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.

REFERENCES

Akiyama, K., Yui, Y., Shida, T. and Miyamoto, T. (1981) Relationship between the result of skin, conjunctival and bronchial tests and RAST with Candida albicans in patients with asthma. Clinical Allergy, 11, 323-351.