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 overgrowth^20,²⁷ 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 In an unpublished presentation, the author reported that 80% of patients with a diagnosis of CFIDS who were infected with the protozoan Blastocystis hominis showed significant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 cells ³⁵ 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.

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