosomiasis developed among personnel of the 51stPortable Surgical Hospital. No snails (Oncomelania quadrasi) were foundin 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.
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medical officers of this unit were aware of the existence ofschistosomiasis on Leyte, they had no idea of the very real danger of infectionfrom streams in the immediate vicinity of the hospital. Surveys of the area inquestion had been made for snails, and when none were found an unjustifiedfeeling of confidence in the freedom of the water from cercariae pervaded theunit. The stream is one which runs between Tanuan to the north and Tolosa to thesouth. Of a medical detachment consisting of approximately 500 enlisted men, 164admitted contact with this fresh water or with swamps draining into it. By 30April 1945, 75 of these men had been found to have schistosomiasis by thedemonstration of ova in their stools. Others may have been found to have thedisease at a later date, or may have remained undiagnosed.
Hospital admissions on Leyte Island, for the periodJanuary-May 1945, due to schistosomiasis were listed as follows:6
| Number of cases |
January | 69 |
February | 305 |
March | 313 |
April | 197 |
May | 78 |
|
| 962 |
A breakdown of a random 575 of these cases shows theoccurrence 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 ofschistosomiasis japonica had been diagnosed in American troops infected on LeyteIsland. Comparatively few cases were diagnosed on Leyte after the last of May1945, but other cases were found, as follows:
1. Among units that had been exposed to infested water andhad moved on to more advanced bases before the onset of symptoms. An example7of 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 thesurvey.
2. Among soldiers evacuated from Leyte through medicalchannels for diseases other than schistosomiasis.
3. Among personnel who had been infected immediately beforereturning home on rotation and whose symptoms first occurred either in transitor in the United States.
Disposition of Patients Infected on Leyte
As has been indicated, the theater was not fully prepared tohandle efficiently a sudden outbreak of acute schistosomiasis japonica amongAmerican troops on Leyte. At first, the criteria for diagnosis, the method oftreatment, and the final disposition of these cases were somewhat haphazard andwere decided for the most part by individual hospitals. Some patients withschistosomiasis were evacuated as soon as the diagnosis was made. Others weretreated and then evacuated, while still others were treated and held forobservation.
Finally, a disposition policy, based on suggestions from theSurgeon General's Office, was announced,8 as follows:
Seriously ill cases and those with present evidence ofinvolvement of the central nervous system should be evacuated to the UnitedStates without delay. Other patients who after a course of treatment havepersistent clinical signs or positive laboratory findings should also beevacuated. Mild cases which appear to have been cured and have regained theirprevious state of health may be returned to duty where they can be givenperiodic examinations of their general conditions and of the blood and stoolspecimens 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 allpatients in whom a diagnosis of schistosomiasis japonica had been made beevacuated to the United States, after a course of treatment, for furtherobservation and treatment in the centers designated for the care of tropicaldiseases-Moore General Hospital, Swannanoa, N.C., and Harmon General Hospital,Longview, Tex. This stand was taken by The Surgeon General because it was knownthat followup of these patients was both important and time consuming (by manymonths) and that treatment in many cases would have to be repeated. It wasthought that the number of patients who would have to be evacuated for thiscause 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.
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tion and in clinical evaluation to determine which patientsto keep and which to send home. For this reason, in a letter to section and basesurgeons dated at Headquarters, USAFWESPAC (U.S. Army Forces, Western Pacific),18 July 1945, the theater surgeon directed that all patients with a diagnosis ofschistosomiasis japonica be evacuated to the Zone of Interior. It was emphasizedin this letter that the period of treatment and observation in the theatershould not exceed 120 days and that any soldiers with schistosomiasis, who hadalready been sent to limited duty under previously existing directives, shouldbe rehospitalized and evacuated to the United States.
Actually, after February 1945, very few patients ill withschistosomiasis were seen.9 The majority admitted to hospitalsthereafter had mild or asymptomatic cases, diagnosed by routine examinations ofstools during unit surveys or during hospitalization for other causes.
Postscript from Mindanao
In the early part of December 1945, it was brought to theattention of the Office of The Surgeon General, by the Walter Reed GeneralHospital, Washington, D.C., that the chief of the Tropical Disease Section atthat hospital, Capt. Joseph H. Burchenal, MC, had made a definite diagnosis ofschistosomiasis japonica in five soldiers whose only possible common source ofinfection had been at the Davao Penal Colony, 51 kilometers north-northeast ofDavao, Mindanao, Philippine Islands. Actual exposure to infection was believedto have occurred in the Mactan ricefields, 8 kilometers east of the penalcolony. These soldiers had been prisoners of war, following the surrender of thePhilippine Islands to the Japanese. Some 600 soldiers and sailors were reportedby officers imprisoned there to have survived to return to the United States. Ofthese, it was possible to follow up approximately 50, all of whom were giventhorough tests for schistosomiasis, including examinations of the stools. Thediagnosis was made in approximately 30 of them. It is possible that otherindividuals among these 600 men had schistosomiasis which remained undiagnosed.
THE DISEASE PICTURE
The course of schistosomiasis japonica in all three of itsstages has been discussed in textbooks of tropical medicine. A full descriptionof the early manifestations of the disease is justified here, however, by theextensive experience with American troops infected during the Leyte campaign,affording an unusual opportunity to make numerous observations on the earlyphase of the disease. Hitherto, the repeatedly infected, chronically illpopulations of endemic regions were the principal subjects available for
9See footnote 6, p. 94.
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large-scale study, with, on occasion, much smaller groups ofAmericans and Europeans exposed to the same environment.10
As the three stages into which it is customary to divide thecourse of the disease are continuous, the clinical phenomena attributed to themusually overlap. The first stage includes the period from the penetration of thebody by the cercariae to the settling of the paired worms in the mesentericvenules. The second stage is initiated when eggs are deposited by the femaleworms in the small vessels of the intestinal wall, the liver, or occasionally elsewhere. Allergic manifestations are common at this time. The third stage ischaracterized by proliferation and repair of damaged tissue and by continuedheavy deposition of eggs. The present review will be largely concerned with thesecond stage, when the acute manifestations occur.
It should be reemphasized that this division into stages ispurely for the sake of convenience. Experience with American troops with acuteschistosomiasis japonica on Leyte showed that, in clinically severe andmoderately severe cases, the onset of symptoms was directly associated with thematuration 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 thestools and, in some cases, diagnosed only by the demonstration of ova in thestools, maturation of worms and deposition of ova caused no symptoms.11It seems probable that the severity of symptoms is a measure of the severity ofthe infection.
Billings and his associates, in their clinical study of 337cases of acute schistosomiasis japonica in American troops, including a detailedanalysis of 75 of them, discussed at length the interval of time betweenexposure to infection and the occurrence of symptoms. In 12 cases in which theexact time of the only exposure to infection was known, symptoms first occurredfrom 26 to 58 days after exposure, an average of 42 days. In the remaining 63cases, it was more difficult to estimate this latent period because the time ofexposure varied from several days to several weeks, and penetration of the skinby cercariae could have occurred on any one or all of the days on which theindividual was in contact with fresh water. However, even when contact withinfested water covered a period up to 14 days, the latent period was fairlyuniform. In 14 of the 75 cases analyzed in detail, there was a close correlationbetween the onset of symptoms and the appearance of ova in the stools, and therewas definite indication that the infection was asymptomatic during the period ofdevelopment 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 PhilippineIslands; Clinical Study of 337 Cases With Preliminary Report on Results ofTreatment With Fuadin in 110 Cases. Bull. Johns Hopkins Hosp. 78: 21-56,January 1946.
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SYMPTOMS, PHYSICAL FINDINGS, AND EARLY COURSE
The manifestations and early course of the acute phase of thedisease as it appeared among American troops who took part in the invasion ofLeyte Island are described in the study by Billings and his associates and inseveral other papers.12
Symptoms
"Swimmers' itch," symptomatically the firstpossible indication, occurs very soon after exposure to water infested withcercariae. Its incidence is apparently highly variable. On Leyte, three groups13of patients were carefully questioned about itchingimmediately 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 158patients. The extensive recent work on swimmers' itch, which is due toschistosomes, usually in newly infected men in whom sensitization plays a largerole, should be related to these data.
Following an asymptomatic latent period during which theparasite developed to adulthood, the onset of symptoms was usually abrupt withheadache, chills, feverishness, cough, urticaria, aches, and anorexia of varyingseverity. In some cases, the onset was insidious, and the symptoms in some ofthese remained mild throughout the symptomatic phase and in others wereintensified after several days. In a few instances, the onset was not onlyabrupt but severe or fulminating in character. Lastly, the disease sometimes hadan asymptomatic course; such cases were detected through group surveys. On thebasis of the intensity and severity of symptoms and the height of thetemperature 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, 168cases; and asymptomatic, 25 cases. The incidence of the chief symptoms as shownin table 13, however, is based on 75 cases subjected to detailed analysis. Itshould be stated that this classification is made on clinical grounds only, andit is not known whether the severity of symptoms is necessarily correlated withthe degree of infection.
Moderately severe cases.-Since these cases present the mostcommon symptomatology, they are discussed first. Thesymptoms usually began suddenly with fever, chills, headache, generalized achesand pains, soreness and stiffness of the neck, discomfort in the upper part ofthe abdomen accompanied by anorexia, urticaria, and an irritating dry hackingcough, all or
12(1) Thomas, H. M., and Gage,D. P.: Symptomatology of Early Schistosomiasis Japonica. Bull. U.S. ArmyM. Dept. 4: 197-202, August 1945. (2) Johnson, A. S., Jr., and Berry, M. G.:Asiatic Schistosomiasis; Clinical Features, Sigmoidoscopic Picture and Treatment ofEarly Infections. War Med. 8: 156-162, September 1945. (3) Thomas, H.M., Bracken, M. M., and Bang, F. B.: Clinical and Pathological Picture of EarlyAcute Schistosomiasis Japonica. Tr. A. Am. Physicians 59: 75-81, 1946.
13See footnote 11, p. 97, and footnote 12 (1) and (2).
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some of which lasted from 1 to 8 weeks. The clinical courseof schistosomiasis, acute, moderately severe, is shown in figures 33 and 34.
TABLE 13.-Incidence ofsymptoms in 75 patients with acute schistosomiasis japonica
Symptoms | Patients affected | |
| 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 ofthe disease, subsided partially or entirely in from 2 to 8 days; thereafter, thesymptoms persisted in mild form, or remained completely in abeyance for a weekor two, and then recurred, gradually or sharply. This initial acute illnessoften suggested dengue, atypical forms of which occurred on Leyte. Typical skineruptions of dengue were never noted in these cases, however, in which the acutefebrile period may represent the host reaction to the initial dissemination ofthe ova of S. japonicum.
The first chief complaints in many cases were fever, chills,headache, cough, and urticaria with or without angioneurotic edema; in severalcases, 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 upperquadrants of the abdomen, anorexia, loss of weight, headache, fatigue towardevening, stiff neck, and varied myalgic and arthralgic pains persisted, thoughfluctuating from day to day.
The febrile stage lasted from 1 to 8 weeks; the fever wasremittent and of the saw-toothed type, with the temperature rising sharply to102? to
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101
102
104? F. in the evening and, with rare exceptions, returningto normal or below normal in the morning. Likewise, there was diurnal variationin the intensity of symptoms; the majority of patients felt better or"tolerably" well in the morning but worse in the afternoon andevening, when all symptoms were characteristically intensified.
Urticaria or angioneurotic edema, which was noted in 52percent of the patients, varied from an occasional small and fleeting wheal tolesions of tremendous size. The lesions were indolent and persistent. They werenot strikingly responsive to adrenalin. Swelling of the posterior half of thetongue was noted in one patient, but edema of the fauces and larynx was notseen.
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 wasstriking. Usually, it developed suddenly and lasted from 24 to 48 hours, thensubsided only to recur in several days' time. In one patient, the head washeld rigid, incapable of any movement, for a period of 2 weeks. Lateral rotationwas especially restricted and, less commonly, flexion. This symptom is probablynot due to involvement of the meninges, but is more likely myalgic in origin, assoreness of the trapezius and sternocleidomastoid muscles was elicited onpalpation. Meningitis was occasionally suspected, but examinations of thespinal fluid revealed no abnormalities.
In association with anorexia and discomfort in the upperquadrants of the abdomen, abdominal cramps were frequent, but diarrhea occurredin only 21 patients (28 percent), and then it was not clear whether it was dueto the disease or to an intercurrent infection, as attacks of diarrhea werefairly common among persons on Leyte. More frequently, the bowel movements werenormal or were constipated, sometimes severely so as the disease progressed.Blood in the stools was found rarely and only in the occult form. Anorexia andloss of weight, which in cases of long standing may amount to as much as 40pounds, were prominent features.
A nonproductive cough was sometimes accompanied by moistrales or scattered areas of consolidation, especially at the bases of the lungs,or by diffuse signs characteristic of acute asthmatic bronchitis, whichoccasionally dominated the clinical picture at first. In some cases of thelatter type, the true nature of the disease was not suspected until morecharacteristic symptoms appeared.
Alopecia, which was noted by Hunt14 in several of a series of18 patients who contracted the disease on the adjacent island of Samar, was notseen in this series. Lesions of the skin in which ova of S. japonicum weredemonstrated (fig. 35) were reported in one case of the disease among Americantroops on Leyte.15
14Hunt, A. R.: Schistosomiasis in Naval Personnel, aReport 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 MultipleLesions. Am. J. Trop. Med.26: 319-326, May 1946.
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Mild cases.-The symptoms and physical findings inthisform of the disease were often minimal. In many cases, patients complainedtoward evening of occasional cough, slight feverishness, malaise, headache,fatigability, and anorexia. Occasionally, they had mild discomfort in the upperquadrants of the abdomen, transitory scattered aches and pains, and at timesthey complained of a "crick" in the neck. They did not seek medical attention for days or even weeks, but attributed theirsymptoms merely to the unaccustomed tropical environment. When a patientreported to sick call in the morning, as a rule his temperature was normal andhe felt well, so that the infection was easily overlooked. In fact, such vagueand variable symptoms led to the diagnosis of psychoneurosis in several patientsbefore schistosomiasis was discovered.
FIGURE 35.-Schistosome dermatitis-papular eruption on back.
Physical examination in many cases of this type revealed lossof weight, enlargement of the posterior cervical lymph nodes, tenderness in theepigastrium and right upper quadrant of the abdomen, and a slightly en-
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larged liver. The spleen was seldom palpable. Figure 36illustrates such a mild case with a short episode of low grade fever and minimalabnormal physical findings.
Severe cases.-In 21 of the series of 337 patients, thesymptoms and the clinical course were sufficiently severe to justify thisclassification. Figure 37 illustrates the clinical course of the disease in onepatient of this group. The patients were often prostrated and semicomatose; thetemperature was high and spiking; and the headaches, generalized aches andpains, cough, and anorexia were severe. Enlargement and tenderness of the liverwere more pronounced, and the spleen was uniformly enlarged. In a few patientsin this series, mild anemia was observed. Several in the group of severe caseshad neurologic manifestations which are described later (p. 108).
Asymptomatic cases.-In 25 patients of the 337 studied, thedisease developed without symptoms; no such cases were included among the 75studied in detail. Schistosomiasis was suspected in this group because of knownexposure to infested water or because of the discovery of eosinophilia, eitherduring a routine survey of military units in which other members were known tohave schistosomiasis or during hospitalization for another disease. Theincidence of this type of the disease among troops who were stationed in endemicareas was impossible to estimate and could only be determined by extensivesurveys of such units.
Physical Findings
Table 14 presents a list of the most frequent physicalfindings in the 75 cases of acute schistosomiasis japonica studied in detail.The discussion will be limited to the patients with schistosomiasis of moderateseverity. These patients usually appeared thin, the degree depending, however,on the duration of symptoms. They were sallow and appeared chronically ratherthan acutely ill. In the absence of urticaria, the skin was normal. Enlargementof the posterior cervical lymph nodes, and less often a mild general enlargementof all the lymph nodes, was found. The mucous membranes in some patients werepale. The eyes, ears, nose, mouth, and throat were normal. Since cough was afrequent complaint, one might have expected changes in the lungs, but in mostpatients abnormal pulmonary signs were not elicited. Only five patients in thisseries had objective pulmonary changes. These were seen in roentgenograms asscattered areas of infiltration and patchy consolidation at the base of one orthe other lung. In most instances, the abnormal findings disappeared after 1 or2 weeks. In one severe case observed on Leyte,typical miliary seeding (pseudotubercles) of thelungs was demonstrated roentgenographically.
The heart and blood pressure were normal; the pulse varieddirectly with the temperature. The abdomen was usually flat but occasionallysome-
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TABLE 14.-Incidence ofimportant 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 themidepigastrium where tenderness to palpation and percussion was sometimesexquisite. The liver was tender and palpably enlarged in 92 percent of the 75patients. It extended as much as 5 cm. below the costal margin in someinstances, but in many patients the enlargement was demonstrable only as awidening of the area of dullness. Even in these patients, there was tendernessto deep palpation below the right costal margin and to percussion over the lowercostal area. The spleen was enlarged 67 percent. It occasionally extended asmuch as 4 cm. below the costal margin, but in many instances enlargement wasindicated only by increased dullness over the splenic area. The spleen wasslightly or not at all tender. Although testicular pain was complained of byseveral patients, the genitalia appeared normal.
Sigmoidoscopic Examination
The important sigmoidoscopic studies by Johnson and Berry16of patients with acute schistosomiasis japonica are asignificant contribution to observation of the disease. They examined the lowerpart of the large intestine of 63 patients. The following excerpt from theirreport 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 presentabove in the lower sigmoid. In many cases the nodules were found 4 to 5 cm.below the rectosigmoid junction. There was no ulceration, and definiterelationship to the visible blood vessels was not apparent. The mucosa showed noinflammatory or vascular changes. On biopsy of these lesions many ova werepresent in the tissue removed. All were beneath the mucosa. Some were not asmature as the ova seen in stool examination but could be identified easily.
16See footnote 12 (2), p. 98.
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Following these observations, the examination of the lowerpart of the large intestine by means of a sigmoidoscope became a routineprocedure in all hospitals caring for patients with schistosomiasis japonica andin the tropical disease centers in the United States. This examination wasespecially valuable as an aid to definite diagnosis of the disease in cases inwhich difficulty was encountered in finding ova in the stools. It was alsoparticularly helpful as an aid to determining whether treatment of the diseasehad been effective. The appearance of characteristic nodules in the intestinalmucosa after a course of treatment was completed was highly suggestive of thepersistence of live worms in the portal system. A biopsy of such a nodule inwhich ova with live miracidia could be demonstrated furnished proof that a curehad not been obtained, and further treatment was instituted.
Later observations enlarged on the findings of Johnson andBerry. At the 118th General Hospital, small ulcerations were demonstrated,scrapings of which yielded ova. At Harmon General Hospital, 300 patients wereexamined by proctoscope.17 In only three were lesions demonstrated.These were described as "single, flat, oval, moderately induratedgranulomata, 0.5 to 2.0 cm. in their longest diameter. These were 7, 10, and 15cm., respectively, from the anus. They were well demarcated and the low gradeinflammatory appearance did not extend to the surrounding normal mucosa."These lesions were described as bleeding easily with the traumata of theproctoscope, and ova were demonstrated in biopsies of them. In 46 sigmoidoscopicexaminations at Moore General Hospital,18 33 patients were found"abnormal," but only 1 had a polyp and 1 a small nodule, bothcontaining ova of S. japonicum.
Neurologic Manifestations
During the period from the invasion of Leyte on 20 October1944 to March 1946, groups of U.S. Army medical officers reported 33 new casesof schistosomiasis japonica of the central nervous system among Americans whowere on that island.19 These and other cases are fully summarized in a reviewof a large number of patients with neurologic signs and symptoms by Kane andMost.20 It is possible that other cases of this type appeared
17Mason, P. K., Daniels, W. B., Paddock, F. K., andGordon, 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 AmericanMilitary 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, andfootnote 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 HopkinsHosp. 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 ofCase. 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 andReview of the Literature. Arch. Neurol. & Psychiat. 59: 141-183, February1948.
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from time to time as later manifestations of the disease, butcertainly they were few, and it may be said that, among almost 1,300 cases ofthe disease diagnosed, neurologic involvement occurred in approximately 2.5percent.
Nevertheless, further details and observations relating tothe neurologic picture associated with schistosomiasis japonica as it appearedamong American troops seem worthy of consideration and discussion. Data from thereview of this subject by Kane and Most and from the studies of Billings andhis associates have been drawn upon heavily in the preparation of thisdiscussion and description.
Previous workers have well established the fact that theneurologic manifestations are probably due to the presence of ova of S. japonicum in the substance of the centralnervous system.21 No new light has been thrown on the subject of how these ovaarrive there. Although Shimidzu refers to the fact that a second Japaneseinvestigator, Fujinami, found worms in the cerebral veins of monkeys exposed toa very heavy concentration of cercariae, no reports have been found in whichworms have been observed in operative or autopsy material from human brains.This does not preclude the possibility that adult forms may be present incerebral blood vessels at some distance from the main pathological processincited by the ova. Although some ova may filter through the liver-lung barrierfrom the portal system and reach the central nervous system, it is difficult toexplain the occurrence of "nests" of eggs within the brain by thedeposition of eggs in areas other than the cerebral veins. It should beemphasized that the discovery of adult worms in thrombosed veins at post mortemis difficult if the veins are full of blood.
Many of the gross and microscopic findings from localizationof these ova in the central nervous system had been described before theexperience with the disease in American troops in World War II. Suffice it tosay that the ova have now been demonstrated in practically all areas of thebrain but seem to have been found in greater abundance in the pia-arachnoid, thecortex, the subcortex, the basal ganglia, the internal capsules, and thechorioid plexuses of the lateral ventricles.
With such a wide distribution of the ova, it is notsurprising that, when the central nervous system is involved, the neurologicsymptoms and other manifestations are protean.
Clinically, a striking feature of the complication is thesuddenness of the onset regardless of whether the neurologic signs and symptomsoccur in association with the first acute stage of the disease or as a latermanifestation. Kane and Most, analyzing 18 neurologic cases, found that theaverage interval from the time of first potential exposure to the onset ofneurologic manifestations was 14 weeks with a range of from 6 to 36 weeks. Theaverage 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.
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systemic symptoms to the occurrence of signs and symptomsreferable to the central nervous system was 5.3 weeks with a range of from 3days to 24 weeks. The neurologic manifestations were the presenting features ofthe disease in two of their cases.
The intervals from first exposure to manifest involvement ofthe 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 ofschistosomiasis 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, dependingon the location of the ova in the brain, the number present, and the rate ofdevelopment and repression of the inflammatory process.
In addition to the usual indications of infection with S.japonicum, patients with involvement of thenervous system may exhibit a variety of other symptoms. Kane and Most tabulatedthe significant symptoms occurring in their cases of neurologic schistosomiasis(table 15) and discuss the significance of the most outstanding. Althoughheadache was experienced by all the patients on whom they report, they foundthat for the most part it was either transitory or intermittent in character andof little value in localizing the lesion. In a few of their patients, it was asevere and persistent complaint, and, in three out of four patients on whom anoperation was eventually performed for a brain lesion the headache was locatedover the area where the pathological process was found.
There were disturbances of the sensorium at some time duringthe course of illness in all of the 18 patients. This varied from momentaryperiods of confusion resembling petit mal attacks to prolonged periods ofunconsciousness lasting hours, especially in those with convulsive seizures.Disorientation and confusion was a striking feature and in six patients lastedas long as 2 weeks. Many of this group of patients were listless and apatheticfor several weeks but four showed marked restlessness, at times bordering mania.Of the four patients operated upon, all experienced convulsions of one type oranother with coma lasting up to 12 hours. All types of seizures were noted-sensory,motor (Jacksonian, tonic-clonic, adversive, atypical), and psychomotor-andthese were associated with a variety of transient sequelae-motor aphasia,cranial nerve and visual field defects, alexia, micropsia, plus pyramidal tractdefects usually consisting of hemiparesis or hemiplegia.
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Symptoms | Patients affected | |
| 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 ofsight, and visual field defects were noted in a few patients who were found atoperation to have granulomatous tumors.
Disturbance of the higher speech centers was noted in 10 ofthe 18 patients. These were usually transitory in nature and varied from slightinability to use the right words or slurring to true motor aphasia.
Weakness in one or more extremity was observed in all 18patients. The onset of this phenomenon was usually sudden, and the type ofparalysis consisted in the different cases of hemiplegia, quadraplegia,hemiparesis, or paralysis of one extremity. In some patients, the paralysis wasflaccid; in others, spastic; and, in one, it was mixed, the patient havingspastic paralysis of the upper extremities and flaccid paralysis of the lowerextremities.
Kane and Most conclude on the basis of the neurologicfindings that in practically all their cases there was diffuse encephalitis andinvolvement of the pyramidal tracts. In several of them, the nuclei of some ofthe cranial nerves seemed to be involved, and in others there appeared to bechanges in the cerebellum. In those patients on whom operations for brain tumorwere performed, lesions were chiefly found in the left parietotemporal oroccipital lobes.
LABORATORY FINDINGS
Stool Examinations
Final diagnosis of schistosomiasis japonica depended on thedemonstration of the characteristic ova of the parasite either in the stools orin the
112
tissues of the patient. In the great majority of cases seenduring the outbreak among American troops on Leyte, ova were found in the stoolsbefore a diagnosis was definitely made and treatment begun. It was the generalpolicy both overseas and in the hospitals in the United States to withholdtreatment until ova had been demonstrated, except in severe cases requiringimmediate treatment. This was considered a sound policy because other parasiticinfections were extremely prevalent, and sometimes mimicked acuteschistosomiasis. It was thought that in almost every case of schistosomiasis,ova could be demonstrated if enough stools were examined by trained personneland if routine proctoscopic examinations were made.
The following difficulties were, however, encountered in thedemonstration of ova, especially during earlier days of the outbreak:
1. In many cases, especially the mild ones, ova were presentin the stool in relatively few numbers. However, in some mild cases, ova weredemonstrated in the first stool examined, while in occasional severe cases asmany as 15 to 20 stool specimens were examined before ova were found.
2. Many laboratory officers were not familiar with theappearance of the ova of S. japonicum in all its stages of development, and confusion arose between identificationof vegetable cells and maturing and degenerating ova. Vogel22 had described theova of S. japonicum in all stages. In addition, a manual based on a series of studies in locallyinfected dogs was written and illustrated by Lt. N. G. Hairston, reproducedlocally, and distributed by the Office of the Surgeon, USAFFE. Thesepublications were of great assistance in the training of laboratory officers.Where immature ova were present in a stool, mature ova could also be found, andit was safer and less likely to be confusing to base a definite diagnosis of thedisease on mature ova containing miracidia.
3. The technique used to find ova in stools was tedious andnecessitated painstaking and thorough adherence to procedure. Many laboratoryofficers were not familiar with the best technique, and faced with hundreds ofsuspected cases the problem of careful stool examinations on all of them was inmany instances overwhelming. Varied techniques were employed reflecting thediversity of training and differences of opinion among laboratory officers as tothe most efficient method.
It soon became clear that, inaddition to the direct examination of any bloody mucous that might be present inthe stool, some method of concentrating the eggs from a larger portion of thestool was worthwhile, and a number of techniques were compared. A methodoriginally described by Hunninen23 was frequently used. Baroody and Most24at the Moore General Hospital concluded that among avariety of techniques, including acid ether,
22Vogel, H.: Ueber Entwicklung, Lebensdauer und Tod der Eiervon 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 ofStool Examination for Diagnosis of Schistosomiasis Japonica. J. Lab. & Clin.Med. 31: 815-823, July 1946.
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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.
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genograms of the lungs28 andoccurred five times in 75 cases analyzed in detail by Billings and hisassociates. For the most part, these abnormal findings were present for only ashort time, a matter of 1 or 2 weeks, and only in the severe or moderatelysevere 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 smallvessels of the portal system, it would have been of interest to know the effectof this seeding upon that organ. Unfortunately, however, no studies werereported relating to hepatic function in the acute phase of the disease. On theother hand, Lippincott and his associates,29 at Harmon GeneralHospital, studied the hepatic function of patients with schistosomiasis japonicawho had been evacuated to the United States after the acute phase. In thisstudy, they used several tests including determinations of Bromsulphalein (sulfobromophthalein)retention, galactose tolerance, hippuric acid excretion, icterus index, serumbilirubin, formol-gel reaction, and urinary urobilinogen in serial dilutions.They found that diminution of hepatic function was minimal and were inclined toattribute the abnormal findings to the antimony used in treatment.
Spinal Fluid Examinations
Lumbar punctures and examinations of the spinal fluid werecarried out only in those cases in which the central nervous system wasapparently damaged. In the acute stage overseas, abnormal findings were limitedto an increased cellular content of the fluid in a few cases. In by far thegreatest number of examinations, the spinal fluid was normal. The amounts ofglobulin and protein and the patterns of colloidal gold curves were notreported. There was an increase in the protein and globulin content of thespinal fluid in a few of the neurologic cases studied in the United States, anda 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 overseahospitals, patients with schistosomiasis japonica were evacuated to the Zone ofIn-
28Weinberg, H. B., and Tillinghast, A. J.: PulmonaryManifestations 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 inSchistosomiasis Japonica, With Particular Reference to Antimony Treatment andWith Report of 2 Autopsies. Arch. Int. Med. 79: 62-76, January 1947.
30See footnote 21 (2), p. 109.
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terior. On reaching the United States, they were sent to oneor the other of two centers for the study of tropical diseases in the Army,Moore General Hospital or Harmon General Hospital. Each hospital receivedapproximately 600-650 patients with this diagnosis. Three very completereports of the disease as observed following the acute stage, in the so-calledlatent stage, at these hospitals were prepared for publication by Most and hisassociates (p. 108) and by Mason and his associates (pp. 108 and 113). FromHarmon General Hospital, a thorough evaluation of the clinical status at thetime of initial examination and during followup of 300 patients31diagnosed and treated overseas was reported. Thesepatients appear to be a representative cross section of all those received atthe two tropical disease centers, although it should be noted that they wereprobably as a group more severely infected than those patients received fromoverseas at a later date, who not only had less severe acute manifestations ofthe disease but had been treated more extensively before evacuation to the Zoneof Interior. Suffice it to say that these 300 patients received at HarmonGeneral Hospital were in strikingly good physical condition. None were acutelyill, although 255 (85 percent) had a combination of residual complaints ofrelatively mild degree, such as abdominal discomfort (155), weakness (75), andheadache, myalgia, and nervousness (186); positive stools were obtained in 76(30 percent) of the 255 patients. Of 46 (15 percent) patients with nocomplaints, positive stools were obtained in 17 (38 percent). The liver andspleen were palpable in 32 and 4 patients, respectively. All patients had lostweight. The general condition of the 300 patients was such that for only 6 didfurlough have to be delayed beyond the initial 2-week period of evaluation. Allof 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 veryfew of the neurologic complications cleared up before evacuation to the UnitedStates, and in addition several cases were reported in which signs referable tothe central nervous system developed as a late manifestation (p. 110). The general prognosis for patients with schistosomiasis japonica ofthe central nervous system does not seem to be favorable as far as completerecovery is concerned, though marked improvement of function has been observedin most cases.
TREATMENT AND RESULTS
Methods
Before experience with schistosomiasis japonica in American troops, noopportunity had presented itself to study various methods of treatment of thisdisease in large numbers of acutely infected individuals. Observations had forthe most part been limited to patients chronically infected and reinfected,living in endemic areas where adequate followup studies were impossible, and onecould not be sure of the duration of the disease before treatment nor of theamount of reinfection occurring during and after treatment. In a few isolatedinstances where small numbers of individuals were infected by brief exposureto infested water, adequate followup studies on the efficacy of the treatmentemployed were not reported. The epidemic of schistosomiasis on Leyte brought theArmy Medical Department face to face with the challenging problem of determiningwhat the best method of treatment was. If the known methods of therapy were noteffective, new ones would have to be evolved.
The drugs accepted as most useful in treating this infection before World WarII were the trivalent antimony compounds, Fuadin (stibophen) and tartar emetic,which contain 13.6 percent and 36 percent antimony, respectively. Emetine andAnthiomaline (lithium antimony and thiomalate) were quickly shown to beineffective. The data to be presented deal with the use of Fuadin and tartaremetic.
Before the epidemic on Leyte, little was known by the Army Medical Corpsabout the toxicity to man of large amounts of trivalent antimony or about itsparasiticidal properties against S. japonicum. It was used carefully and, as it turned outlater, too sparingly in the beginning. No complete studies are availableregarding the results of treatment overseas, for the most part with amounts ofantimony now known to be much less than adequate for a complete cure. It issignificant, however, that of 300 patients diagnosed as being infected with S.japonicum in oversea hospitals, in thelarge majority on the basis of positive stool examinations, only 31 percent werefound to have positive stools on arrival at Harmon General Hospital. At MooreGeneral Hospital, closer to 45 percent of such patients had stools
117
positive for the ova. All of these patients had been treatedoverseas, 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 ofmost of the treatment schedules used, especially in the United States, withresults of treatment.
Treatment schedule1 | Trivalent antimony compound | Gram of antimony | Number of patients treated | Treatment failures | Where treated | ||
| Tarter emetic (0.5 percent solution) | Number | Percent | ||||
|
| 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 amountsof Fuadin. These results are not conclusive because the followup period was notlong enough, but the data serve to emphasize that this method of treatment inthe early days of the epidemic was not effective. One-third of the patientssuffered a relapse before evacuation to the United States interruptedobservations. 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 WithReport of Results of Treatment With Fuadin in 184 Cases. Bull. JohnsHopkins Hosp. 79: 406-435, December 1946.
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antimony recommended in the early days of the epidemic wereconfirmed at the Army tropical disease centers. A final report on 72 casestreated with tartar emetic was published by Carroll and Hunninen.33
It soon became apparent that if thetrivalent antimony compounds were to be effective at all, they would have to begiven in larger doses. Consequently, several methods of treatment were used,employing one or the other of the two drugs, Fuadin and tartar emetic, andgradually increasing the amounts administered to each patient as more and morewas learned of the individual's tolerance to the drug and the parasite'sresistance to its effects.
The following were treatment schedules used (see table 16):
1. Fuadin (6.4 percent solution) intramuscular injections onalternate days of 1.5 and 3.5 cc., then 5.0 cc. for 7 doses to a total of 40cc. in 17 days.
2 and 3. Fuadin (6.4 percent solution) intramuscularinjections on 5 successive days of 1.5, 3.5, 5.0, 5.0, and 5.0 cc., then onalternate days 5.0 cc. for 9 doses to a total of 65 cc. in 23 days.
4. Fuadin (6.4 percent solution) intramuscular injections on3 successive days of 1.5, 3.5, and 5.0 cc., then on alternate days 5.0 cc. for12 doses to a total of 70 cc. in 27 days.
5. Fuadin (6.4 percent solution) daily intramuscularinjections of 2, 4, 6 cc., then 8 cc. for 11 doses to a total of 100 cc. in 14days.
6. Fuadin (6.4 percent solution) intramuscular injections onalternate days of 5.0 cc. to a total of 105 cc.
7. Tartar emetic (0.5 percent solution) intravenousinjections on alternate days of 5, 10, and 15 cc., then 20 cc. for 13 doses to atotal of 290 cc. in 31 days.
8 and 9. Tartar emetic (0.5 percent solution) intravenousinjections on alternate days of 8, 12, 16, and 20 cc., then 24 cc. for 11 dosesto a total of 320 cc. in 29 days.
10. Tartar emetic (0.5 percentsolution) 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 (0.5percent solution) intravenous injections on alternate days of 8, 12, 16, 20, and24 cc., then 28 cc. for 12 doses to a total of 416 cc. in 33 days.
Some interesting considerations as to the results oftreatment are suggested by table 17. In the first place, as has been indicated,the observations on patients treated by the first method were terminated toosoon by evacuation to the United States, and more than 33 percent undoubtedlyrelapsed. This conclusion is based on the fact that a much higher percentage ofpatients relapsed at the tropical disease centers even though they received 65-70cc. of Fuadin.
33Carroll, D. G., and Hunninen, A. V.: Studies onSchistosomiasis Japonica in Philippine Islands; Clinical Study of 72 CasesTreated With Tartar Emetic. Bull. Johns Hopkins Hosp. 82: 366-372, March 1948.
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In the second place, it can be definitely stated that tartar emetic is a moreeffective drug in the treatment of schistosomiasis japonica than is Fuadin underthe conditions described here. This conclusion is based on the fact that, bymethods 2 and 3 and 8 and 9, approximately the same amount of antimony isadministered to the patients yet a higher percentage suffered a relapse in thegroup receiving Fuadin than in the group taking tartar emetic. There is somediscrepancy in the results of treatment by methods 8 and 9, although thesemethods are identical. This may be accounted for by the fact that the patientsunder method 8 were treated and followed at Harmon General Hospital, while thoseunder method 9 were treated at Harmon General Hospital and followed at MooreGeneral Hospital. All stools at Moore General Hospital were examined by theconcentration method, whereas many at Harmon General Hospital were examined bydirect smear alone.
Thirdly, it is of great interest to note that the most effective schedule oftreatment was the one that employed the largest amounts of tartar emetic; thatis, 416 cc. or 0.75 gm. of antimony. The use of Fuadin, even when as much as0.91 gm. of antimony was administered, was not so effective. However, relativetoxicities are not known.
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 veryrare cases only by the reappearance of ova in the stools. In a few instances,clinical signs and symptoms recurred, and more frequently the eosinophils againincreased in number. In relapses, ova reappeared in the stools in from 4 to 11weeks after cessation of therapy. Both Moore and Harmon General Hospitalsarbitrarily set a 3-month followup period as sufficient time to allow for thereappearance of ova. This time limit was fixed after many patients had beenfollowed without relapse for much longer periods of time. It is possible thatfurther followup of these patients by the Veterans' Administration willindicate that relapse can occur months after the completion of a course oftreatment. Numerous very careful and very exhaustive examinations ofconcentrated specimens of stool are necessary before it can be stated that apatient has been cured of this disease.
Toxicity of Fuadin and Tartar Emetic
A striking fact that has been emphasized by theadministration of large amounts of trivalent antimony, either as Fuadin ortartar emetic, to large numbers of patients is that neither of these drugs is astoxic as it was once thought to be. At Harmon General Hospital, 2,100 injectionsof 0.5 percent solution of tartar emetic in 5 percent glucose and saline weregiven to 102 patients and the toxic manifestations summarized.34 There were noserious reactions. Table 17 presents the types of reactions that wereencountered while using tartar emetic and Fuadin. Transient electrocardiographicchanges persisting several days after termination of a course of treatment havebeen described by Tarr35 at Moore General Hospital and by Schroeder and hisassociates36 at HarmonGeneral Hospital. The latter analyzed 315 electrocardiograms of 100 patientsduring various stages of treatment with Fuadin and tartar emetic. They observedincrease in the amplitude of P waves in 11 percent of the patients; fusion of STsegment and T waves, in 45 percent; in 99 percent, varying degrees of decreasein 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, sincein all cases the changes were transient, they were probably not indicative ofcardiac damage nor of serious impairment of cardiac function.
SUMMARY
Approximately 1,300 cases of acuteschistosomiasis japonica resulting from exposure to theparasites on Leyte, Philippine Islands, were diagnosed
34See footnote 26 (1), p. 113.
35Tarr, L.: Effect of Antimony Compounds, Fuadin andTartar 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.: Effectof Antimony on the Electrocardiogram. Am. J.M. Sc. 212: 697-706, December1946.
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and treated by members of the U.S. Army Medical Department. An opportunitywas taken for careful study of the disease in its early stages, and advanceswere made in methods of diagnosis and treatment.
