Excerpts from Power Healing by Leo Galland, M.D.
In keeping with its immense surface area and intense exposure to foreign antigens, the intestinal tract is the largest organ of immune surveillance and response in the human body (Targan et al., 1987). It should not be surprising that events occurring in its lumen or on the mucosal surface have systemic effects on immune function and disease resistance. This chapter examines the contribution made by luminal organisms commonly encountered in humans: bacteria, protozoa and yeasts. Particular attention win be given to data concerning a role for Giardia lamblia infestation and Candida albicans colonization in the pathogenesis of chronic fatigue and immune dysfunction.
Over 500 species of bacteria live in the healthy human alimentary canal; in the average adult they weigh about one kilogram. The normal colonic microflora ferment soluble fibre to yield short-chain fatty acids which supply 5-10% of human energy requirements (McNeil, 1984). Endogenous flora synthesize at least seven essential nutrients, supplementing dietary intake: folic acid, biotin, pantothenic acid, riboflavin, pyridoxine, cobalamin and vitamin K (Mackowiak, 1982). They participate in the metabolism of drugs, hormones and carcinogens, including digoxin (Lindenbaum et al., 1981), sulphasalazine, and estrogens (Gorbach, 1982). By demethylating methylmercury, gut flora protect mice from mercury toxicity (Rowland et al., 1984). They prevent potential pathogens from establishing infection by numerous mechanisms, which include: production of short-chain fatty acids and bacteriocin, induction of a low oxidation-reduction potential, competition for nutrients, deconjugation of the bile acids (which renders them bacteriostatic), blockade of adherence receptors and degradation of bacterial toxins (Savage, 1980).
Germ-free animals have mild to moderate defects in immune function when compared to control animals. These include lower levels of natural antibodies, hyporesponsive macrophages and neutrophiles, defective production of colony-stimulating factors, leukopenia, lymphoid hypoplasia, subnormal interferon levels and weak delayed hypersensitivity (DHS) responses. They are more susceptible to infection with intracellular parasites such as Listeria, Mycobacterium and Nocardia, but are not more susceptible to viral infection (Mackowiak, 1982). Adverse effects of endogenous bacteria have also been described, indicating the complexity of the host-saprophyte relationship. In diseases where host immune response is the primary cause of pathology, such as lymphocytic choriomeningitis, germ-free animals fare better than control animals (Mackowiak, 1982).
The immunologic effects of normal gut flora are in part due to antigenic stimulation and in part to the bacterial origin of specific immune activators, such as endotoxin lipopolysaccharicle (LPS) and muramyl dipeptides Worrison and Ryan, 1979; Mackowiak, 1982; Stokes, 1984). An important role for these substances in normal immune regulation has not been established, however (Mayrhofer, 1984).
The gut flora of healthy individuals is very stable (Sears et al., 1950,19-%); this stability may in part be due to interbacterial inhibition (Sprunt and Redman, 1968). Alteration in the level of normal flora by antibiotics has long been known to allow secondary infection by pathogenic bacteria and yeasts (Keefer, 1951; Seelig, 1966).
Occasional publications describe abnormal fecal flora in patients with atopic eczema. Kuvaeva et al. (1984) studied 60 infants in Moscow with IgE mediated food allergy and eczema. They reported a decrease in anaerobic bacteria and lactic acid-producing aerobes and an increase of Enterobacteriaceae. Severity of eczema was directly proportional to severity of dysbiosis. No control data are given. Ionescu et al. (1986) studied fecal flora in children and adults with atopic eczema. Compared with healthy controls, there was a marked reduction in Lactobacillus, Bifidobacterium and Enteroccoccus species in the great majority of cases. This was associated with increased concentrations of Candida species, Proteus, Klebsiella, and Staphylococcus allreus, and appearance of atypical coliforms and Clostridium innocutan. The high frequency of hypoalbumenernia, indicanuria and steatorrhea in the eczema group suggested small bowel bacterial overgrowth with secondary malabsorption. In neither of these studies is it possible to determine whether abnormal bowel flora caused allergy or whether food-allergic disease destabilized gut flora.
Immunologic reactions to normal or abnormal components of the bacterial gut flora are implicated in the etiology of some inflammatory disorders. Reactive arthritis may occur after intestinal infection with Salmonella typhimurium, Yersinia enterocolitica serotype 3, Shigella flexneri, Campylobacter jejuni and Clostridium difficile (Inman, 1988). Because arthritogenic potential is strain-specific and because 60-80% of patients with reactive arthritis carry the HLA-B27 gene, it is likely that genetically determined antigenic crossreactivity plays a role (Yu et al., 1989).
Ankylosing spondylitis (AS) occurs almost exclusively in HLA-B27 positive individuals. An increased rate of intestinal colonization with Klebsiella pneumoniae has been described in this condition, according to some but not all studies (Kinsella, 1988). Immunologic cross-reactivity has been shown for HLA-B27 antigen expressed on the host cell membrane and antigens present in K. pneumoniae, S. flexneri and Y. enterocolitica, suggesting molecular mimicry in the pathogenesis of this disease (Yu, 1988). Workers in Australia have demonstrated bacteria with cross-reactive antigenic determinants in bowel flora of B27-positive AS patients; these bacteria are almost never found in B27-positive controls without AS (McGuignan et al., 1986).
Endotoxemia has been described in patients with psoriasis (Rosenberg and Belew, 1982a) and cystic acne (Juhlin and Michaelson, 1984). Activation of the alternative complement pathway (APC) by gut-derived endotoxin may play a role in the pathogenesis of these disorders. Exposure of macrophages to endotoxin causes release of cytokines, such as interleukin-1 (Il-1) and tumor necrosis factor (TNF). These peptides have powerful effects on the immunologic and metabolic response to infection. Whether gutderived endotoxins influence cytokine production in vivo is unknown.
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Although it was first described by van Leuwenhoek in 1681, it is only in the past 25 years that G. lamblia has been acknowledged as an important pathogen (Gillon, 1984). Giardiasis is the commonest cause of parasitic disease in the United States (Myer and Jarroll, 1980) with an overall prevalence estimated at 7.4%, which is about the same as its average worldwide prevalence (Mahmoud and Warren, 1975). Prevalence in Great Britain varies from 2% to 10% (Felman and Nikitas, 1985). At least 27% of Giardia infections identified at the University of Edinburgh Medical School had been acquired within the UK and a diagnosis of giardiasis had not been suspected in two-thirds of cases (Gibb, 1989).
Reports based on stool screening may underestimate the prevalence of giardiasis. Comparison of stool examination with duodenal aspiration has consistently shown that stool examination fails to identify infected patients even at the height of acute infection. Single stool specimens have a sensitivity of zero (Rosenthal and Liebman, 1980) to 50% (Kamath and Murugasu, 1974). Collecting multiple specimens over several days increases the sensitivity to 85-90% (Gillon, 1984).
To overcome the limitations of stool analysis we developed a diagnostic technique by which rectal mucus obtained at anoscopy is stained with a monoclonal antibody to Giardia cysts and examined by epifluorescence microscopy (Galland and Bueno, 1989). We recently conducted a two-year retrospective study of 218 patients who presented to our medical clinic with a chief complaint of chronic fatigue (Galland et al., 1990). G. lamblia infection was identified by rectal swab 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 syndrome (CFS) or ME, 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%. This study shows that giardiasis can present with fatigue as the major manifestation, accompanied by minor gastrointestinal complaints and sometimes by myalgia and other symptoms suggestive of ME. It indicates that G. lamblia infection may be a common cause of CFS, at least in the United States. It is noteworthy that tricyclic antidepressants, a standard treatment for CFS, suppress the growth of Giardia in vitro (Weinbach et al., 1985).
The mechanism by which G. lamblia causes disease is not known. Experiments with human volunteers demonstrate that the ability of Giardia to produce infection and to cause diarrhea depends upon the strain of G. lamblia used (Nash et al., 1987), the inoculum dose (Rentdorff, 1954; Rentdorff and Holt, 1954), and previous exposure to the organism (Nash et al., 1987). Heterogeneity of Giardia isolates from humans in the same city occurs and has been proposed as one mechanism for variability of clinical response to infection (Korman et al., 1986).
Table 1 Systemic symptoms of CFS patients
(%) (N = 63)
(%) (N = 157)
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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 in RA.
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).
Candida species are part of the normal flora of the lower intestinal tract of adult humans, being cultured from stool and rectal mucus of 23.2-82.4% of healthy subjects (Odds, 1988). Serious infection with Candida albicans has increased dramatically over the past 40 years; this increase is largely iatrogenic and may be attributed to widespread use of antibiotics and immunosuppressive drugs (Seelig, 1966; Kirkpatrick, 1984). Candida albicans is an opportunist par excellence and its ability to exploit pre-existing immune deficiency in a host animal is well known, although the precise mechanisms involved in the switch from commensalism to parasitism remain uncertain (Odds, 1988). In contrast, little scientific attention has been focused on the effect of Candida infection or colonization on immune responses of the host.
That C. albicans is a potential allergen has been known for years. Over 90% of a healthy adult population has delayed skin test hypersensitivity (type IV) to antigenic extracts of C. albicans (Dwyer, 1984). There are numerous reports of atopic diseases, primarily asthma and allergic rhinitis, associated with type I Candida hypersensitivity. Positive immediate hypersensitivity reactions to intradermal or prick tests with C. albicans antigen are more prevalent among asthmatics than among non-atopics (Itkin and Dennis, 1966; Pepys et al., 1968; Kurimoto, 1975; Kabe et al., 1971). One study found no difference (Gordon and Klaustermeyer, 1986) but observed that ‘strong skin test reactivity' to Candida was associated with atopy. El-Hefny (1968a) found Candida reactivity to vary directly with severity of asthma. When challenged with inhaled Candida antigen, asthmatics with immediate skin test hypersensitivity develop acute bronchoconstriction (Itkin and Dennis, 1966; Pepys et al., 1968; Kabe et al., 1971; Kurimoto, 1975; Edy and Pepys, 1980; Akiyama et al., 1981). Pretreatment with inhaled cromolyn sodium prevents experimental bronchoconstriction under these conditions (Gordon and Klaustermeyer, 1986). Kurimoto (1975) concluded that type I hypersensitivity, is involved in both the early and late phase responses to Candida antigen but that late bronchial responses may also involve type III hypersensitivity, as a transient drop in C3 and C4 levels occurred.
Candida infections can induce an Arthus reaction in guinea pigs (Kabe et al. 1971); Arthus-type reactivity to C. albicans was demonstrated in 26% of asthmatics, being positively associated with severity and duration of asthma (EI-Hefny, 1968b). Kurimoto (1975) frequently provoked systemic reactions when administering Candida antigen by inhalation to his Candida-allergic subjects and attributed this to type III allergy. There are few published reports on the value of hyposensitization with Candida extract in asthma treatment. El-Hefny (1968a,b), who used an antigen she prepared herself, demonstrated in a controlled study that Candida-sensitive asthmatics undergoing hyposensitization with multiple antigens had a significantly better outcome if C. albicans extract was included in the antigen mixture. Other reports of improvement in asthma with Candida hyposensitization are uncontrolled or anecdotal (Sclafer, 1957; Charpin, 1958; Kabe et al., 1971; Gumowski et al., 1987).
Eczema and urticaria are also mentioned in the literature on Candida allergy and are also reported to respond to immunotherapy (Sclafer, 1957; Charpin, 1958; Hold, 1966; Planes et al., 1972). James and Warin (1971) found positive prick tests to C. albicans in 36 of 100 consecutive patients with chronic urticaria; they induced hives by blind oral challenge with Candida extract in 25 of 33 patients. Candida allergy was associated with immediate skin test reactivity to inhalant molds and with positive responses to blind oral challenge with Saccharomyces cerevisiae. Oral antifungal therapy with nystatin tablets and amphotericin t:roches was combined with a yeast-free diet in treatment of all Candida-allergic patients and 18 patients with negative Candida prick tests. Clearing of urticaria occurred for 81% of Candida prick-test-reactive patients and 39% of prick-test-negative patients W < 0.01).
Gastrointestinal manifestations of Candida allergy have been reported by Sclafer (1951), Liebeskind (1962), Holti (1966) and Alexander (1975). Holti studied 65 patients with irritable bowel syndrome and symptoms of explosive diarrhea and colicky abdominal pain; they had been sick for an average of five years. All 56 patients with positive skin wheals to C. albicans also had positive stool cultures for yeasts. C. albicans was isolated from none of the nine patients with a negative skin test to C. albicans and from 24% of a healthy control group. Sixty-one per cent of Candida-allergic patients also reacted to Saccharomyces cerevisiae. Treatment with oral nystatin was associated with permanent disappearance of symptoms in 17 of 57 patients. Thirty-two additional patients were placed on yeast-free diets and, within three days, nine were totally symptom-free and 14 were much improved. A double-blind controlled study of the effects of administering C. albicans extract by mouth was conducted using five patients with mucous colitis who had been free of symptoms for at least four weeks. C. albicans extract, but not placebo, produced diarrhea and borborygmi within 20 minutes in all five. In five control subjects with positive Candida skin tests but no digestive complaints, oral Candida extract produced no symptoms.
These studies are described in some detail because they indicate that Candida allergy is not a rare disease with limited symptoms, as maintained by some authorities (American Medical Association Council on Scientific Affairs, 1987), but a relatively common disorder with protean manifestations.
A relationship between Candida allergy and Candida infection is suggested by clinical research in vaginitis. Candida allergy has been well described in patients with chronic vaginitis (Tomsikova et al., 1980). Mathur et al. (1977) found that total IgE was elevated in sera and cervicovaginal secretions of women with recurrent Candida vaginitis and that most of this IgE reacted with Candida antigens. Witkin et al. (1988, 1989) found anti-Candida IgE in vaginal secretions of 18.8% and 27.8% of women with chronic vaginitis. Vaginal specimens with IgE antibodies also contained detectable levels of prostaglandin E2 (PGE2), an important mediator of inflammation. Witkin et al. (1986, 1988) suggest that production of PGE2, stimulated by vaginal allergy to Candida and other substances, inhibits lymphocyte responses to Candida in the vagina, permitting Candida infection to flourish. They found that macrophages of women with recurrent vaginal candidiasis inhibit response of control lymphocytes to Candida antigen: this inhibition is reversed by PG-synthesis inhibitors and by exogenous 11-2. This group has recently shown (Witkin et al., 1989) that cervical infection with human papilloma virus (HFV) is strongly correlated with the presence of anti-Candida IgE; 47.4% of 19 women with HPV and only 5.9% of 17 women without HIPV were positive for anti-Candida IgE (p < 0.025). Conversely, nine out of 10 women with anti-Candida IgE compared to 10 out of 26 women without anti-Candida IgE harbored HPV. They speculate that the immunosuppressive effects of Candida allergy permit chronic viral infection of the uterine cervix. In small, uncontrolled studies Palacios (1976) and Rosedale and Browne (1979) had demonstrated reduction in episodes of vaginal thrush by hyposensitizing injections of C. albicans extract, suggesting clinical utility for Witkin's findings.
There are several clinical case reports of immunosuppression occurring in vivo as an apparent side effect of Candida infection (Cuff et al., 1986). Paterson et al. (1971) described a 20-year-old female patient with a 15-year history of chronic mucocutaneous candidiasis (CMC) who was anergic and whose plasma contained a factor capable of extinguishing the blastogenic response of normal lymphocytes to Candida and mumps. Treatment with intravenous amphotericin B cleared the Candida infection and simultaneously eliminated the circulating plasma inhibitor, slowly restoring normal cell-mediated immunity (CMD. The patient remained free of yeast infection and immunologically normal for at least seven months after discontinuation of amphotericin B. The authors speculated that the circulating inhibitor was yeast-derived.
Circulating immunosuppressive factors have been described in other cases of CMC (Valdimarsson et al., 1973). The immunosuppressive factors are thought to be soluble polysaccharides, such as mannan, contained in the yeast membrane and released into the circulation (Fischer et al., 1978). Mannan at high dose inhibits mitogen- and antigen-stimulated proliferation of human lymphocytes in vitro. Lower concentrations specifically inhibit the lymphocyte blastogenic response to C. albicans, probably by competing for polysaccharide-antigen binding sites (Nelson et al., 1984). In that macrophages normally remove mannan from the circulation, the immunosuppressive effects of mannan in vivo probably depend upon defective macrophage function, which may be a factor in some cases of CMC (Fischer et al., 1982).
A Candida albicans cell wall glycoprotein rich in mannan causes histamine release from rat mast cells in vitro (Nosal et al., 1974; Svec, 1974). An experiment in mice suggested that some immunosuppressive effects of the glycoprotein reside in the protein moiety and are mannan-independent (Carrow and Domer, 1985). There is a case reported of refractory esophagitis caused by C. tropicalis in a 28-year-old nurse that was associated with cutaneous anergy and a circulating inhibitor that was not mannan but a lowmolecular-weight protein derived from the yeast itself (Lee et al., 1986).
Additional mechanisms of Candida-induced immunosuppression exist. Mouse lymphocytes incubated with formalin-killed C. albicans induce a suppressor B lymphocyte, the appearance of which may explain the increased susceptibility of mice treated with Candida extracts to infection by a number of micro-organisms (Cuff et al., 1986). Human T lymphocytes incubated with C. albicans polysaccharide produce a nonspecific inhibitor of macrophage function which decreases macrophage production of 11-1 and hence lymphocyte production of 11-2, inhibiting lymphocyte proliferation (Lombardi et al., 1985). On the other hand, injection of heat-killed C. albicans augments natural killer (NK) cell activity in mice (Marconi et al., 1985; Wojdani and Ghoneum, 1987). Glucan, another yeast-derived polysaccharide, may initiate this effect by stimulating macrophages to release TNF, which raises NK levels (Reynolds et al., 1980). This effect is similar to the immunoenhancing effect of bacterial endotoxin.
Zymosan, an insoluble yeast membrane polysaccharide, activates the APC in vitro (Ray and Wuepper 1976); in vivo, the inflammation seen in patients with CMC may be mediated by APC. Rosenberg and his colleagues have proposed that psoriasis and Crohn's disease both involve excessive and unregulated activation of the APC and state that various microbial products, including zymosan from C. albicans, may be stimulating the APC in vivo, causing the appearance of disease in genetically susceptible individuals (Rosenberg et al., 1982, 1983). Having successfully treated scalp psoriasis with ketaconazole (Rosenberg and Belew, 1982b), they proceeded to use oral nystatin for treating psoriasis, with positive results (Crutcher et al., 1984). They postulate that psoriasis is a systemic disease, which can be triggered by Candida in the intestine, as well as by other infectious agents.
Iwata et al. (1966) first described a high-molecular-weight protein, isolated from a strain of C. albicans, with inflammatory and nerve-growth-stimulating effects; they called it canditoxin. They have since discovered several other substances, of low and high molecular weight, which may serve as endo- or exotoxins by activating the classical complement pathway Uwata, 1977a, 1977b). These substances are not thought to be widely distributed, but rather confined to just a few strains; their role in the pathogenesis of candidiasis is unclear.
In summary, there are numerous and complex immunologic responses to Candida constituents, both antigenic and non-antigenic, which may follow colonization or infection; these cause release of inflammatory mediators and alterations in CNU. Local infections may have systemic effects.
CMC is known to occur in association with endocrine dysfunction and circulating autoantibodies (Wuepper and Fudenberg, 1967). Although chronic infection and autoimmune disease may result from defective T lymphocyte function, some workers have speculated that polyclonal B cell activation induced by Candida components may trigger autoantibody formation (Zouali et al., 1983/1984). Mathur et al. (1980) studied 40 women with chronic vaginal candidiasis (CVC). Anti-ovarian and anti-thymocyte antibodies were present at a titer of 1 : 64 or greater in the sera of 27 and 19 patients, respectively. Both autoantibodies were found at significant titers in 16. Mean autoantibody levels of CVC patients were much higher than those of controls. Autoantibody levels were strongly and positively associated with Candida antibody levels. Absorption of sera from CVC patients with thymocytes, ovarian follicles or C. albicans, significantly lowered antibody titers to all three, suggesting antigenic cross-reactivity. The authors speculated that a high level of multispecific Candida antibody produced by chronic yeast infection in these patients cross-reacted with ovarian and T cell antigens, producing autoimmune phenomena.
In 1978, Truss first published six case reports of patients with baffling neurological, psychiatric and inflammatory diseases who were cured following treatment with oral nystatin and injections of Candida antigen. A series of papers followed in which he d,-schbed several cases of multiple sclerosis and one of Crohn's disease which responded to the same therapy (Truss, 1981); he presented a comprehensive treatment program for this condition which included avoidance of dietary carbohydrates, limitation of exposure to food-borne or air-bome fungi, administration of oral antifungal drugs and immunotherapy with Candida extract (Truss, 1980a, K He initially proposed that chronic Candida antigenemia may be responsibl~ for this polymorphic illness (Truss, 1981), and later published a theory that acetaldehyde production by intestinal yeast was the cause of metabolic, immunologic and neuroendocrine abnormalities seen in his patients (Truss, 1984). Although direct evidence for Truss' hypopthesis has not been forthcoming, investigations by others since his last paper have demonstrated that C. albicans can produce ethanol in infant food formulas (Bivin and Heinen, 1985) and in the human stomach (Bode et al., 1984), and that acetaldehyde, the principal metabolite of ethanol, by conjugating with mammalian protein, induces formation of polyclonal antibodies to acetaldehyde-protein adducts that may mediate tissue damage (Israel et al., 1986).
Truss's concept that systemic illness may be provoked by mucosal Candida infection has itself provoked considerable controversy (Crook, 1984; Turner, 1985; Blonz, 1986; American Academy of Allergy and Immunology, 1986). Although Truss's original case reports primarily described patients with autoimmune or neurological diseases, most patients diagnosed with this Candida-related complex (CRQ have symptoms of fatigue, depression, allergy, food intolerance, and a variety of gastrointestinal, gynecologic and musculoskeletal complaints which are generally regarded as 'functional' (Truss, 1982; Zwerling et al., 1984; Crook, 1986; Kroker, 1987; Mabray, 1988).
The first published controlled treatment study to test the CRC hypothesis was done by Schinfeld (1987). He studied 30 patients with premenstrual syndrome (PMS) that had not responded to treatment which included psychotherapy, high-dose vitamin B6 and, in some cases, psychotropic drugs. Twelve patients had no evidence of vaginal yeast infection, symptomatic or asymptomatic, and the remainder suffered from recent Candida, vaginitis. Both Candida-free and Candida-infected groups were subdivided into active treatment (oral nystatin and yeast-free diet) and contact-only treatment groups. All patients remained symptomatic, with premenstrual depression as their major complaint, but there were significant differences between treatment and non-treatment groups. The worst outcome occurred in Candida-infected patients who received no active treatment, and the best outcome occurred in Candida-infected patients treated with oral nystatin and a yeast-free diet. The small number of patients limits the number of comparisons that can be made and the interpretation of data.
Another study (Dismukes et al, 1990) reported no significant difference in the effect of oral nystatin or placebo on systemic systems of 42 women with chronic vaginitis. In contrast to Schinfield's study, however, these authors lumped together women with Candida vaginitis and women with culturenegative vaginitis, possibly explaining the high inter-patient variability they observed. They also used a cross-over treatment design with no washout period and failed to control for changes in diet and other self-care activities, although all subjects were aware of Truss' treatment regimen, having been selected from his waiting list. Despite these flaws, and the authors' failure to provide any raw data in their report, a careful reading of this highly publicized study indicates some differences in the effect of oral nystatin and placebo that do not support their main conclusion. Oral nystatin significantly reduced somatization scores Nistress arising from perception of bodily functions') (p = 0.04). Analysis of other systemic symptoms showed benefits from oral nystatin under conditions where placebo responses appeared to have stabilized. Truss (personal communication) has performed a separate statistical analysis and has prepared a critique of this study which demonstrates a strong effect of nystatin on generalized symptoms, when compared to placebo.
The largest study of CRC reported is that of Jessup, who presented a retrospective analysis of 1100 patients to the First International Conference on Chronic Fatigue Syndrome, San Francisco, California, 15 April 1989. These patients had been treated over a nine-year period for fatigue, myalgia, headache, dizziness, depression, arthralgias, night sweats, morning stiffness and post-strain malaise. Posterior cervical adenopathy occurred in 35% and neurological examination was abnormal (serial sevens, tandem gait) in 30%. Although 80% reported the sudden onset of their disease following an acute flue-like illness, pre-morbid characteristics of the group revealed a high frequency of chronic or recurrent health problems. About 80% had repeated antibiotic exposures for acne or respiratory or urinary tract infection; 60% of these had developed sensitivity to antibiotics. Alcohol intolerance, irritable bowel syndrome, recurrent vaginitis, migraine headaches, urticaria and premenstrual tension were very frequently encountered. Almost all patients had experienced addiction to sugar or alcohol prior to the onset of chronic fatigue. Patients treated between 1980 and 1987 showed little improvement. In September, 1987, 685 patients were unemployed and receiving disability payments. At that point Jessup began treating these patients with ketaconazole 200 mg a day, combined with a diet free of alcohol, added sugar, fruit or fruit juice. The average length of treatment was five months (range three to 12 months). By April, 1989, &4% of these patients had recovered and only 12 patients remained on disability. Jessup concluded that Candida infection was the major cause of disease for those patients who responded to ketaconozole and speculated that intestinal colonization with yeast produced a systemic toxin.
The treatment results do not necessarily support Jessup's conclusion. Although ketaconazole is an effective antifungal agent, it has powerful and complex effects on the function of lymphocytes (Schutt et al., 1987a) and monocytes (Claus et al., 1988) which are consistent with inhibition of certain cytokine effects (Schutt et al., 1987b, 1988). Ketaconazole eliminates the spontaneous lymphocyte proliferation of patients with dermatophytoses (Schutt et al., 1988). Elevated levels of 11-2 (Cheney et al., 1989), increased production of alpha-interferon (Lever et al., 1988) and spontaneous lymphocyte blastogenic activity (Olson et al., 1986) have been described in some patients with CFS. It is possible that Jessup's success resulted from alteration of aberrant immune responses by ketaconazole rather than an antifungal effect. The large number of patients treated and the extraordinarily good outcome in this report, however, mandate a prospective controlled study of imidazole therapy for CFS.
Summary and Conclusions
This chapter has reviewed the systemic effects of immune responses to organisms inhabiting the gut lumen and adhering to the intestinal mucosal surface. Type I and type III allergic responses to yeasts and protozoa occur: the former may precipitate asthma, urticaria, vaginitis and irritable bowel syndrome; the latter may cause arthritis. Type I allergic reactions may also produce local immunosuppression. Cross-reactivity between human and microbial antigens occurs for several strains of Enterobacteriaciae and for C. albicans. Enterobacteriaceae are implicated in the pathogenesis of some spondyloarthropathies; C. albicans and Entamoeba histolytica infections may contribute to autoimmune phenomena. Nonspecific activation of immune responses by microbial components is common and may be necessary for normal maturation of the immune system. Bacterial enclotoxin, yeast zymosan and protozoan lectins express non-antigenic immune stimulatory activity, which may be undesirable, eliciting inflammatory reactions, such as psoriasis, in susceptible individuals, or inducing replication of lymphotrophic viruses. Yeast-derived glyoproteins can cause immune suppression in vitro and in vivo. Chronic G. lamblia infection can produce fatigue, myalgia, asthenia and malnutrition without serious gastrointestinal symptoms.
Our results demonstrate that some patients with CFS have Giardia lamblia infection as their primary, and unexpected, diagnosis. The excellent response to ketoconazole reported by Jessup suggests that fungal infection may play an important etiologic role in many CFS patients. Mowbray's group has found chronic enteroviral antigenernia in the majority of patients with post-viral fatigue syndrome (Yousef et al., 1988). It is possible that bacterial clysbiosis, enteric protozoan or yeast infection, or intestinal allergy may alter normal immune responses of the gut, allowing persistence of viral replication. The probable importance of enteric factors in the pathogenesis of ME should guide diagnostic and treatment strategies.
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