CANDIDA ALBICANS

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.