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ABSTRACT |
 TOP ABSTRACT NATURAL HISTORY OF INFECTION...INFECTION IN NONENDEMIC HUMANSEXPERIMENTAL INFECTIONS OF...WHY ARE THERE INFECTED...CONCLUSIONREFERENCES |
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NATURAL HISTORY OF INFECTION IN AN ENDEMIC AREA |
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TOPABSTRACTNATURAL HISTORY OF INFECTION...INFECTION IN NONENDEMIC HUMANSEXPERIMENTAL INFECTIONS OF...WHY ARE THERE INFECTED...CONCLUSIONREFERENCES |
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There are two unusual features of lymphatic filarial infection that one needs to address to understand the natural course. First, it would appear that the organism is not very infectious to normal, immunocompetent individuals. The second is that it is an endemic disease, occurring in certain geographic areas at high rates and skipping other areas.
Most reviews of lymphatic filariasis therefore concentrate on the course of disease and its manifestations among these endemic populations. Within the endemic populations, patients fall into a relatively wide spectrum of manisfestations, which have puzzled and intrigued most investigators. Individuals who are presumably of similar genetic constitution and ethnic origin, exposed to the same parasite strain transmitted by the same vector, exhibit very different outcomes of infection. Individuals may have no evidence of disease or infection (endemic normals), be asymptomatic, but bear significant parasite burdens (asymptomatic microfilaremics), or be amicrofilaremic with disease. The precise distribution among these subsets varies from one geographic area to the other. A great deal of the immunologic literature over the past decade has focused on the nature of this "spectrum of disease" in lymphatic filariasis. In an influential review in 1992, Ottesen suggested that the two polar groups were individuals with chronic pathology and no microfilariae in circulation versus individuals with abundant microfilariae in circulation, but no symptoms.1 Attempts have been made to explain the mechanisms underlying the clinical presentations based on the Th1/Th2 dichotomy. Most of these explanations, however, seem unsatisfactory in explaining the difference.
Although longitudinal studies within an endemic area are difficult to carry out, there have been at least two studies of patients who were moved from endemic areas to nonendemic areas and who were therefore subsequently followed without the further complication of an ongoing transmission. Many of these individuals in both studies were microfilaremic at the time of movement from either Surinam2 or American Samoa3 to The Netherlands or the United States, respectively. Many of these remained microfilaremic for approximately 8 years after their move, consistent with the generally believed life span of the adult female of 8 years. After this period, microfilaremia gradually disappeared. Very important for our understanding of the course of infection, none of these individuals developed chronic disease. Thus, the idea that filarial infection proceeds from microfilaremia to acute to chronic disease may be incorrect. It would appear that most individuals who are microfilaremic remain microfilaremic without developing chronic disease subsequently. Steele and others have also examined the long-term course of filarial infections in the Cook Islands. Here as well, endemic normals remain disease or infection free over the 17 years of follow-up, despite continued exposure to infection.4
Most longitudinal studies seem to suggest that whether one is endemic normal or asymptomatic microfilaremic is fixed relatively early in life and one remains phenotypically consistent over long periods of time. What are the determinants of this difference? In coming to an understanding of its nature, it is probably worth discussing the course of infection not only in individuals in an endemic area, but also in nonendemic individuals and volunteers subjected to experimental infections. I believe that a dispassionate analysis of the literature leads one to a conclusion that is at variance to the prevalent models of infection and disease.
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INFECTION IN NONENDEMIC HUMANS |
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TOPABSTRACTNATURAL HISTORY OF INFECTION...INFECTION IN NONENDEMIC HUMANSEXPERIMENTAL INFECTIONS OF...WHY ARE THERE INFECTED...CONCLUSIONREFERENCES |
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Many of these individuals have been followed over the past 50 years since the end of the Second World War. Many have been lost to follow-up, but it would appear that only about 20 of these individuals have been documented to have developed microfilariae. To quote Wartman, "Microfilariae were not found in the peripheral blood in a great majority of cases." Behm and Hayman (quoted by Wartman) say, "No microfilariae were found in any of these groups (709 patients) while at the hospital (Moore General Hospital, Swannanoa, NC). Microfilariae had been repeatedly demonstrated, however, in one man in Group A while in Woodlark and in a second before arrival at this hospital. Neither of these men was available for study. In addition to these two, the records of two other men of Group A recorded the finding of a single microfilaria in one examination. These two were examined repeatedly over a period of several months, but no microfilariae could be found."
It appears fair to say that of this cohort of 33,000-odd individuals of whom 10,000 were documented to have developed filarial infection, a very small number, at best 20, ever became microfilaremic.
Wartman performed careful pathologic examination of biopsy material from 57 of these GIs at the Armed Forces Institute of Pathology.8 Eight contained adult worms. In all instances, the worms were surrounded by granulomatous inflammation. In his description, Wartman writes, "Typical changes in nodes which were infected with adult worms consisted of marked hyperplasia of cells of the reticulo-endothelial system, tissue eosinophilia, and nodule formation. Macrophages are numerous and moderate numbers of foreign body type giant cell were present. Nodules were found chiefly around adult parasites, but occasionally around microfilariae or even in the absence of parasites. Eosinophils, plasma cells, lymphocytes and neutrophils were present through the granulomas, but were especially numerous at the edges. In older lesions where the worms were dead, or had been present for a long time, macrophages and exudative cells were less conspicuous and they were concentrically arranged layers of bands of acellular collagen." While Wartman refers to the structures around the worms as "nodules," it is important to emphasize that this is not a precise pathologic term. A nodule may be cellular or acellular, neoplastic or inflammatory. It is, however, clear from the histopathology illustrations in his review that his "nodules" are granulomas, composed primarily of macrophages with the formation of some foreign body giant cells. Further, Dr. Wartman clearly concludes that his data prove that the granulomatous inflammation takes place around living, rather than dead, worms.
The other group of nonendemic individuals exposed to filariasis as adults were Indonesians from Irian Jaya who were relocated to Flores. In a review in the CIBA Symposium on Filariasis, Partono describes the clinical course of filariasis in previously unexposed migrants. Within 2 years of migration, a great number of these individuals (43%) had evidence of acute filarial infection as manifested by adenolymphangitis. A substantial percentage of them developed lymphodema or elephantiasis within this period of time (21%). However, only a small percentage (2 individuals or 5%) developed microfilaremia. No detailed pathologic evaluation, similar to that conducted by Wartman, is available for these individuals. However, it appears that this group of nonendemic individuals exposed to the filarial parasites as adults eliminate them, without developing patent infection. There is, however, a major difference between the American GIs who were exposed to parasites for a limited duration and the Indonesian transmigrants who were exposed for the rest of their lives. The former cleared infection without any pathology; the latter developed pathology at high rates.
Thus, it appears that the course of filarial infection in individuals who have not been previously exposed to filariasis is that of quantitative clearance without the development of patent infection. In those instances where the infection is of a limited intensity and duration, as in the case of American GIs, it appears that the disease does not develop and these individuals remain clinically normal for the rest of their lives. On the other hand, if infection is persistent and repeated and takes place over a long period of time, individuals develop chronic pathology rapidly, without necessarily becoming patently infected. Further, it would appear that the mechanism by which the parasites are eliminated ultimately is by surrounding them with "nodules" or, more appropriately, granulomas.
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EXPERIMENTAL INFECTIONS OF HUMANS |
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TOPABSTRACTNATURAL HISTORY OF INFECTION...INFECTION IN NONENDEMIC HUMANSEXPERIMENTAL INFECTIONS OF...WHY ARE THERE INFECTED...CONCLUSIONREFERENCES |
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In another study using a total of four volunteers, Edeson and others10 found microfilariae (mf) in only one. Even in this individual, mf were present transiently in circulation (from Days 84 to 140) and in small numbers. Even more surprisingly, patency developed in one of the two individuals given B. pahangi larvae and not in either volunteer receiving B. malayi. In discussing this issue, Edeson and others write, "The broad similarity of the events in all four volunteers and the appearance of B. pahangi infection in one of them makes the failure to establish a B. malayi infection all the more puzzling. The clinical reaction suggests that the infective larvae had survived and were developing; yet although this particular strain of B. malayi had come from man, it was apparently unable to establish themselves in these two volunteers of the result of a single inoculation."
Equally noteworthy is the communication by Yokogawa,11 which appears to be one of the few instances in which Wuchereria bancrofti was used as the infective agent. The author was one of the five volunteers used in the study. Most did not become microfilaremic at all. In two instances, two microfilariae were recovered from 2 mL of blood examined at night. This is hardly a high level of a microfilaremia. The author further writes, "Since then, several weeks have elapsed, without any microfilariae being discovered in the peripheral blood by continual nightly examination." Thus, in the one well documented experiment with W. bancrofti, patent infection was uncommon and transient.
Finally, in the report by Liu and others, a single volunteer was exposed to infected mosquitoes and subjected to an estimated 200 infective larvae.12 On Day 142, he had 9 mf/µL of blood. Seven days later, this number decreased to 3/µL. It is tempting to speculate that he would have spontaneously cured himself of the infection. But the subject was treated with DEC over the next 16 days. He remained free of mf for all subsequent examinations.
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WHY ARE THERE INFECTED HUMANS? |
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TOPABSTRACTNATURAL HISTORY OF INFECTION...INFECTION IN NONENDEMIC HUMANSEXPERIMENTAL INFECTIONS OF...WHY ARE THERE INFECTED...CONCLUSIONREFERENCES |
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This idea that microfilaremia may occur in very special individuals has been further highlighted by the work of Lammie and others from Haiti13 and Steel and co-workers from the Cook Islands.14 In both instances, there is a substantial increase in the microfilaremia levels in individuals born to mothers who are microfilaremic. This correlation is not perfect. It is clear that there are microfilaremic individuals in these patients in whom maternal microfilaremia cannot be documented and, in converse, not all individuals who had microfilaremic mothers become microfilaremic themselves. Thus, while it appears that having a microfilaremic mother predisposes one to microfilaremia, the correlation is not absolute. It is, however, likely that microfilaremia or a specific antigenemia at a particularly sensitive stage in the development of the fetus may be the relevant fact, and we may still not have a measure of this particular relationship.
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CONCLUSION |
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TOPABSTRACTNATURAL HISTORY OF INFECTION...INFECTION IN NONENDEMIC HUMANSEXPERIMENTAL INFECTIONS OF...WHY ARE THERE INFECTED...CONCLUSIONREFERENCES |
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It appears likely that when exposed to filarial infection, humans either mount an immune response and eliminate the parasite or are unable to mount adequate immune response due to neonatal tolerance and permit it to survive. In the case of those individuals who do kill the parasites effectively, it would appear that there are two classes. One class shows no evidence of infection subsequently and resembles the American GIs. The second class resembles the Indonesian transmigrants with the development of chronic disease. It is tempting to suggest that the endemic normals are individuals who are exposed to relatively low levels of infection, either because of their own resistance to mosquito biting or because of socioeconomic status that makes them less exposed to mosquitoes. On the other hand, those who develop chronic disease may, for unknown reasons, be exposed to substantially larger burdens of the infective parasite, resulting in sequentially increasing amounts of granuloma formation resulting in sclerosis of the lymphatics.
This formulation of the nature of filarial infections in humans has important implications for the global effort to eradicate the disease. A vaccine may not be necessary, possible, or perhaps even desirable. If asymptomatic microfilaremics are tolerant, it might be impossible to break this tolerance post-natally. On the other hand, endemic normals are probably exposed to relatively limited infectious burdens and appear to deal with it quite adequately, and do not require vaccinations. If individuals with chronic symptoms become so because of repeated infections, vaccination may only hasten the development of disease, as happens in the Indonesian transmigrants. Thus, despite the enormous effort that has been placed on vaccine development over the past two decades, it may be well that such efforts have not borne fruit.
On the other hand, the very fact that humans may be more or less resistant to filarial infection implies that once transmission has been lowered to the point that there are not many women in their reproductive phase who are currently infected, filarial infection may not return after one generation. This is an optimistic and encouraging possibility.
Received May 30, 2005. Accepted for publication July 1, 2005.
* Address correspondence to T. V. Rajan, MD, PhD, Boehringer-Ingelheim Professor of Immunology, Professor and Interim Chairman, Department of Pathology, 263 Farmington Avenue, Farming-ton, CT 06032. E-mail: rajan{at}neuron.uchc.edu 
Author’s address: T.V. Rajan, MD, PhD, Boehringer-Ingelheim Professor of Immunology, Professor and Interim Chairman, Department of Pathology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06032, E-mail: rajan{at}neuron.uchc.edu.
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REFERENCES |
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TOPABSTRACTNATURAL HISTORY OF INFECTION...INFECTION IN NONENDEMIC HUMANSEXPERIMENTAL INFECTIONS OF...WHY ARE THERE INFECTED...CONCLUSIONREFERENCES |
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  W. G. Jaoko, E. Michael, D. W. Meyrowitsch, B. B. A. Estambale, M. N. Malecela, and P. E. Simonsen Immunoepidemiology of Wuchereria bancrofti Infection: Parasite Transmission Intensity, Filaria-Specific Antibodies, and Host Immunity in Two East African Communities Infect. Immun., December 1, 2007; 75(12): 5651 - 5662. [Abstract] [Full Text] [PDF]
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