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.
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.