The American Journal of Tropical Medicine and Hygiene - Volume 26, Issue 3, May 1977

As most of you know, one of the duties of the President of the American Society of Tropical Medicine and Hygiene specified by the by-laws is the presentation of an address at the annual meeting. I do not know what type of address those responsible for this provision had in mind, but a review of previous presidential addresses reveals a wide variety both of philosophical and scientific topics. Since I do not feel competent to address you on a philosophical subject, I have chosen to review a scientific topic which has been of interest to me during the past few years. In making this choice, I know that the subject matter will be of relatively little interest to those of you in other fields and for this I apologize. I shall illustrate later, however, that the topic I have chosen is especially appropriate for the site of our gathering this year and for the bicentennial which our joint meeting commemorates.

I am greatly honored by your invitation to give the Craig Lecture in this bicentennial year and at the joint meeting of the American and British Societies of Tropical Medicine.

Not having on this occasion to face subsequent attack from the floor, I am going to try to show that in what goes on in the human host infected with the malaria parasite and in the community exposed to the disease, there exists the common factor of interdependence and that this concept has world-wide implications. The Oxford English Dictionary defines interdependence as “a state of existence conditional on and emanating from the existence of something else.”

As functioning human beings we are all examples of such interdependence; all in some sort of physiological balance. The circulation is ticking over, the liver, kidneys, lungs, heart, and brain are functioning, coordinating, and reacting with one another.

This report summarizes the results of a comparative study of the major features of untreated infections with the B strain of Plasmodium cynomolgi in Macaca mulatta, M. irus (fascicularis), M. nemestrina, M. speciosa (arctoides), and Cercopithecus aethiops. The investigation included: delineation of the courses of trophozoite-induced and sporozoite-induced infections in these Old World primates; evaluation of their efficiencies in transmitting the above plasmodium through Anopheles freeborni; and assessment of host reactions to infection, with particular attention to impacts on erythroid elements of peripheral blood. In all important respects, the parasitic courses of infections in M. mulatta and C. aethiops (Kenyan origin) were identical, as were the reactions of these hosts to disease processes. M. mulatta was slightly more efficient than C. aethiops in transmitting P. cynomolgi through A. freeborni; however, this favored position may have been purchased by experimental design. The features of infections in M. irus, M. nemestrina, and M. speciosa differed significantly from those in M. mulatta. M. irus responded to challenge with trophozoites or sporozoites in a highly reproducible manner, but exhibited peak parasitemias and a long series of parasitic waves (recrudescences and/or relapses) of much lower intensities than were encountered in M. mulatta. M. nemestrina responded to such challenges in diverse manners. A few subjects exhibited parasitic courses almost identical with those encountered in M. irus. The majority exhibited extremely low level parasitemias of great persistence. These diverse parasitic courses were associated with specific physical features of this monkey. M. speciosa failed to support infections following inoculation with either trophozoites or sporozoites. Sporozoite challenges did lead to transient, extremely low level parasitemias, indicating that tissue stage schizogony had taken place. The unusual features of infections in M. nemestrina and M. speciosa could be of substantial interest to those concerned with factors which determine invasion of erythrocytes by plasmodia. Demonstration that untreated infections in M. mulatta and C. aethiops are essentially identical is of far more immediate importance. If responses of infections in these hosts to standard antimalarial drugs are also identical, the way is open to substituting C. aethiops for M. mulatta in studies on the biology and therapy of infections with P. cynomolgi, particularly in the search for radical curative drugs. Such substitution would meet a critical need at a time when access to feral M. mulatta is restricted.

Thirty-six Macaca mulatta monkeys were immunized with different concentrations and regimens of heat-stable, serum-soluble (S-) antigens of Plasmodium knowlesi prior to challenge with the homologous parasite via sporozoite inoculation. Fewer deaths and reduced maximum parasitemias occurred in those animals inoculated with 10 to 40 mg of S-antigen compared to nonimmunized monkeys or those receiving only Freund's adjuvant. Protection was incomplete, however, suggesting that antibodies to S-antigens may have a limited role in protection of hosts to malarial infection.

Mice were immunized subcutaneously, intravenously or in a footpad with antigens prepared from a lethal strain of Plasmodium berghei yoelii. A delayed footpad swelling (DFS) reaction was observed 4 days after immunization, and was detectable at least 42 days after immunization. However, IV immunization was the least efficacious in producing hypersensitivity. Regardless of the type of antigen used for immunization, mice responded similarly when live parasites were used to elicit DFS. This study revealed that hypersensitivity depended on route of immunization and type of antigen.

The effect of length of treatment of Trypanosoma cruzi with Bayer 2502 (Bay 2502, Lampit, Nifurtimox) on resistance to challenge and parasite isolation was studied in two experiments. In each, 200 mice were divided into groups of 20, infected with T. cruzi, and then treated with Bay 2502 for 1 to 8 consecutive weeks. Sixteen weeks after exposure, 10 mice from each experimental group were challenged with 150,000 trypomastigotes. The remainder were maintained for 8 more weeks and killed for isolation of parasites. Mice treated with Bay 2502 for up to 8 consecutive weeks were uniformly resistant to challenge, and parasites could not be isolated from groups treated for over 6 weeks. Results suggest that prolonged treatment with Bay 2502 eliminates T. cruzi from infected hosts and that resistance to challenge is not dependent on the presence of the organisms in mice.

The antigenic anatomy of Entamoeba histolytica and the variation in response of 148 patients with amebic disease are described. Immunoelectrophoretic patterns and indirect hemagglutination titers were studied in sera obtained from patients with amebic disease acquired in several areas of the world, i.e., Canada, Vietnam, Africa, India, Central America, and southern United States. The various populations are compared and similarities and differences are discussed.

Axenically cultured Entamoeba histolytica inoculated intracerebrally into newborn Swiss mice invaded the cerebrum and produced multiple abscesses containing viable trophozoites. As few as 20 amebae of a virulent strain (HM-1:IMSS) occasionally produced fatal disease, 200 killed about 75% of animals and higher doses regularly killed all animals. In contrast, avirulent strains (HK-9 and HB-301:NIH) failed to produce acute brain disease in comparable time periods even when mice were inoculated with as many as 20,000 amebae. Two other strains (1295 and H-458:CDC) were of intermediate virulence. High doses of avirulent amebae often produced hydrocephalus as a late manifestation. In newborn, 3-week-old, and 6-week-old mice resistance to infection increased with age, and older animals often responded late to virulent strains by developing hydrocephalus.

Newborn hamsters inoculated intrahepatically were highly susceptible to infection by axenically cultured Entamoeba histolytica. Inoculations were performed through the abdominal wall, and lesions could be observed through the skin as early as 4 days after inoculation. The most virulent amebal strain, HM-1:IMSS, produced liver lesions in 19% of newborn animals inoculated with 20 amebae, and in about 90% receiving 2,000 amebae. Eleven other strains similarly tested either produced no lesions with 20,000 amebae or were of intermediate virulence. Two hamster strains did not show appreciable differences in susceptibility to the HM-1:IMSS amebal strain. Newborn hamsters were more susceptible to HM-1:IMSS amebae than animals which were 2, 4, or 7 days old at the time of inoculation. Three-week-old animals were resistant to doses below 20,000 virulent amebae.

The Naegleria ameba cytopathogenic material (NACM) obtained from freeliving and/or pathogenic amebae has been partially isolated and characterized. The evidence indicates that the material is a protein or has a protein component, and is in the estimated molecular weight range of 50,000 daltons. The partially isolated NACM, like its counterpart in the amebic lysates, is capable of sustaining itself in tissue cultures at a temperature which otherwise would inactivate it, and in serial passages through multiple dilutions. No distinctions between the NACMs from amebae of different Naegleria species or strains have been found in the biological response to the various treatments studied.

Two areas of intradermal swelling removed from the upper thigh and iliac crest of a 43-year-old man in Louisiana were each found to contain a larval tramatode about 0.5 mm in length. Based on morphology reconstructed from serial sections, the two worms were identified as a mesocercaria of an underscribed species belonging to the subfamily Alariinae.

The American Schistosomiasis Delegation's trip to China was sponsored by the Committee on Scholarly Communication with the People's Republic of China. Since the Shanghai agreement in 1972, this Committee has been the primary American organization operating scholarly exchanges between the two countries. It is jointly sponsored by the National Academy of Sciences, the Social Science Research Council, and the American Council of Learned Societies. Schistosomiasis was among the first exchanges negotiated between this Committee and China's Scientific and Technical Association in May 1973. The delegation's visit actually took place from 8 April to 2 May 1975.

While in China the American Schistosomiasis Delegation visited six cities—Peking, Shanghai, Soochow, Wuhsi, Hangchow, and Kwangchow—and several rural communes near these metropolitan areas. Our itinerary included three provinces with a well-known previous record of schistosomiasis endemicity—Chekiang and Kiangsu in the Yangtze Delta, and Kwangtung on the southern coast.

This brief afterword seeks to place the findings of the U.S. Schistosomiasis Delegation (April–May 1975) in context. To appreciate the Delegation's findings, a longitudinal perspective is necessary. Present Chinese programs must be seen in the context of the policy problems which have been encountered in the past. We must identify the ways in which present policy reflects “a learning experience” and specify present difficulties which will probably produce further changes. Secondly, as the Delegation is well aware, we must preliminarily ask, How “representative” were the areas visited?

The Antischistosomiasis Program: “The Learning Experience”. The Chinese would certainly agree that the program which the American Schistosomiasis Delegation saw in the Spring of 1975 was the product of a “trial and error” process; that process continues. While policy changes have occurred along a broad front, three are particularly important in assessing the likelihood of continued progress and evaluating the transferability of these programs to other countries.

The prevalence and morbidity of schistosomiasis haematobium were studied in three geographically different villages in Giza governorate in Egypt. The survey included 786 children ranging in age from 6 months to 10 years. There was a marked variation in the prevalence of infection in the three areas, correlated with the socioeconomic standards and sanitary habits, emphasizing their role in the spread of the disease. The youngest child infected was a 14-month-old boy, while the peak of prevalence of infection was in children 8 to 10 years old. The intensity of infection, as indicated by the heaviness of urinary egg output (mean of 3 successive days), was unrelated to the degree of prevalence in the area concerned. On the other hand, such intensity of infection correlated well with the severity of the clinical picture. Immediate skin-test reactivity was related to the intensity of infection, though unreliable as a single diagnostic test in children. Delayed reactivity was less sensitive. Stool examination showed a higher prevalence of other helminthic infections in schistosome-infected children aged 6 to 10 years than in uninfected children. The impact of schistosomiasis on the general health of children as shown by the anthropometric measurements was mild, except in heavily infected children in whom it was significant. The study focused on the overshadowed young age period when infection can be radically cured and even easily avoided. The data point to the importance of considering the intensity of infection, and not the prevalence, in weighing the need for therapy against its toxic effects in children, or in discussing the priorities of treatment in an endemic area.

We report the preliminary findings of a comprehensive schistosomiasis survey in the Qalyub region of the Nile Delta. A systematic sample of households in eight villages was studied, and 8,712 individuals submitted stool and urine specimens for parasitologic examinations. The prevalence of Schistosoma mansoni infection (40.5%) was much higher than that reported previously in this area, and the prevalence of S. haematobium (27%) was much lower. The geometric mean egg output for both parasites was surprisingly low. The apparent increase in S. mansoni infection may be largely due to the use of a very sensitive parasitologic technique, but the decrease in S. haematobium prevalence is unexplained. Preliminary results of snail surveys, however, indicate a profound decrease in the population levels of Bulinus species, a phenomenon which may be related to ecological changes since construction of the Aswan High Dam.

Morbidity from infection with Schistosoma mansoni was investigated in a population of school children, aged 7 to 16 years, from the town of Chwahit, located north of Lake Tana in Highland Ethiopia. Malaria was under control in the area, and S. haematobium was not endemic. Quantitative fecal egg counts were determined for 336 children (94% of those in the school) by the Kato thick-smear method; other intestinal parasites were determined by the Ritchie formol-ether concentration method. Morbidity was measured by a standardized medical examination of 272 of these children and was analyzed in four categories of egg count intensity: 0 (12%), 1–100 (19%), 101–500 (40%), and 501 + (29%) eggs per gram (epg). Prevalence was 88%, and the geometric mean egg count was 259 epg. The highest prevalence and intensity were found in 12-year-olds (95% and 300 epg, respectively). No schistosomiasis-associated symptoms were significantly related to the intensity of S. mansoni infection, although the complaint of blood in the stool was more frequent in groups with higher egg counts. There was a trend for hepatomegaly (especially of the left lobe) to increase in frequency with increasing egg count, but this trend was not significant. These children had no splenic enlargement. Anthropometric weight-for-height measurements, average school grade, and days absent from school were not related to the intensity of S. mansoni infections. Physical performance in a standardized 12-minute walk-run was better in uninfected boys, but there was no correlation with the intensity of infection. The minimal morbidity found in this population is compatible with the moderately low intensity of S. mansoni infection and with the findings of a previous population-based study in a neighboring village.

Levels of IgG, IgE, IgM, and IgA were determined, specific antibodies were detected by the fluorescent antibody test, hemagglutination test, complement fixation test and immunoelectrophoresis, and intradermal tests for delayed hypersensitivity to Schistosoma mansoni antigens were performed in Brazilian patients with schistosomiasis mansoni. The results were compared according to the clinical forms of the disease. IgG levels and antibody titers increased progressively in the subclinical, hepatomegalic, and hepatosplenic forms and there was a statistical relationship between IgG levels and the intensity of responses to the four serological tests. Delayed hypersensitivity (DHS) was found more frequently in hepato-splenic patients and more particularly in those with splenomegaly. DHS also correlated with age, but not with sex or with skin color. The strongest DHS reactions were observed in patients 20 to 34 years old, and in those having the highest fecal egg output. IgG levels, antibody titers, and DHS responses decreased after splenectomy and portal filtration of the worms. No significant variation was observed between untreated subjects, patients who were splenectomized and a group not subject to reinfection for 4 years.

Schistosoma mansoni cercariae secrete preacetabular gland material in association with skin penetration. The material is heterogeneous and contains proteolytic enzyme(s) which comprise a small proportion of the total protein. We have immunized mice with cercarial secretion material in several protocols designed to induce a variety of antibody responses. The cercarial secretion material is sufficiently immunogenic to induce precipitating and reaginic antibody production. The antibodies obtained were not of the necessary quantity and/or quality to afford protection from a challenge infection.

A workshop on mathematical models of schistosomiasis was convened by The Edna McConnell Clark Foundation from 9 to 14 May 1976, at the Rockefeller Foundation's Villa Serbelloni Study and Conference Center in Bellagio, Italy. The meeting was remarkable as the first conference devoted entirely to mathematical models of a single infectious disease. It was further remarkable in successfully bringing together 19 specialists from seven countries representing very different disciplines—medicine, epidemiology, public health, sanitary engineering, parasitology, malacology, mathematics, statistics, and economics—all of whom shared a common interest: the application of mathematical models to research on, and control of, schistosomiasis. The 4 days of plenary sessions began with a review of published and unpublished work, moved on to a detailed discussion of the biology of schistosomiasis and of the relationship of various models to current biological knowledge, and concluded with a discussion of major gaps in our quantitative understanding of this important infectious disease.

Development of a model to predict the impact of water resource projects on transmission of schistosomiasis is described and verified with data from 54 villages in Khuzestan Province, Iran. Changes in disease prevalence following construction of an irrigation project are related to the linear extent of snail habitats and size of the infected human population. The model is used to compare the costs and effectiveness of alternative disease control measures. Results indicate that a combined controls program is most cost-effective but further work is needed to determine the optimal combination of controls.