The American Journal of Tropical Medicine and Hygiene - Volume 2, Issue 5, September 1953

The present century and the last years of the 19th form an epoch that will be marked in the annals of medicine by its immense progress in elucidating the etiology and the mode of transmission of tropical diseases and in deducing therefrom measures to prevent them. Inductive and deductive epidemiology, in searching for sources of infection, recognized rather early in this period the relationship of three genera of mosquitos to the transmission of filariasis, malaria and yellow fever, the rôle of ticks in Texas fever and the tsetse fly in African sleeping sickness. In this era also falls the first experimental proof of insect transmission of a plant disease: in 1891, Waite showed that bees and wasps, while visiting pear blossoms in search of nectar, are active vectors of bacteria causing fire blight of pears.

But at the beginning of this period the concept of infection chains; in fact, the biologic approach to the solution of the living contagia, had not been formulated.

The effect of single and multiple doses of pyrimethamine (Daraprim) against blood- and sporozoite-induced Plasmodium gallinaceum infections in chicks was examined. When administered twice daily for 4 days, the maximum tolerated dose for the chick was 0.016 mg./gm.; the minimum effective dose, 0.00002 mg./gm.; the drug was completely prophylactic at 0.00025 mg./gm. and partially prophylactic at 0.00003 mg./gm. When administered as a single dose, the minimum effective dose was 0.00025 mg./gm.; the completely prophylactic dose, 0.004 mg./gm.; and the partially prophylactic dose, 0.0005 mg./gm. When chicks were pretreated with single doses of pyrimethamine, about 50 per cent of the antimalarial activity disappeared per day. Single doses of 0.005 mg./gm. given to chicks with well established sporozoite-induced infections prevented deaths from tissue forms, but doses as high as 0.016 mg./gm. did not cure the infection.

This study was undertaken to evaluate the protective and therapeutic efficacy of pyrimethamine (Daraprim) against Chesson strain Plasmodium vivax in human volunteers. The drug was highly effective as a suppressive agent, 0.8 to 25 mg. gave complete protection during drug administration; it was less efficient when used for therapy of acute attacks. Pyrimethamine does not appear to be a true causal prophylactic although prolonged delays before patent parasitemia suggested some deleterious effect against early tissue stages of the parasite. Weekly administration of the drug for 8 or more weeks resulted in suppressive cure of many infections. Probably the greatest usefulness of the drug will be for routine suppression.

Pyrimethamine (Daraprim) was given to 12 healthy volunteers for 49 days at a dosage of 25 mg. single dose daily. Six subjects developed a megaloblastic type of anemia with rapid remission when the drug was stopped.

A more than twenty-five-fold resistance to pyrimethamine was induced in the Chesson strain of Plasmodium vivax by treating blood-inoculated infections with gradually increasing dosages of the drug over prolonged periods. This acquired resistance was transferable by the mosquito. These pyrimethamine-resistant infections were also resistant to chlorguanide but remained as sensitive to chloroquine as the parent strain. Because the development of resistance was obtained only after careful planning and execution, it appears doubtful if resistance will become a serious problem under field conditions.

Eighty-two Hondurans were treated for malaria with 7-chloro-4-[4-(N-ethyl-N-β-hydroxyethylamino)-1-methylbutylamino] quinoline diphosphate (Plaquenil). Sixty-eight of them (21 with P. falciparum, 47 with P. vivax) were given a single oral dose of 1.25 gm. Fourteen others with P. falciparum infections were given an intravenous dose of 0.36 gm. in 500 cc. of normal saline solution. Both the immediate and the late results were encouraging. Toxic side-effects of the drug were not encountered. Plaquenil, therefore, warrants further investigation; its experimental use will be continued in this and other locations.

To find the most suitable location for an antimalarial drug evaluation project, 160 places in 14 states of the Republic of Guatemala were surveyed in 1948 and 1949. Malaria parasites were found in 3,106, or 13.27 per cent of 23,390 blood films taken during the surveys, and splenomegaly was found in 1,474 or 19.41 per cent of 7,694 examinations. The parasite incidence ranged from zero in the highlands to as high as 60 per cent in the lowlands. Correspondingly high spleen indices were also found in the lowlands. The percentages of the species of parasites found were: Plasmodium vivax 51.5 per cent, P. falciparum 45.9 per cent, P. malariae 2.6 per cent, species undetermined 16.8 per cent, and multiple infections 2.0 per cent. The parasite indices were highest in children and women and lowest in men and infants. The spleen indices were highest in the older children. The principal vector of malaria in the regions surveyed was Anopheles albimanus.

The trials of suppression by chloroquine and chlorguanide were conducted in six areas on the Pacific coastal plain in southern Guatemala. In each area part of the population was treated with chloroquine, part with chlorguanide, and the remainder served as the control. Four population groups received weekly treatments, and two groups received treatment every two weeks. The experimental populations consisted of 2,087 people. The individuals on the weekly regimens of chloroquine, chlorguanide and placebo totaled 538, 683, and 337, respectively. In the biweekly treatment groups, 229 received chloroquine, 73 chlorguanide, and 227 served as the control. Mass movements of the population occurring during treatment periods accounted for the uneven numbers available for study in some groups.

With weekly chloroquine treatments, the incidence of malaria was reduced from 23.1 per cent to 5.3 per cent, and increased to 9.0 per cent in the follow-up period. The parasite index in the chlorguanide-treated groups dropped from 25.9 per cent before treatment to 14.6 per cent during treatment, and was 14.5 per cent after treatment was discontinued. In the control group, parasite indices increased from 18.2 per cent at the base-line to 27.4 per cent during treatment, and dropped to a low dry-season level of 16.9 per cent in the follow-up period. Chloroquine treatments appeared to reduce the spleen index and the size of the average enlarged spleen. Chlorguanide did not appear to affect the spleen index, but seemed to cause a slight reduction in the average enlarged spleen. Treatments were about equally effective in all ages.

Chloroquine more effectively suppressed both P. vivax and P. falciparum than chlorguanide. The gametocyte rate of P. falciparum rose from 55.7 per cent in the pre-treatment period to 77.6 per cent during treatment; a corresponding increase was noted in the controls, in which the gametocyte rate was 54.7 per cent in the pre-treatment period, 63.8 per cent in the treatment period, and 77.7 per cent in the post-treatment period. About 50 per cent of the blood films with falciparum gametocytes also showed ring forms.

Even in individuals taking treatment irregularly, there was a decrease in parasitemias with the increase in the number of treatments taken. Thus, most of the positives, found in the 151 persons given chlorguanide, and in the 31 persons given chloroquine, were reported in individuals who had received but few treatments. Even a small number of doses of chloroquine rapidly and effectively cleared both vivax and falciparum parasitemias. On the other hand, with falciparum at least four doses of chlorguanide were required to obtain results comparable to one treatment with chloroquine.

Biweekly treatments with either drug were not as effective as weekly treatments.

A report is given of a case of visceral leishmaniasis diagnosed and treated in Dhahran Hospital, northeastern Saudi Arabia, the first autochthonous case from Saudi Arabia to be reported in medical literature.

The acquisition of liver specimens for histopathologic examination from monkeys during the activity of the current epizoötic of yellow fever in Costa Rica has demonstrated that the progress of a wave of the sylvan (jungle) form of the disease can be traced in this manner as well as by similar studies on human fatalities. Out of 35 specimens obtained in Costa Rica, 24 are considered to exhibit the typical liver lesion. It was possible to secure satisfactory specimens in only about 10 per cent of the investigations of the reports of the presence of dead monkeys in the localities involved. An analysis of this experience will be applied to the formulation of a project designed to attempt to check the movement of the wave in the vicinity of La Ceiba, Honduras, in order to prevent involvement of northern Guatemala and Yucatan.

The histopathologic features of yellow fever in the livers and kidneys of the arboreal primates closely parallel those found in man. The Councilman necrosis in the liver, as well as the heme casts, basophilic concretions and colloid material (“lime casts”) in the kidney tubules are highly resistant to postmortem autolysis. Intranuclear acidophilic inclusions (Torres bodies) were found in a large percentage of the monkey livers, and an evaluation of their diagnostic significance is now in progress.

A strain of rabbit-adapted “B” virus (Sabin and Wright, 1934) has been successfully transmitted intracerebrally to 1-day-old White Leghorn chicks. Virus from a chick-brain suspension of the 5th intracerebral passage was transmitted successfully to baby chicks by the following routes of exposure: intraperitoneal, intrarectal, intradermal, intracardial, intramuscular, intralingual, intranasal, and intracerebral. Baby chicks showed typical symptoms of “B” virus disease between 3 and 4 days after inoculation.

Female albino mice were re-exposed to cercariae of Schistosoma mansoni at intervals of one hour, five hours, one day, two days, one week, one month and two months after an original exposure, together with previously unexposed control mice. Exposures were to 50 cercariae per mouse by tail for one hour. For all except the longest interexposure interval the parasites of the initial and challenging infections were tagged by their sex, and the mice were initially exposed at the age of about six weeks. When the interval between exposures was two months, each exposure was to both male and female cercariae, and the initial infection was presented to the mice when they were one week old. In all studies autopsies were performed six weeks after the second exposure.

The following conclusions have been drawn:

• 1.  The percentage of schistosomes maturing from the challenging exposure in the superinfected mice was significantly reduced below that in the control mice when the interexposure interval was one hour, five hours, one day and two months.
• 2.  On the other hand, the number of adult schistosomes maturing in the superinfected mice from challenging exposures presented two days, one week and one month after the initial exposure was essentially equal to that from specific control exposures.
• 3.  This reduction was the result of a local inhibition of penetration by the cercariae of the challenging exposure when the second exposure followed the first by an interval of one hour, five hours and one day. Each exposure was to cercariae of one sex only.
• 4.  When the interexposure period was longer than one day, no significant inhibition of penetration was noted. No clue was found to the mechanism of reduction of the worm burden from the challenging exposure when it was presented two months after the original exposure.

• 1.  The histopathological lesions produced in bisexual infections with Schistosoma mansoni in experimentally infected mice, hamsters, rats, guinea pigs and rabbits have been described, and have been compared with those produced by S. japonicum and S. haematobium.
• 2.  In hosts in which the worms mature with greatest rapidity and attain the largest size, fertile eggs are deposited in, or are carried to, the smallest blood vessels. The most typical lesions are those seen in the liver. They are circumscribed, are more or less acute at first, develop into a characteristic pseudotubercle and finally result in a scar. The intensity of the pathology depends upon the number of eggs deposited.
• 3.  In hosts in which the worms mature slowly and remain relatively small, egg deposition is delayed and most of the eggs may be unfertilized and appear as collapsed shells, producing little or no acute reaction or ultimate scarring of the tissue.
• 4.  The eggs of S. japonicum usually produce more severe lesions than those of S. mansoni or S. haematobium, partly because they are often deposited in large groups, and partly because each fertilized egg seems to exert a more acute toxic effect on the surrounding tissue.
• 5.  Living worms in terminal vessels do not apparently stimulate a tissue reaction, but dead worms stimulate thrombosis of the vessel and an intense perivascular reaction which leads to disappearance of the worm, scar formation and often recanalization of the vessel. Dead worms are found more frequently in unsuitable hosts.
• 6.  In the liver periportal infiltration of leucocytes, described previously in unisexual infections, is also found in bisexual infections. It is more acute and extensive in early infections than later and is more frequent and intense in S. mansoni than in S. japonicum and S. haematobium infections. It does not appear to contribute significantly to ultimate fibrosis of the liver and is interpreted as an allergic reaction to the worms inhabiting the portal-mesenteric veins.
• 7.  Areas of red-staining “coagulative necrosis” of liver parenchyma, previously described in unisexual infections, are also sometimes found in bisexual infections regardless of the duration of the infection. They may represent infarcts caused by occlusion of a portal venule or hepatic arteriole.
• 8.  In the animals studied there was no visible evidence that the mere presence of living worms in the portal-mesenteric veins contributed significantly to the development of cirrhosis of the liver.
• 9.  In the mucosa and submucosa of the intestine fertile eggs often do not stimulate much tissue reaction, but in the muscularis and serosa the egg lesions are similar to those in the liver.
• 10.  In the urinary bladder lesions produced by eggs of S. japonicum and S. haematobium are similar to those in the intestine.
• 11.  Eggs and adult worms of all three species were found in the lungs in some animals of each species employed in these experiments. This was probably the result mainly of migration of worms from the portal-mesenteric veins through anastomoses into the pelvic systemic veins or into the vena cava in the upper abdomen. Enlargement of these anastomoses, caused by obstruction to the portal circulation in the liver, probably facilitates passage of both worms and eggs through the anastomoses.
• 12.  Lesions produced in the lungs by eggs were similar to those produced in the liver by the same species of egg. Worms were found mostly in arterioles but occasionally in alveolar cavities. Living worms caused little or no tissue reaction, but dead worms produced thrombosis of vessels and intense perivascular cellular reaction and ultimate scarring. In some late infections with S. japonicum in rabbits the lung pathology was intense, with fibrinous pleural adhesions and fluid in the pleural cavities.
• 13.  In the spleen, areas of focal necrosis were found in some of the mice with early S. mansoni infections, and increase of fibrous tissue was seen in some late infections. Extensive fibrosis and thickening of the capsule were present in some late infections with S. japonicum. Egg lesions were sometimes found in the spleen.
• 14.  From the histological observations in this study it is concluded that most of the pathology in the species of animals employed is produced by fertilized eggs and dead worms, forming localized lesions which, if numerous enough, lead to extensive scarring. If the infection becomes inactive or is terminated, and if the scars are not too extensive they may entirely disappear, and normal structure and function of the tissues may be restored. The early periportal cellular infiltration in the liver is interpreted as an allergic phenomenon resulting from the presence of worms in the portal-mesenteric veins. It decreases as the infection continues, and does not appear to contribute significantly to ultimate cirrhosis of the liver.

An extensive survey of Oncomelania nosophora, the intermediate snail host of Schistosoma japonicum was made in the Tone River valley from Sakai to Sukayama, a distance of about 75 miles.

Snail collections were made at 40 different places, being about equally divided between the two sides of the river. Ten collections consisted of 100 or more specimens and infections of S. japonicum occurred in five. Various epidemiologic factors in the distribution of the snails are discussed.

All of the agouties exposed to the cercariae of S. mansoni became infected, with eggs demonstrable in the feces 65–72 days after exposure. The majority of worms were located in intrahepatic portal veins. Adult worms were also found in the mesenteric veins but very few were close to the intestinal wall, possibly accounting for the scant, irregular passage of eggs in the feces. The agouti, which occurs in many areas of tropical America where S. mansoni is endemic, supports the sexual cycle of this parasite and therefore might enter into the epidemiology of this disease. The following conclusions may be drawn:

• 1.  The agouti is suceptible to schistosomiasis mansoni.
• 2.  The agouti is suitable for laboratory studies with S. mansoni which do not require that eggs be passed in the feces.

In a series of ten experiments which involved a total of 120 A. quadrimaculatus, 31 or 25.8 per cent were infected with P. cathemerium in the canary. The number of oocysts per stomach varied from 3 to 600, averaging 33. Although the oocysts matured and appeared normal in every respect, sporozoites have not yet been found in the salivary glands of A. quadrimaculatus kept as long as 21 days after the infectious blood meal. Two lots of C. quinquefasciatus fed simultaneously with the Anopheles revealed infection rates of 75 and 93 per cent.

A study of production sources and seasonal abundance of the more common muscoid flies from May 1950 through April 1951 showed that Musca domestica was produced by a wide range of breeding media throughout the entire period, far exceeding all other fly species in this respect. This wide adaptibility, plus the house fly's enormous reproduction potential, probably accounts for its demonstrated ability to develop insecticide-resistant populations rapidly. The occasional high production of other common species from any one of five principal fly breeding media categories was offset by its relatively infrequent occurrence or its restriction to certain items of breeding material.

Animal refuse (excrements, pen litter and wastes) not only occurred most frequently of all categories of media examined, but were also the most fly productive breeding materials occurring in the two study towns. Fruit-vegetable wastes and miscellaneous wastes were found to occur less frequently and to produce fewer flies, and were considered of secondary importance.

Species composition of flies counted indoors during the period of this study showed that 99 per cent were house flies. This species preference for human association, coupled with its abundance coincidentally with diarrheal disease in the study area, further establishes it as the major species to be considered in this area. Certain other species such as Phaenicia spp., Callitroga macellaria and Sarcophaga spp., while frequently noted in houses, actually comprised less than one per cent of flies in houses.

Note: Books received for editorial consideration will be intermittently listed. This acknowledgment must be regarded as an adequate expression of appreciation for the courtesy of the author or publisher. Selections will be made for review in the interest of our readers.

The Natural History of Infectious Disease, by Sir Macfarlane Burnet, M.D., F.R.S., Director of the Walter and Elisa Hall Institute, Melbourne, Australia. 356 pp. with illustrations. New York: Cambridge University Press, 1953. $4.50.

African Highway—The Battle for Health in Central Africa, by Sir Malcolm Watson, M.D., LL.D., Hon. Consultant, Ross Institute of Tropical Hygiene, London; with an introduction by Sir Eric Macfadyen. 294 pp. with illustrations and maps. London: John Murray, 1953. Price £3/3.

World-Atlas of Epidemic Diseases, Part I., edited by Ernst Rodenwaldt, Heidelberg, with collaborators, and sponsored by the Bureau of Medicine and Surgery, U.S. Department of the Navy, Washington, D. C. Hamburg: Falk-Verlag, 1952. Price DM 225.

This volume inaugurates an important new medical monograph series, covering current significant advances in the broad field of elinical medicine, and of the applications of fundamental research to clinical problems. Series I contains contributions ranging from “Talking with the patient” by Steward Wolf, to “Chemical agents used in the treatment of inoperable and far advanced neoplastic disease” by David I. Karnofsky.

Of particular interest to workers in tropical medicine are the following articles: “Prevention of rheumatic fever” by Charles H. Rammelkamp, Jr., and Floyd W. Denny; “Amebiasis” by Henry E. Hamilton; “The present status of the chemotherapy of human malaria” by L. H. Schmidt; “The seasonal arthropod-borne, virus encephalitides” by R. Walter Schlesinger, and “Sickle cell anemia” by Byrd S. Leavell and William A. MacIlwaine.

It is emphasized that the most effective method available for the prevention of initial attacks of acute rheumatic fever is the treatment of the preceding streptococeal infection with either penicillin or aureomycin.

This second edition is a concise treatise on the essential features of virus and rickettsial diseases of man and their causative agents. It is presented in orderly manner, contains sections on most of the essential technics and includes some very good illustrative material. The electron micrographs are especially fine.

Emphasis seems to have been misplaced in dealing with some matters. The highly specialised equipment for electron microscopy is described in considerable detail, yet the procedure of freeze-drying, so important in preparation of diagnostic reagents, vaccines, etc., is not mentioned. There are a number of misquotations in the volume and a few misstatements which might be dangerous. Example of the latter is the statement that “viruses are destroyed by the same disinfectants as destroy bacteria.” Many viruses are, in fact, quite resistant to common bactericidal agents.

This volume was not intended to be a reference book and it does not deal exhaustively with any of the subjects covered.

The book is divided into two parts. The first deals on 12 pp. briefly with the general biology, epidemiology, and pathology of helminths, and in a somewhat more detailed way with general diagnostic (15 pp.) and therapeutic (40 pp.) procedures. The second part describes those trematodes (27 pp.), cestodes (29 pp.), nematodes (54 pp.), acanthocephala (3 pp.), and gordiacea (2 pp.) that have been found as parasites of man in Europe. The more important parasites are treated according to the following scheme: Distribution, morphology, development, biology, epidemiology, pathology, diagnosis, prognosis, prophylaxis, and therapy. The book contains 35 illustrations, mainly good original photographs. It is concluded by a fairly brief bibliography and a subject index.

The book is written mainly for the physician. In view of the European post-war increase in helminthic infections, it certainly will be of value to the European clinician, especially in drawing his attention to the possibility of the occurrence of rarer parasites.

This excellent manual was written with the avowed intention of bringing the pertinent information concerning chiggers between the covers of a single volume. In this the authors have succeeded admirably, although information on the Trombiculidae is accumulating rapidly as indicated by a publication noted in the appendix which adds over 70 new species to the 440 species included in the manual. The main section of the manual deals with classification of 4 recognized subfamilies, 31 genera and 17 subgenera, with keys and brief diagnoses. The species are listed with synonyms, distribution and host lists. The classification is based wholly upon larvae. A brief chapter is devoted to the impact of chiggers upon public health. This is considered under three headings: relationship to rickettsia, dermatitis and control.

A review of the literature interspersed with original observations is presented in brief chapters on the behavior of chiggers, life cycles, and anatomy, particularly of the larvae.

This monograph brings together 18 papers of a symposium held to celebrate the opening of the International Research Center for Chemical Microbiology. The monograph is a veritable gold mine of information rarely assembled in one volume. One can only indicate here the range of subjects discussed. For example, C. J. Hinshelwood deals in his paper with growth, adaptation, decline and death of bacterial populations and presents a most provocative idea suggesting that, in the intimate linkage of protein and nucleic acid, the spacings of each affect the mode of synthesis of the other; and that although the production of protein and of nucleic acid are not autocatalytic by themselves, a steady state may ensue in which the two kinds of cell material increase autocatalytically. L. Califano discusses the liberation of nucleic acid from cells under the influence of heat as an index of the heat of inactivation of the organism and of the physiological age of the cell.

This is an important contribution to the field of endemic syphilis, defined by the author as a treponemal disease usually non-venereal, acquired in childhood through use of common utensils, known to be endemic in Bosnia for many centuries. This monograph gives a complete description of case finding, treatment, clinical signs and epidemiology. The author's conclusion that successful campaigns must be followed up at fairly short intervals and that all familial contacts must be treated seems vital. The experiences as related can be applied in certain areas of this country and in other parts of the world and to other treponemal diseases.

Questions by the reviewer arise in regard to the author's data given on congenital syphilis. Too high a per cent of discovered cases in all age groups in the secondary stage is indicated to make his explanation seem completely valid.

This well-printed pocket-size book is difficult to appraise by American standards. The 31 collaborators, some in respected academic positions, have created, according to the editor, a “biologic plan” of therapy which may be applied to the more common ailments of mankind—from constitutional diseases of the metabolism, skin diseases, blood dyscrasias and respiratory, digestive and renal disturbances to the maladies of infants and “supportive cure by nature” (Naturheilbehandlung) in surgery. Even a casual perusal of the text discloses a state of German medicine not reflected in current scientific journals received in this country. There is apparent a shallow uncritical acceptance of herbs, extracts, infusions and drugs long ago classed as patent medicines. Use of these preparations is encouraged by the advertisements, book markers and other tricks of the trade so freely interspersing the leaves of the book. Over 215 pages are devoted to an alphabetical catalog and price list of the “Heil- und Kurmittel” under their respective tradenames and the address of the manufacturer.

August 27,1953

Editor American Journal of Tropical Medicine and Hygiene Berkeley 4, California

Sir:

The last sentence, first paragraph, on page 570 of my article in the July 1953 issue of the Journal contains the following error:

The statement that “the sanitary engineer whose main interest is in progress had better stay at home” should have been: “the sanitary engineer whose main interest is in process had better stay at home.”

Were I writing this article today I would modify my statement on the same page that night soil is almost universally used for crop fertilization in rural Asia. Such use of night soil is the prevailing practice in some countries; in others adjoining croplands are the community defecation grounds, with resultant benefit to crops, but this is not exactly a night-soil practice.

Thank you.

Yours truly, John M. Henderson