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 <
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
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.