Protozoan Infestation and Systemic Illness
Leo Galland M.D.
Foundation for Integrated Medicine, New York, N.Y.
gastrointestinal tract is the largest organ of immune surveillance in the
body, home to two-thirds of the total lymphocyte population.
Intestinal lymphocytes manifest a
variety of responses which depend upon their CD phenotype, histologic location and communication with other effector cells. Stimulation of intestinal immune response
networks by lumen-dwelling microbes may produce a variety of systemic
responses that are independent of gastrointestinal symptoms.
Immunologic hypersensitivity to Giardia lamblia has
been shown to provoke asthma
arthritis (reference 11 + 
Hypersensitivity reactions may occur in the absence of digestive complaints (refs
6. 10, 15). In none of these cases was the mechanism of hypersensitivity
known; eosinophilia. was a
feature in only two cases (refs 10,11)). A high frequency of pre-existing
atopic disease occurs in patients with chronic giardiasis and may be a factor in susceptibility to
Immunologic mechanisms other than
hypersensitivity reactions may also be associated with chronic giardiasis. In
humans, chronic giardiasis has been associated with
deficiency of secretary IgA
and with impaired macrophage cytotoxicity,
characteristics that may predispose to systemic illness. Athymic
mice chronically infected with Giardia muris do not develop mucosal damage.
Gillon et al. have proposed that the release
of enteropathic lymphokines
by intraepithelial T cells is the cause of the intestinal injury in chronic giardiasis.
In humans, the severity of malabsorption observed
with chronic giardiasis is more closely related to
the presence of intraepithelial lymphocytes and the antibody titer to Giardia cyst antigen than to the estimated
A normal immunologic response to the parasite may be necessary to avoid
chronic infection but also creates much of the tissue damage associated with
Giadia may provoke systemic illness by non-immunologic
mechanisms. G. lamblia can cause intestinal
protein loss without producing diarrhea.
Specific micronutrient deficiencies have also been described in chronic giardiasis. Low levels of carotene and folate
and abnormal vitamin A, folic acid and vitamin B12 absorption (ref 24) occurs
in a large minority of patients with chronic symptoms. Nutritional deficiency
associated with chronic giardiasis may add to the
burden of illness. Bacterial overgrowth of the small bowel has been described
in giardiasis and may contribute
to malabsorption (ref 24 + .
Colonization of the jejunum with Candida albicans
was reported in 30% of patients with giardiasis and
was absent in controls.
A role for intestinal candidosis in provoking
systemic illness has been debated for a quarter century (review in ref # 2 ). Some strains
of G. lamblia contain double-stranded RNA viruses .
The role of Giardia as a vector for viral
infection requires further study.
Galland et. Al.
conducted a two-year retrospective study of 218 patients who presented to our
medical clinic with a chief complaint of chronic fatigue (ref 18). G. lamblia infection was identified in 61 patients. The
symptoms of patients with and without giardiasis, are shown in Table 1. All patients with giardiasis and 86% of patients without giardiasis complained of digestive symptoms, but these
were generally mild. The most interesting difference between the two groups
lies in the positive association between giardiasis
and symptoms such as myalgia, muscle weakness,
flu-like feelings, sweats and adenopathy. In fact,
61% of fatigued patients with giardiasis had been
diagnosed elsewhere as suffering from chronic fatigue immune dysfunction syndrome
(CFIDS), compared to only 19% of fatigued patients without giardiasis. Cure of giardiasis
resulted in clearing of fatigue and related 'viral' symptoms (myalgia, sweats, flu-like
feelings) in 70% of cases, some palliation of fatigue in 18%, and was of no
benefit in 12%. The association between intestinal protozoa and chronic
fatigue in patients without prominent digestive complaints may not be limited
to giardiasis. In an, unpublished presentation, Galland 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.
Chronic infestation with Entamoeba histolytica, another common protozoan parasite, has
been associated with autoimmune phenomena, including the appearance of antibodies
to colonic epithelial cells
and the development of ulcerative colitis after cure of amebic colitis.
Extra-intestinal autoimmune reactions to intestinal amebiasis
include a case of antiphospholipid antibody
syndrome with deep vein thrombosis and pulmonary embolism
and development of symmetrical polyarthritis very
similar to rheumatoid arthritis (RA) 
Singh et al.
measured amoebic antibody levels in 41 Indian patients with a primary
diagnosis of RA, 35 age- and sex-matched healthy volunteers, 162 hospital
inpatients and 26 patients with other arthritides.
Amoebic antibodies were elevated in 39% of RA patients and 0-11% of the
various control groups. Only two patients with RA had experienced recent
diarrheal disease. These authors suggest that an excessive and prolonged
antibody response to Entamoeba histolytica or other enteric organisms may contribute
to joint inflammation in RA.
Galland (ref 15)
described a patient with rheumatoid-like arthritis and antinuclear antibodies
whose arthritis went into rapid and complete remission upon treatment of G.
lamblia infection with metronidazole.
Relapse occurred when the patient acquired Entamoeba
histolytica during a trip to Egypt;
remission occurred slowly following treatment of amoebiasis.
Diarrhea, polyarthritis and circulating antinuclear
antibodies developed in a United
States serviceman heavily infested with Endolimax nana, an allegedly non-pathogenic
Metronidazole rapidly reversed all abnormalities.
The reported cases of amoebic arthritis may represent a variant of parasitic
rheumatism, an inflammatory polyarthropathy
produced by circulating antigen-antibody complexes.
The presence of autoantibodies, however, is not
characteristic of parasitic rheumatism, and suggests other mechanisms of
immune dysfunction: either a pre-existing disease is exacerbated by intercurrent amoebic infection or amoebic infection
itself provokes autoirnmunity, perhaps mediated by
the action of immune response genes (ref 23). Reiter’s Syndrome (arthritis, uveitis and urethritis) has
been reported as a complication of infection with two other intestinal
has also provoked Guillain-Barre syndrome, a severe
Entamoeba histolytica contains a soluble lectin
which is mitogenic for T lymphocytes
T helper cell activation by this lectin may induce
HIV replication in vivo. A soluble Entamoeba
histolytica protein, although not mitogenic itself, induced HIV replication in tissue
culture of lymphocytes obtained from three out of seven men with chronic HIV infection .
Infection with E. histolytica and other
parasites may promote the development of AIDS in HIV-infected individuals
Epidemiologic evidence associates
pre-existing intestinal protozoan infection with the appearance of Kaposi’s
sarcoma among homosexual men in the United States.
Although the influence of treating intestinal protozoan infection on the
course of HIV infection has not been systematically studied, treatment of
intestinal helminth infestation decreases the HIV
viral load among African patients with AIDS.
Synergism between intestinal parasites and other lymphotrophic
retroviruses has been advanced as an explanation for the pathogenesis of Burkitt's lymphoma 
and adult T cell leukemia/lymphoma
Protozoan infection is usually
diagnosed by stool examination, however, comparison
of stool microscopy with duodenal aspiration has consistently shown that
stool may fail to contain identifiable parasites even at the height of acute giardiasis.
multiple specimens over several days increases the sensitivity to 85-90%.
Laboratories that specialize in tropical medicine or parasitology
are more likely to find organisms in stool specimens than are general or
hospital laboratories [reference to be supplied]. Some authors 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 on a cost effective basis, given the safety of
current medical therapies.
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.
Numerous naturally occurring
substances have anti-protozoan 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
anti-malarial compounds widely used in Asia and Africa..
Artemisinin is thought to owe its anti-protozoan
effects to its content of endoperoxides and to kill
parasites through oxidation. Its activity, at least in the treatment of
Simian malaria, is enhanced by co-administration of cod liver oil and
diminished by co-administration of vitamin E (reference to follow). Artemisinin has low toxicity. In addition to its
antibiotic activity, it stimulates macrophages, an important component of the
immune response to protozoan infestation.
Artemisinin may induce abortion if given during
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 protocial activity against E. histolytica, G. lamblia
and B. hominis.
 It has shown benefit in the treatment of giardiasis in children
Allium sativum (garlic) and Juglans nigra (black walnut) have a long history of use as
antimicrobials. Allicin inhibits growth of E. histolytica
and may be responsible for the antimicrobial activity of garlic.
. Soffar SA. Mokhtar GM.
Department of Parasitology,
Faculty of Medicine, Ain Shams
Evaluation of the antiparasitic
effect of aqueous garlic (Allium
sativum) extract in hymenolepiasis
nana and giardiasis.
Journal of the Egyptian Society of Parasitology.
The effect of serial dilutions of crude
garlic (Allium sativum)
extract on adult
Hymenolepis nana was studied to detect the minimal
which was found to be 1/20. A. sativum was tried in
the treatment of
10 children infected with H. nana and 26 infected with
G. lamblia as 5 ml crude extract in 100 ml water in 2 doses
per day, or
preparation (0.6 mg capsules) 2 capsules twice/day for 3
days. A sativum was found to be efficient, safe and shortens the
duration of treatment.
The possible mode of action of A. sativum and the
between the clinical and parasitological findings were
The intestinal bacterial milieu
may be important in the treatment of protozoan infestation, especially for
colonic oprganisms like E. histolytica. Pathogenic strains of Entameba
histolytica are able to evade lysis by both classical and alternative pathways of complement.
Intestinal bacteria, E. coli in particular, are necessary for complement
resistance and for amebic virulence.
Mirelman has suggested that ingested bacteria lower
the redox potential within the parasite and allow
the amebae to escape destruction by oxidative
He has reported that one can reversibly change the zvmodeme
patterns of Entameba histolytica
isolates from non-pathogenic to invasive by culturing amebae
with the gut flora of patients who have either invasive disease or no
Optimal treatment of protozoan infection requires not only the administration
of antimicrobial substances, but strategies aimed at enhancing the function
of intestinal resistance factors like secretory IgA and phagocyte function and creating a bacterial milieu
that is not parasite friendly.
1 Systemic symptoms
of CFS patients
(%) (N = 63)
(%) (N = 157)
 Targan, R. S., Kagnoff,
F. M., Brogan, M. D. and Shanahan, F. (1987) Immunologic mechanisms in
intestinal disease. Annals of
Internal Medicine, 106, 854-870.
 Galland L. The Effect of Systemic Microbes on intestinal Immunity. Post-Viral fatigue Syndrome, R. Jenkins and J. Mowbray,
editors. John Wiley & Sons Ltd. London. 1991. pp 405-430.
 Fossati, C. (1971) Manifestazioni broncopulmonari in corso di infestazione da Giardia lamblia. Revista Iberica de Parisitologia, 31,
 Lopez-Brea, M., Sain, Z. T., Camarero, C. and Baquero, M.
(1979) Giardia lamblia
associated with bronchial asthma and serum antibodies, and chronic diarrhoea in a child with giardiasis.
Transactions of the Royal Society of Tropical Medicine and
Hygiene, 73, 600.
 Harris, R. H. and Mitchell, J. H. (1949) Chronic urticaria due to Giardia lamblia. Archives
of Dermatology and Syphilology, 59, 587-589.
R. E. (1958) Urticaria associated with giardiasis lamblia. Journal of
Allergy, 28, 351-353.
 Webster, B. H. (1958) Human infection with Giardia
lamblia. American Journal of Digestive
Diseases, 3, 64-71.
 Dellamonica, P., Le Fichoux, X., Monnier, B. and Duplay, H. (1976)
Syndrome dysenterigue et urticaire, au cours d'une giardiase. Nouvelle Presse Medicale, 5, 1913.
 Weisman, B. L. (1979) Urticaria and Giardia lamblia
infections. Annals of Allergy, 49,91.
 Kennou, M. F.
(1980) Skin manifestation of giardiasis. Some clinical cases. Archives de Institut
Pasteur de Tunis, 51, 257-260.
 Farthing, M. J. G., Chong, S. K. F. and Walker-Smith, J. A.
(1983) Acute allergic phenomena in giardiasis.
Lancet, 2, 1428.
 Goobar, J. P. (1977) Joint symptoms in giardiasis. Lancet,
 Woo, P. and Panayi, G. S. (1984) Reactive
arthritis due to infestation with Giardia lamblia. Journal of Rheumatology, 11, 719.
 Shaw, R. A. and Stevens, M. B. (1987) The
reactive arthritis of giardiasis. A
case report. Journal of the American Medical Association, 258,
 Galland, L. (1989) Intestinal protozoan infection is a common
unsuspected cause of chronic illness. Journal of Advancement in Medicine,
 Carroll, M. E., Anast, B. P. and
Birch, C. L. (1961) Giardiasis and uveitis. Archives of Ophthalmology, 65, 775-778.
Chester, C. A., Macmurray,
F. G., Restifo, M. D. and Mann, 0. (1985) Giardiasis
as a chronic disease. Digestive Disease and Sciences, 30,
 Galland, L., Lee, M., Bueno,
H. and Heirnowitz, C. (1990) Giardia
lamblia infection as a cause of chronic fatigue. Journal of Nutritional Medicine, 2, 27-32.
 Vinayak, V. K., Kij, K., Venkateswarlu, K., Khanna, R. and
Mehta, S. (1987) Hypogarnmaglobulinaernia in children
with persistent giardiasis. Journal of Tropical
Pediatrics, 33, 140-142.
 Smith, P. D., Gillin, F. D., Spira, W. M. and Nash, T. E. (1982) Chronic
giardiasis: Studies on drug sensitivity, toxin
production, and host immune response. Gastroenterology, 83, 797-803.
 Roberts-Thompson, 1. C. and Mitchell, G. F. (1978) Giardiasis
in mice 1. Prolonged infections in certain mouse sh-ains and hypothymic (nude)
mice. Gastroenterology, 75, 42-46.
 Gillon, J., Althamery,
D. and Ferguson, A. (1982) Features of small intestinal pathology (epithelial
cell kinetics, intraepithelial lymphocytes, disaccharidases)
in a primary Giardia muris
infection. Gut, 23, 498-506.
 Solomons, N. W. (1982) Giardiasis:
nutritional implications. Reviews of Infectious Diseases, 4, 859-869.
 Sherman, P. and Liebman, W. L.
(1980) Apparent protein-losing enteropathy
associated with giardiasis. American Journal of
Diseases of Children, 134, 893-894.
 Brasitus, T. A. (1983) Parasites and malabsorption. Clinics
in Gastroenterology, 12, 495-511.
 Tompkins, A. M., Wright, S. G., Draser, B. S. and James, W. P. T. (1978) Bacterial
colonization of jejunal mucosa in giardiasis. Transactions of the Royal Society of Tropical Medicine
and Hygiene, 72, 33-36.
 Naik, S. R., Rau, N. R., Vinajak, V.
K., Narayanna, V. A., Zunzurwade,
S., Sehgal, S. C. and Talwar,
P. (1978) Presence of Candida albicans in
normal and in Giardia lamblia
infected human jejunum. Annals of Tropical Medicine and Parasitology,
 denHollander, N., Riley, D. and Befus, D.
(1988) Immunology of Giardia. Parasitology Today, 4, 124-133.
 “Patient-centered diagnosis and treatment for chronic
fatigue syndrome”, annual scientific session of the American Acadeemy of Environmental Medicine, Virginia beach, Virginia, October 7, 1994.
 Salem, E., Zaki, S.
A., Moneim, W. A., Kadrv,
S., Eisa, H. and Ezz, F. A.
(1973) Antoantibodies in amoebic colitis. Journal of the Egyptian Medical Association, 56,
 Sturgess I, Greenfield SM, Teare
J, O'Doherty MJ. (1992). Ulcerative colitis developing
after amoebic dysentery in a haemophiliac patient
with AIDS. Gut. 33, 408-410.
 Korkmaz C, Harmanci E, Metintas I, Gulbas Z . (2001). Antiphospholipid
syndrome associated with intestinal amoebiasis. Scandinavian Journal of Infectious Disease 33,:938-40
 Zinneman, H. H. (1950) Ten cases of amebiasis with arthritic complaints. American Journal of
Digestive Diseases, 17, 343-344.
 Rappaport, E. M., Rossieu, A. X. and Rosenblum, L. A. (1951) Arthritis due to intestinal amebiasis. Annals of Internal Medicine, 34,
 Kasliwal, R. M. (1970) Correlation between amoebic colitis and
rheumatoid arthritis. Journal of the Association of Physicians of India, 18,
 Singh, 1. P., Das, S. K., Sharma, P., Dutta, G. P. and Agarwal, S. S.
(1985) Antibodies to Entamoeba histolytica in patients with rheumatoid arthritis.
Tropical Gastroenterology, 6, 141-144
 Burnstein, S. L. and Liakos, S. (1983) Parasitic rheumatism presenting as rheumatoid arthritis. Journal
of Rheumatology, 10, 514-515.
 Bocanegra, T. S., Espinoza, L. R., Bridgeford,
P. H., Vasey, F. B. and Germani,
B. F. (1981) Reactive arthritis induced by parasitic infestation. Annals of
Internal Medicine, 94, 207-209.
Cron RQ, Sherry DD (1995).
Reiter's syndrome associated with cryptosporidial
gastroenteritis. Journal of Rheumatology
Connor BA, Johnson EJ, Soave R. (2001) Reiter syndrome following
protracted symptoms of Cyclospora infection.
Emerging Infectious Diseases 7, 453-4
 Richardson RF Jr, Remler
BF, Katirji B, Murad MH.
(1998), Guillain-Barre syndrome
after Cyclospora infection.Muscle
nerve. 5, 669-671.
 Chen, Z. C., Herrmann, F., Koleski,
F. and Diamantstein, T. (1985) Mitogenic
factor for T inducer/ helper cells in Entamoeba
histolytica extracts. Acta
Academiae Medicina Wuhan, 5 (4),
 Petri, W. A. and Ravdin, J. I.
(1986) Treatment of homosexual men infected with Entamoeba
histolytica. New England Journal
of Medicine, 315, 393.
 Croxson, S., Mildran,
D., Mathews, H. and Poiez, B. J. (1988) Entamoeba histolytica
antigen-specific induction of Human Immunodeficiency Virus replication. Journal of Clinical Microbiology, 26, 292-294.
 Pearce, R. B. and Abrams, D. (1987) Entamoeba histolytica
in homosexual men. New
England Journal of Medicine, 316, 690-691.
 Archer, D. L. and Glinsman, W. H.
(1985) Enteric infections and other co-factors in
AIDS. Immunology Today, 6, 292-294.
 Abrams DI. (1990). The relationship
between Kaposi's sarcoma and intestinal parasites among
homosexual males in the United States.Journal of the
Acquired Immune Deficiency Syndrome ;3 Suppl 1:S44-6
 Wolday D, Mayaan S, Mariam ZG, Berhe N, Seboxa T, Britton S, Galai N, Landay A,
Bentwich Z. (2002). Treatment of
intestinal worms is associated with decreased HIV plasma viral load. Journal
Immune Deficiency Syndrome 31, 56-62
 Burkitt, D. P. (1983) The discovery of Burkitt's lymphoma. Cancer, 51, 1777-1786.
K., Tominaga, S., Shimizu, H. and Suchi,
T. (1981) A hypothesis on the etiology of adult T-cell leukemia/ lymphoma. Gann, 72,684-691.
Rosenthal, P. and Liebman, W. M. (1980) Comparative study of stool
examinations, duodenal aspiration, and pediatric Entero-Test
for giardiasis in children. Journal of Pediatrics, 96, 278-279.
 Kamath, K. R. and Murugasu, R. (1974) A comparative study of four methods for detecting Giardia lamblia in
children with diarrheal disease and malabsorption. Gastroenterology,
 Gillon, J. (1984) Giardiasis:
Review of epidemiology, pathogenetic mechanisms and
host responses. Quarterly Journal of Medicine, 53, 29-39.
 Muenning P, Pallin D, Sell RL et al (1999). The
cost effectiveness of strategies for the treatment of intestinal parasites in
England Journal of
Medicine, 340, 773-779.
 Hien TT, White NJ. (1993) Qinghaosu. Lancet. 341, 603-608.
 Tang W,
Eisenbrand G. (1992) Chinese Drugs of Plant Origin. Springer-Verlag,
 Kaneda Y, Tori N, Tanaka T, Aikawa M. (1991) In vitro effects of berberine sulfate on the growth and structure of Entamoeba histolytica, Giardia lamblia and Trichomonas vaginalis.Annals of tropical Medicine and Parasitology. 85, 417-425.
 Subbaiah TV, Amin AH. (1967) Effect of berberine
sulfate on Entamoeba histolytica..
 Yang LQ, Singh M, Yap EH, et al (1996). In vitro eresp[onse of of Blastocystic hominis against traditional Chinese
medicine. Journal of Ethnopharmacology.
 Gupte S. (1975). Use of berberine in treatment of giardiasis.
American Journal of Diseases of Childhhod.
 Mirelman D, Monheit D, Varon S (1987). Inhibition of growth of Entaoeba histolytica
by allicin, the active principle in garlic extract
(allium sativum). Journal of Infectious Diseases. 156, 243-244.
CW, Phillipson JD, (1987). Natural products and the
development of selective antiprotozoan drugs. Phytotherapy esearch. 4, 1127-139.
 Wittner, M. and Rosenbaum, R. M. (1970) Role of
bacteria in modifying virulence of E. histolytica. Studies of amoebae from axenic cultures. American Journal of Tropical
Medicine and Hygiene, 19, 755-761.
 Gitler, C. and Mirelman, D. (1986)
Factors contributing to the pathogenic behavior of Entamoeba
histolytica. Annual Reviews of Microbiology,
 Mirelman, D., Bracha, R., Chayen, A., Anst-Kettis, A. and
Diamond, L. S. (1986) Entamoeba histolytica: effect of growth conditions and bacterial
associates on isoenzyme patterns and virulence. Experimental
Parasitology, 62, 142-148.
 Mirelman, D. (1987) Effect of culture condition and bacterial
associates on the zymodemes of Entamoeba
Today, 3, 37-40.
This article is provided for general educational purposes only and is not intended to constitute (i) medical advice or counseling, (ii) the practice of medicine or the provision of health care diagnosis or treatment, (iii) the creation of a physician--patient relationship, or (iv) an endorsement, recommendation or sponsorship of any third party product or service by the sender or the sender's affiliates, agents, employees, or service providers. If you have or suspect that you have a medical problem, contact your doctor promptly.