Chapter 57 Intestinal Protozoan Infestation and Systemic Illness
Introduction
The gastrointestinal tract is the largest organ of immune surveillance in the body, home to two thirds of the total lymphocyte population.1 Regulatory T cells play a crucial role among the lymphocytes responding to protozoan infestation, so parasitic infestation may alter the immune response environment, exerting a major impact on systemic responses, including allergy and autoimmunity.2 Systemic immunologic reactivity may occur in the absence of digestive complaints.3–7
Protozoa
Giardia spp.
Human giardiasis may provoke asthma,8,9 urticaria,10–14 arthritis,5,14–17 and uveitis,18 presumably by inducing immunologic hypersensitivity. Urticaria induced by Giardia has been associated with specific anti-Giardia immunoglobulin-E (IgE), which is not found in patients with intestinal symptoms only. IgE production is associated with increased activity of vascular and intercellular adhesion molecules.19 Giardia may also provoke systemic illness through malabsorption or protein loss, which can occur without diarrhea.20 Iron deficiency,21,22 low levels of carotene and folate,23 and abnormal absorption of vitamin A,24–26 folic acid, and vitamin B1220 can result from chronic giardiasis and add to the burden of illness, even in patients who appear well-nourished.25 Giardiasis may also induce small intestinal bacterial overgrowth20,27 and jejunal candidosis,28 each of which may independently cause systemic symptoms. G. lamblia may also act as a vector for double-stranded RNA viruses.29
Giardiasis was identified in 61 of 218 consecutive patients presenting to the author’s medical clinic with a chief complaint of chronic fatigue.30 The symptoms of patients with and without giardiasis are shown in Table 57-1. Giardiasis was strongly associated with myalgia, muscle weakness, flu-like feelings, sweats, adenopathy, and a previous diagnosis of chronic fatigue immune dysfunction syndrome (CFIDS). Cure of giardiasis resulted in clearing of fatigue and related “viral” symptoms (myalgia, sweats, flu-like feelings) in 70% of cases and in some palliation of fatigue in 18%. The association between intestinal protozoa and chronic fatigue in patients without prominent digestive complaints may not be limited to giardiasis. In an unpublished presentation, the author reported that 80% of patients with a diagnosis of CFIDS who were infected with the protozoan Blastocystis hominis showed significant improvement of fatigue associated with treatment that cleared the protozoa from stool specimens.31As in giardiasis, infestation with B. hominis has also been associated with several patterns of urticaria: acute, chronic, and pressure-induced.32–34
TABLE 57-1 Systemic Symptoms of Patients with Chronic Fatigue Immune Dysfunction Syndrome
| SYMPTOM | WITH GIARDIASIS (%) (n = 63) | WITHOUT GIARDIASIS (%) (n = 157) |
|---|---|---|
| Depression | 61 | 41 |
| Muscle weakness | 46 | 19 |
| Headache | 41 | 36 |
| Sore throat | 41 | 11 |
| Lymphadenopathy | 36 | 8 |
| Arthralgia | 36 | 27 |
| Myalgia | 34 | 18 |
| Flu-like symptoms | 34 | 6 |
| Poor exercise tolerance | 30 | 10 |
Modified from Galland L, Lee M, Bueno H, et al. Giardia lamblia infection as a cause of chronic fatigue. J Nutr Med 1990;2:27-32.
Entamoeba histolytica
Chronic infestation with Entamoeba histolytica has been associated with autoimmune phenomena, including the appearance of antibodies to colonic epithelial cells35 and the development of ulcerative colitis after cure of amebic colitis.36 Extraintestinal autoimmune reactions to intestinal amebiasis include a case of antiphospholipid antibody syndrome with deep vein thrombosis and pulmonary embolism37 and development of symmetrical polyarthritis mimicking rheumatoid arthritis.5,38–41 Diarrhea, polyarthritis, and circulating antinuclear antibodies developed in a United States serviceman heavily infested with Endolimax nana, an allegedly nonpathogenic ameba.42 Metronidazole rapidly reversed all abnormalities. Amebic arthritis may be an example of parasitic rheumatism, an inflammatory polyarthropathy produced by circulating antigen–antibody complexes.43,44 Reiter syndrome (arthritis, uveitis, and urethritis) has been reported as a complication of infection with two other intestinal protozoa, Cryptosporidium45–47 and Cyclospora.48 Cyclospora cayetanensis has also provoked Guillain-Barré syndrome, a severe autoimmune neuropathy.49
E. histolytica contains a soluble lectin that is mitogenic for T lymphocytes.50,51 Activation of helper T cells by this lectin may induce replication of human immunodeficiency virus (HIV) in vivo. In one report, soluble E. histolytica protein, although not mitogenic itself, induced HIV replication in tissue culture of lymphocytes obtained from three of seven men with chronic HIV infection.52 Infection with E. histolytica and other parasites may promote the development of acquired immunodeficiency syndrome in HIV-infected individuals.53,54 Epidemiologic evidence associated preexisting intestinal protozoan infection with the appearance of Kaposi’s sarcoma among homosexual men in the United States.55 Although the influence of treating intestinal protozoan infection on the course of HIV infection has not been systematically studied, treatment of intestinal helminth infestation decreased the HIV viral load among African patients with AIDS.56 Synergism between intestinal parasites and other lymphotrophic retroviruses was considered an explanation for the pathogenesis of Burkitt lymphoma57 and adult T-cell leukemia and/or lymphoma.58
Diagnostic Considerations
Protozoan infection is usually diagnosed with stool examination; however, comparison of results of stool microscopy and duodenal aspiration has consistently shown that stool may fail to contain identifiable parasites even at the height of acute giardiasis.59,60 Some authorities have suggested empirical treatment for intestinal parasites in high-risk groups, such as immigrants to the United States from Asia, the Middle East, sub-Saharan Africa, Eastern Europe, Latin America, and the Caribbean, and have justified this approach on a cost-effective basis, given the safety of current medical therapies.61 A similar case might be made for treating chronically ill patients at high risk for parasitic infection because of residence, travel, sexual practices, or the context in which illness occurred.
Therapeutic Considerations
Artemisia annua
Numerous naturally occurring substances have antiprotozoan activity. The most extensively studied is Artemisia annua (sweet Annie or qinghao), a plant that yields the lactone artemisinin (qinghaosu), which is the basis for a new class of antimalarial compounds widely used in Asia and Africa.62 Artemisinin is thought to owe its antiprotozoan effects to its content of endoperoxides and killing of parasites through oxidation. Its activity, at least in the treatment of Simian malaria, is enhanced by coadministration of cod liver oil and diminished by coadministration of vitamin E. Artemisinin has low toxicity. In addition to its antibiotic activity, it stimulates macrophages, an important component of the immune response to protozoan infestation.63 Artemisinin may induce abortion if given during pregnancy.
Berberine
The alkaloid berberine can be extracted from the roots of several plant species, notably Berberis aquifolium (Oregon grape), Hydrastis canadensis (goldenseal) root, and Coptis chinensis (goldthread). Berberine has protostatic and protocidal activity against E. histolytica, G. lamblia, and B. hominis.64–66 It has shown benefit in the treatment of giardiasis in children.67
Allium sativum and Juglans nigra
Allium sativum (garlic) and Juglans nigra (black walnut) have a long history of use as antimicrobials. Allicin inhibits growth of E. histolytica in culture68 and may be responsible for the antimicrobial activity of garlic.69 Human studies on the efficacy of garlic and black walnut in treatment of protozoan infections are lacking.
Intestinal Bacterial Milieu
The intestinal bacterial milieu may be important in the treatment of protozoan infestation, especially for colonic organisms like E. histolytica. Pathogenic strains of E. histolytica are able to evade lysis by both classic and alternative pathways of complement. Intestinal bacteria, Escherichia coli in particular, are necessary for complement resistance and for amebic virulence.70 Gitler and Mirelman71 suggested that ingested bacteria lowered the redox potential within the parasite and allowed the amebae to escape destruction by oxidative enzymes.71 Mirelman et al72 reported that one can reversibly change the zymodeme patterns of E. histolytica isolates from nonpathogenic to invasive by culturing amebae with the gut flora of patients who have either invasive disease or no symptoms. Optimal treatment of protozoan infection requires not only the administration of antimicrobial substances but also strategies aimed at enhancing the function of intestinal resistance factors such as secretory IgA and phagocyte function and creating a bacterial milieu that is not parasite friendly.
Conclusion
Intestinal protozoan infestation is a significantly underrecognized cause of systemic illness. Undiagnosed infestations with Giardia spp., E. histolytica, and other organisms have been associated with diverse diseases such as arthritis, asthma, Reiter syndrome, urticaria and uveitis, CFIDS, increased rate of progression of HIV infection, and a wide range of systemic dysfunction, such as fatigue, malabsorption, muscle weakness, and myalgia. Effective eradication of protozoa can result in surprisingly quick and complete clinical response.
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