Pathology in tropical medicine

Parasitology Today, voL 2, no. 10, 1986

261

P,4R.4S TE Pathology in Tropical Medicine PATHOLOGY C.D, Mackenzie The pathology of a parasitic disease is a major link between the investigating parasitologist and those concerned with its epidemiology, socioeconomic impact, clinical treatment and control. The epidemiologist requires information about the incidence and prevalence of major pathological lesions attributable to an infection, which in turn will determine the social and economic impact of the disease and thus its priority for control. For both diagnosis and treatment, the clinician requires an understanding of the pathological mechanisms, and the potential for new drugs or vaccine development largely depends on such understanding. Recent years have seen remarkable improvements in determining the nature of pathology associated with parasitic infections, and in understanding their causative mechanisms. With this issue, Parasitology Today begins a series of special reviews designed to bring together these insights into parasite pathology (see pages 271-282). In this introductory overview, Charles Mackenzie traces the origins and development of the science. Pathology (or pathophysiology) is a primary discipline of medical science encompassing both the form of tissue changes (their derivation in producing diseases states), and their functional significance, It is therefore the major link between the laboratory investigator and the clinician, But despite major studies and technical developments during the many years of establishment of this branch of medicine, the pathologies of many parasitic diseases common in the tropics remain poorly studied, is this due to lack of interest - or perhaps more a lack of fiscal motivation? In practical terms a lack of post-mortem samples from sufferers of these diseases has cer-

tainly been a major drawback. Social customs and religious practices in many areas do not allow autopsies. Facilities for performing such investigations and subsequent processing of the material are often poor or non-existent, even in areas where social practices would allow it. Medicine at a field level often does not include the luxury of clinicohistopathological support for diagnosis - logistic problems are too great and time too limited for any clinical value in the short term. In the long term however, collection, examination and reflection on such material can be of great value to tropical medicine. The examination of mammalian tis-

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sues, and therefore the beginnings of pathology, .necessarily occurred after invention of the microscope. Histology blossomed in the late 1800s with the development of the German chemical industry and in particular the production of natural and synthetic dyes. Within a few years, pioneers such as Ehrlich and Grubler (who standardized commercial 'non-biological' dyes for histological use) laid the basis for histopathology as we know it today. Chance, as in many scientific developments, played its role when Blum, in the late nineteenth century, discovered the fixation properties of formaldehyde whilst examining anthraxinfected mice rendered non-infective by treatment with this reagent. The development of cryostat sectioning of tissues by Pearse in the 1930s heralded the advance of enzyme histochemistry, and was thus the basis for the many techniques that incorporate enzymes as markers. Perhaps the most exciting development in the last thirty ,years, other than the development of electron microscopy, has been in immunocytochemistry - the use of immunological reagents in examining tissues. This was boosted by monoclonal antibody techniques and the rapid development

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Parasitology Today,vol.2,no.I0,1986

262 of practical procedures which in many cases allow the retrospective study of preserved material.

Definitions

The term 'pathology' is commonly used, perhaps often with little thought to its meaning and implications. To some it just conjures up images of formalin fumes and bottles of yellowing tissue samples, but in its purest sense pathology is the study of the causes and nature of disease (as opposed to infection), or abnormal bodily affections or conditions. In a more functional sense it encompasses the changes that occur when the host interacts with the parasite. In the UK, the term 'pathology' is used more generally to include the causes of disease and their effect on structure and function of the body tissues, and is often used to cover biochemical, microbiological and parasitological features as well as histopathology. In the USA the term is used more restrictedly to encompass only morbid anatomy and histopathological studies. 'Pathophysiology', a word also in usage, pertains to the study of pathological changes in the normal physiological processes.

studies retain a vital role, for it is in tissues, in the whole being, that we ultimately wish to understand these phenomena, not in a plastic dish. The ultimate proof of any pathological hypothesis must be at the tissue or organ level.

'lmmunopathology' is also a widely used term, and can be defined as 'the study of tissue alteration made manifest by various types of hypersensitivity or allergic reactions'L Immunopathology is used by some in a more restricted sense relating to just the pathology of the immune system itself (e.g. autoimmunity). This confusion underlines the intimate and inseparable relationship between pathology and immunology. Virtually every phase of inflammation involves immunological phenomena (Fig. I ). Pathology examines changes at many levels: biochemical changes, microscopic physiological and cellular tissue changes, and macroscopic alterations. Thus information can be obtained at many levels of analysis from gross and microscopic examination, to immunocytochemical studies and detailed biochemical analysis. In this way, pathology as a discipline caters for those who wish to separate and probe individual components (a serialistic approach), and also those who prefer to examine the entities in the context of whole tissues or whole beings (a holistic approach). These two groups are sometimes not as close as might be most beneficial to the science; researchers and diagnosticians are often kept apart. Currently there is financial and academic accentuation of the detailed dissection of the responses at a subcellular level, but tissue

Inflammation and Healing The two essential components of pathology are firstly, the response of the host to an intruding organism or to an injurious insult (inflammation), and secondly, the means by which the tissue returns to normal (healing and repair) (Fig. I). Although this sequence has a basic form with a limited number of outcomes, there are aspects that are accentuated depending on the initiating injury and on the status of the host's defence system. Some of the organisms found in tropical diseases promote aspects of inflammation that are of interest to the more general pathologist - an example being the biology of eosinophils (Fig. 2) which remained largely unknown until the development of parasite immunology. Such contributions make the histopathology of tropical diseases an exciting and important contributor to the discipline as a whole. Tropical parasitic diseases manifest themselves in a very wide range of tissue

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Parasfl:oloooyToday, voL 2, no, I0, 1986 changes, and it should be remembered that these include most diseases seen in the temperate climates, such as neoplasia and cardiovascular pathology. Amongst the commonest are helminthic diseases, which are - almost by definition - long lasting and often involve repeated infections. They can cause chronic granulomatous fibrous changes (schistosomiasis, onchocerciasis), or earlier acute manifestations akin to immediate hypersensitivity reactions (onchocercal pruritus, filarial fever). Protozoa also can induce unique forms of tissue change. The extent of inflammatory reactions to parasitic agents can vary with parasite, with host and sometimes with organ. An especially important consideration in tropical pathology is the role of concurrent infections; this is paramount to both diagnosis and more basic studies, The immune system and tissue status may be altered by other diseases either advantageously or disadvantageously. Nutritional status is known to be able to affect inflammation and healing, and malnutrition is unfortunately common in tropical countries. Nevertheless, the degree of multiple infection to which an individual *In next month's issue, the Parasite Pathology series continues with: The Immunopathology of Granuloma Formation in Schistosomiasis- by S.M Phillips and PJ. Laramie.

263 can still maintain homeostasis without overall physiological disability is surprising. It is also quite possible that some life cycles of parasites may actually require inflammation for their continuation; for example eggs are not passed in Angiostrongylus infection of rats unless there is considerable inflammation in the lung. The study of tropical pathology and the pathogenesis of tropical diseases can reveal much basic information about host responses to injury and infection. Although there are many similarities to the responses seen in the better investigated bacterial and viral diseases, tissue changes in parasitic diseases often have their own peculiarities which are ripe for investigation. For example, granulomata associated with filarial infection are often associated with tissue eosinophilia; what is the role of these cells in inducing the long term tissue changes? Does the eosinophilia in onchocerciasis induce damage of dermal collagen? What is the role of parasite-derived chemicals such as lipids in the chronic inflammation common to many nematode diseases? Are parasite products involved in the acute phases of inflammation: do they cause the severe and very discomforting pruritus and fevers in filariasis? The answers to such questions will affect many millions of sufferers around the world.

In this issue, Parasitology Today begins a series on the pathology of parasitic diseases with an article on The Pathophysiology of Severe Falciparum Malaria (pp. 271-282)*. The series will cover many of the protozoal and helminth infections mentioned in Fig. I, comparing the basic inflammatory processes with the better defined changes seen in bacterial and viral diseases. The series should help investigators to reconfirm their awareness of responses in whole tissues, for it is in these 'experiments of nature', in the infected tissues, that many of the answers lie. It may be more difficult to analyse responses in vivo but efforts in this direction may be more efficient than many in vitro studies where findings can be misleading due to the absence of natural interacting systems. This series of articles is presented with this holistic approach in mind, and it is hoped that they will serve to remind investigators of the full complexity of parasitic diseases, helping to place in context the many detailed studies currently in progress. Charles Mackenzie is Director of the Wolfson Tropical Pathology Unit, London School of Hygiene and Tropical Medicine, Keppel Street, London WC l E 7HT, UK. References

t Sell,S,(1972)in Immunolo~/,Immunopathology c]ndimmunity, Harperand Row,New York