The ease with which G. muris infections are established in mice varies
with the genetic background of the host (Belosevic et al., 1984). Acute
murine giardiasis suppresses the response of splenic and mesenteric lymphocytes
to sheep erythrocytes; susceptible mice express a greater degree of immunosuppression
than do resistant mice (Belosevic et al., 1985a). Acute giardiasis in
rodents is associated with increased intestinal production of prostaglandins
E and F (Ganguly et al., 1984b) and cyclic AMP (Ganguly et al., 1984a),
probably a result of macrophage activation (Kanwar et al., 1987). Just
as production of PGE by host macrophages may contribute to diarrhea, activation
of a population of suppressor macrophages in mesenteric lymph nodes contributes
to immunosuppression in acute giardiasis (Belosevic et al., 1985b). Disaccharidase
deficiency, a frequent complication of giardiasis, may also be immunologically
mediated. Sensitized gerbils develop a depression of disaccharidase activity
when exposed to Giardia antigens; live organisms are not required (denHollander
et al., 1988).
In chronic infection, the immune response to the host also appears to be a
critical determinant of outcome (denHollander et al., 1988). Chronic
giardiasis in humans has been associated with deficiency of secretary IgA (Vinayak
et al., 1987) and with impaired macrophage cytotoxicity (Smith et
al., 1982). In animals infected with G. muris, both T helper/inducer
lymphocytes and mast cells are critical for clearance of the parasite (Heyworth
et al., 1987; denHollander et al., 1988), whereas cytotoxic T
cells and natural killer cells are not (Heyworth et al., 1986). It is
noteworthy that athymic mice with chronic giardiasis do not develop mucosal
damage (Roberts-Thompson and Mitchell, 1978). Gillon et al. (1982) 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 parasite burden (Solomons, 1982).
In rodents and humans, therefore, acute Giardia infection elicits a
protective response from mast cells and T helper lymphocytes (responsible for
stimulating sIGA secretion) which is essential for clearance of parasites. A
macrophage response occurs as well; this is both protective (Smith et al.,
1982) and immunosuppressive (Belosevic et al., 1985b), depending
perhaps on the activity of different macrophage populations. Chronic giardiasis
is a disease of immune dysregulation in which effector lymphocytes mediate tissue
damage. Defective control of macrophage-lymphocyte communication in Giardia
infection is likely, and appears to be genetically determined. Defective macrophage-lymphocyte
communication is also a feature of human atopic disease (Galland, 1986) and
the relationship between human giardiasis and allergy is therefore of interest.
Immunologic hypersensitivity to G. lamblia has been reported; the result
may be asthma (Fossati, 1971; Lopez-Brea et al., 1979), urticaria (Harris and
Mitchell, 1949; Wilhelm, 1958; Webster, 1958; Dellamonica et al., 1976; Weisman,
1979; Kennou, 1980; Farthing et al., 1983), arthritis (Goobar, 1977; Farthing
et al., 1983; Woo and Panayi, 1984; Shaw and Stevens, 1987; Galland, 1989) and
uveitis (Carroll et al., 1961). Hypersensitivity reactions may occur in the
absence of digestive complaints (Wilhelm, 1957; Kennou, 1980; Galland, 1989).
In none of these cases was the mechanism of hypersensitivity known; eosinophilia.
was a feature in only two cases (Kennou, 1980; Farthing et al., 1983). A high
frequency of pre-existing atopic disease occurs in patients with chronic giardiasis
(Chester et al., 1985; Galland et al., 1990) and may be a factor in susceptibility
to infection. We have observed that when several members of a family are infected
with Giardia, symptoms tend to be more prominent among those with allergy.
We suspect that the immune dysregulation which underlies atopy allows the immunologic
response to Giardia infection to favor chronic disease.
Two other features of chronic giardiasis are relevant to an understanding of
CFS: the effect of G. lamblia infection on nutritional status and its
interaction with other organisms, specifically viruses, bacteria and fungi.
G. lamblia can cause intestinal protein loss without producing diarrhea
(Sherman and Lieberman, 1980). Specific micronutrient deficiencies have also
been described in chronic giardiasis. Low levels of carotene and folate (Brasitus,
1983) and abnormal vitamin A and folic acid absorption curves (Solomons, 1982)
occur in a large minority of patients with chronic symptoms. Serum vitamin B12
may be low (Cowan and Campbell, 1973), and abnormal Schilling tests occur in
a substantial number of patients (Solomons, 1982). Direct competition between
parasite and host for vitamin B,2, as suggested by Cowan and Campbell (1973),
seems unlikely, as Giardia selectively damages the duodenum and upper
jejunum, and cobalamin is absorbed in the distal ileum. Bacterial overgrowth
of the small bowel has been described in giardiasis (Yardley et al., 1965; Tandon
et al., 1977; Tompkins et fil., 1978; Rogers, 1979) and is associated with severity
of malabsorption (Tompkins et al., 1978; Tandon et al., 1977). Solomons (1982)
has proposed bacterial overgrowth as a possible cause of abnormal Schilling
tests in giardiasis. Bacteroides fragilis produces a substance which
binds the B12-intrinsic factor complex (Mackowiak, 1982) and may cause malabsorption.
Colonization of the jejunum with Candida albicans was reported in 30%
of patients with giardiasis and was absent in controls (Naik et al., 1978).
The implications of intestinal candidiasis for CFS are described later in this
chapter. Some strains of G. lamblia contain double-stranded RNA viruses
(denHollander et al., 1988). The role of Giardia as a vector for
viral infection requires further study.
Entamoeba histolytica infects 10% of the world's population (Walsh,
1986a,b). Cysts can be found in stool samples of 2% to over 40% of individuals,
depending on the area and level of hygiene and sanitation (Guerrant, 1986).
Amoebic antibodies, indicative of past or present invasive infection, were found
in 1% of general hospital patients, 2% of random serum specimens, and 4% of
healthy military recruits in the United States (Walsh, 1986b). Amoebic infection
is found in about one-third of homosexual men attending clinics for sexually
transmitted diseases in the United States (Petri and Ravdin, 1986). Over 90%
of individuals infected with Entamoeba histolytica are asymptomatic.
The clinical response to amoebic infection is better understood than the clinical
response to Giardia infection. Pathogenic strains of Entamoeba histolytica
are able to evade lysis by both classical and alternative pathways of complement
(Reed et al., 1986). Intestinal bacteria, E. coli in particular,
are necessary for this complement resistance and for amoebic virulence (Wittner
and Rosenbaum, 1970). It is suggested that ingested bacteria lower the redox
potential and allow the amoebae to escape destruction by oxidative enzymes (Gitler
and Mirelman, 1986). Whereas amoebae of low virulence are killed by granulocytes,
highly virulent amoebae resist phagocytosis and instead kill the attacking leukocytes
(Guerrant et al., 1981; Chadee et al., 1985). Mirelman (Mirelman,
1987; Mirelman et al., 1986) has reported that one can reversibly change
the zvmodeme patterns of Entamoeba histolytica isolates from non-pathogenic
to invasive by culturing amoebae with the gut flora of patients who have either
invasive disease or no symptoms. His work, which is controversial, suggests
that pathogenicity may actually be determined by the bacterial milieu.
The immunologic effects of amoebic infection have been the focus of a recent
trans-Atlantic controversy. Workers in London observed that Entamoeba histolytica
infestation of HIV-infected homosexual men involved only non-pathogenic amoebic
zymodemes; amoebic antibodies were absent and there was no association with
diarrhea or increased morbiditv (AllasonJones et al., 1986). Several
North American groups, on the other 6nd, have found that AIDS patients with
diarrhea are often infected with 'nonpathogenic' amoebae. Treatment with metronidazole
or paromomyci Produces relief of diarrhea in parallel with the disappearance
of these amoebae from feces (Rolsten et al., 1986; Sullam et al.,
1986; Pearce and Abrams, 1987). Several researchers in the United States
have advanced the notion that infection with E. histolytica and other
parasites may promote the development of AIDS in HIV-infected individuals (Pearce,
1983; Pearce and Abrams, 1984, 1986; Archer and Glinsman, 1985; Krogstad, 1986;
Petri and Ravdin, 1986; Croxson et al., 1988). Entamoeba histolytica
contains a soluble lectin which is mitogenic for T lymphocytes (Chen et al.,
1985; Petri and Ravdin, 1986). 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
(Croxson et al., 1988).
Synergism between intestinal parasites and lymphotrophic retroviruses has also
been advanced as an explanation for the pathogenesis of Burkitt's lymphoma (Burkitt,
1983) and adult T cell leukemia/lymphoma (Tajima. et al., 1981). It seems likely
that the clinical importance of amoebic infection is related as much to the
characteristics of the host as of the parasite.
Chronic Entamoeba histolytica infection of humans has been associated
with autoimmune phenomena, including the appearance of antibodies to colonic
epithelial cells (Salem et al., 1973) and development of symmetrical polyarthritis
very similar to rheumatoid arthritis (RA) (Zinneman, 1950; Rappaport et al.,
1951; Kasliwal, 1970). Singh et al. (1985) 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
Galland (1989) 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, allegedly a non-pathogen (Burnstein and
Liakos, 1983). 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
(Bocanegra, 1988). 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 (Singh et al., 1985).