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Pathogenesis and Diagnosis of Parasitic Infection
The pathogenesis of both protozoan and helminthic disease is highly variable. Many factors contribute to this variability and included among them may be factors such as parasite size, induced injury, reproductive potential, nutritional requirements (including metabolites or toxins produced), niche selection (often influenced by individual life cycles and migration patterns through the host), and last, but not the least, immunologic consequences of infection.
Parasite size may or may not be a predictor of pathogenesis. Many of the parasitic Protozoa, including those that cause malaria (Plasmodium), African sleeping sickness (Trypanosoma brucei subspecies), Chagas disease (T cruzi), and leishmaniasis (Leishmania), are among the most pathogenic. The giant cestode, Diphyllobothrium latum, can reach sizes exceeding 10 m, yet produces a pernicious anemia due to vitamin B12 competition with the host in less than 1% of the infected individuals. Ascaris lumbricoides, which can grow up to a foot in length can cause severe intestinal blockage if enough worms are present. The larval hydatid cyst of the tapeworm Echinococcus granulosus can achieve considerable size if given long enough to grow and can put tremendous pressure on organs it may be found within.
Parasite-induced injury frequently results from parasite invasion of host tissues. Hookworms, Strongyloides and Trichuris, repeatedly probe the intestinal or colon lining, promoting and inducing extensive, immunologically mediated inflammatory responses. In these cases, worm burden determines the extent of the pathogenesis. The egg laying of schisto-some parasites determines the pathology of this infection as many eggs get trapped in tissues in their attempt to leave the host. The result is extensive inflammation and eventual fibrosis of affected tissues.
The reproductive potential of parasites varies considerably. Protozoa generally have very short generational times. In large part, this is due to the asexual nature of their reproduction for much of their life cycles. Rates vary from several hours (African trypanosomes) to several days (malaria). This can place tremendous pressure on host resources with attendant consequences. Helminthes, however, are usually incapable of reproducing within their definitive hosts, so overall worm burden becomes a greater determinant of pathogenesis. This, in turn, will depend on how many eggs, or larvae, initiated the infection. An exception is encountered in Trichinella, in which fertile female residing within the intestinal lining give birth to larvae that migrate to the musculature.
Nutritional requirements among parasites vary tremendously, although most tend to be facultative anaerobes. All Trypanosoma spp. metabolize carbohydrates from their host, but the metabolites are fermentation-like end products of pyruvate that can affect endothelial linings within the host. Malaria parasites of the genus Plasmodium ultimately have rather synchronous infections and produce byproducts of metabolism, including insoluble hemozoin, which when released from infected cells trigger a rise in proinflammatory cytokines that cause fever and impair the functioning of macrophages. Hookworms, because of their voracious appetite and wasteful digestive methods, deplete the iron in the host, resulting in severe anemia if the worm burden is great enough. Hookworms, and many of their allies, also produce powerful enzymes to help predigest what they take in. These enzymes help produce inflammatory responses. Entamoeba histolytica and Trichomonas vaginalis produce enzymes that help mediate contact-dependent cytotoxicity reactions. In the case of E histolytica, this helps the parasite establish extraintestinal sites of infection. In one very interesting case, the death of filarial parasites or their larvae in a definitive host also releases mutualistic endosymbionts. These are felt to contribute to inflammatory responses seen in such infections as those caused by Onchocerca volvulus and resulting in river blindness.
Where the parasite resides or migrates during establishment in the host can also be a strong determinant of pathogenesis. Many helminth parasites undergo an obligatory migration through the blood stream that brings them in contact with lung tissue. This required migration often results in Loeffler syndrome that is manifest as an eosinophilic inflammatory response. Larval stages of Taenia solium are frequently encountered in brain tissue, resulting in neurocysticercosis. Parasites such as Toxocara canis may be unable to complete full development in humans, but larvae try to migrate through tissues, causing visceral larval migrans. Many more examples will be expanded upon in chapters that follow.
Finally, there can be numerous immunologic consequences of infection that help promote pathogenesis. Antigen, antibody, and complement complexes combine to cause excessive anemia and glomerulonephritis in African trypanosomiasis. Allergic reactions play a major role in the cutaneous reactions to invading hookworm, Strongyloides, and schistosome larvae (ground itch, swimmers’ itch). Transient pneumonias induced by the pulmonary migration of Ascaris and other nematode larvae (Loeffler syndrome), nocturnal paroxysms of asthma in some patients with filariasis (tropical pulmonary eosinophilia), and the shock, asthma, and urticaria that follow rupture of a hydatid cyst all are immunologically mediated. The latter frequently results in anaphylaxis. Cardiac damage in Chagas disease is thought, at least in part, to reflect immune-induced inflammatory responses, or perhaps autoimmune-related phenomena. Immune complex diseases are seen in schistosomiasis (Katayama syndrome) and malaria (nephrosis). The granulomatous reaction to schistosomal eggs is the result and antibody-dependent, cell-mediated cytotoxic (ADCC) responses. The entire clinicopathologic spectrum of manifestations arising from leishmanial infections appears to be caused by differences in the ability of cell-mediated immune responses to function properly.
Immunopathologic mechanisms contribute to parasitic diseases
IMMUNITY AND IMMUNE EVASION
The large size, complex structure, varied metabolic activity, and synthetic prowess of most parasites provide their human host with an intense antigenic challenge. Generally, the resulting immunologic response is vigorous, but its role in modulating the parasitic invasion differs significantly from that in viral and bacterial infections. It is apparent from the chronic course and frequent recurrences typical of many parasitic diseases that complete acquired resistance resulting in sterile immunity is often absent. Immunity does, however, frequently serve to moderate the intensity of the infection and its associated clinical manifestations. In fact, clinical recovery and resistance to reinfection in some instances require the persistence of viable organisms at low concentration within the body of the host (premunition = infection immunity). An excellent example of this is seen in patients infected with Toxoplasma gondii.
Immune response to parasites vigorous but often relatively ineffective
All those immune responses generally exercised against the more primitive viral and bacterial microorganisms, including innate responses, driven by the complement system, dendritic cells and natural killer cells, and adaptive (acquired) responses, driven by antibodies, cytokines (lymphokines), cytotoxic T lymphocytes, activated macrophages, memory cells, and ADCC mechanisms, have been shown to play a part in modulating parasitic infection.
Innate immune responses are usually immediate, less specific and evolutionarily considered older than adaptive responses. Innate responses often depend on pattern recognition molecules leading to the destruction of bound organisms by complement activation and phagocytosis. Receptor engagement and activation is often critical to further involvement by adaptive responses. One example of innate responses manifest against parasite infections including those seen against malaria. The innate immune response to malaria involves multiple mechanisms, but rarely results in clearance of the parasite. Similar to other protozoan parasites, P falciparum