Restoration of Immunologic Competence to Candida Albicans
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Restoration of Immunologic
Competence to Candida Albicans
C. Orian Truss, M.D.1
The existence of Candida albicans in the human paralysis, anergy, and unresponsiveness.
body is entirely compatible with a lifetime of Disseminated tuberculosis (miliary) and lep-
excellent health. It also may at any time, under romatous leprosy are illustrative of chronic
the influence of various factors, succeed in bacterial infections that persist in association
colonizing tissues, primarily of the intestinal tract with, and possibly because of, an inadequate
and vagina. It then calls attention to its presence immune response by the host. Chronic
by symptoms originating in the infected organs or mucocutaneous candidiasis is a fungous
in remote organs related to immunologic and infection exhibiting the same phenomenon. The
possibly toxic responses to soluble yeast products, immunologic impairment associated with these
and exerts a paralyzing influence on the infections has been reviewed previously (Truss,
capability of the host to mount an effective 1978).
immunologic response. Restoration of immune It follows, then, that a pathogen is eradicated
competence to its genetically determined rather than tolerated when the immune system is
maximum should be the goal of treatment, and is competent to respond effectively to the antigenic
the means by which both infectious and allergic determinants of the organism. Such response
manifestations may be terminated. embraces both cellular and humoral components
of the immune system, even though one may
INTRODUCTION predominate in controlling a particular type of
Persistence of a foreign organism in human pathogen.
tissues requires the absence of an effective Miliary tuberculosis, lepromatous leprosy, and
immunologic response to the exposed antigenic chronic mucocutaneous candidiasis are advanced
determinants of the pathogen. This loss or chronic infections with widespread
absence of immunologic competence is variously dissemination of the organism in the tissues; in
referred to as tolerance, all three conditions it is often possible to
demonstrate impairment of the immune
response. Lymphocytes may fail to respond to
1
- 26)4 Highland Ave.,
the antigenic challenge in vitro, as in the MIF
Birmingham, Alabama 35205 and lymphocyte transformation tests. This
defective cellular (T-cell) response
287RESTORATION OF IMMUNOLOGIC COMPETENCE
is often expressed in vivo by the failure of these infecting the mucous membranes of the G.I.
antigens to elicit a delayed (tuberculin-type) skin tract, vagina, skin and nails.
test response.
Yet in each instance, in the more limited stage RECOGNITION OF CHRONIC
of infection, these tests of T-cell response will CANDIDIASIS
usually be normal. Indeed, many instances have The concept of candidiasis (non-congenital) as
been documented of actual disappearance of a chronic systemic condition with multiple
previously positive lepromin or tuberculin skin manifestations was previously presented at the
tests as the antigenic load reaches that critical eighth Scientific Symposium, Academy of
point beyond which the immune system becomes Orthomolecular Psychiatry, Toronto, Canada,
unresponsive; it is no longer "competent" with May 1, 1977, and later published (Truss, 1978).
respect to the antigenic determinants of the It is conceived as analogous to the more limited
organism in question. A state of "immunologic but chronic forms of leprosy and tuberculosis.
tolerance", or "paralysis", is said to exist, and The manifestations vary greatly from patient to
may be expected to persist as long as the patient, depending in part upon the location and
antigenic load remains undiminished. extent of tissue colonization, but principally
The influence of antigenic load on the immune upon the patient's immunologic and allergic
response was demonstrated by Budtz-Jorgensen response to yeast antigens and to possible toxins
(1973). In children with chronic mucocutaneous released by the fungus. Implicit in this concept is
candidiasis, treatment with amphoteracin-B was that presently available tests of the immunologic
continued until the skin and mucous membranes response to Candida may be normal, but with
were essentially free of the fungus. Before impairment of immunologic competence never-
treatment both MIF and lymphocyte theless clearly indicated by the inability of the
transformation responses were absent, indicating immune defenses to rid the host of the organism.
marked impairment of the T-cell response to the It is "tolerated" in the tissues because the
antigens of this organism. As therapy with immune response is "paralyzed"
amphoteracin-B led to progressive clearing of the If the term "immunologic tolerance" is re-
yeast from the tissues, competence returned and stricted to conditions with abnormal in vitro tests
tests of the T-cell response became normal. of the immune response, these patients with
Following discontinuation of the drug, tissue chronic infection but normal in vitro tests may be
involvement with Candida returned and the T- said to be "clinically immunologically tolerant".
cells again lost their capacity to respond when The eventual development of in vitro tests
the antigenic load again overwhelmed the allowing more subtle quantitation of the immune
immune defenses. response should eliminate this distinction.
Thus, loss of immune competence may be At the present time the recognition of patients
associated with chronic infection with Candida with chronic candidiasis must be based on
albicans, just as with the tubercle and leprosy clinical evidence and confirmed by therapeutic
bacilli. The latter two, however, are also trial; no help is available from the laboratory.
recognized as the cause of chronic illness that Everyone has antibodies, and most have a
may persist for years in a more limited form positive skin test; the yeast may be cultured from
without measurable loss of immune competence. many asymptomatic individuals. Many patients
With Candida no such chronic systemic disease with this condition show an immediate (IgE)
has been recognized with the exception in skin hypersensitivity with a weak or absent
children of the congenital disease "chronic delayed response, but there are too many
mucocutaneous candidiasis". Except for this exceptions for this test to be definitive. A careful
condition and the occasional patient who history that traces the illness from its onset
develops Candida septicemia in association with suggests the diagnosis. It invariably includes a
leukemia or similar disease characterized by an story of
impaired immune response, it has been viewed as
an opportunistic organism characteristically
288ORTHOMOLECULAR PSYCHIATRY, VOLUME 9, NUMBER 4, 1980, Pp. 287-301
futile efforts by many competent specialists to presented (Truss, 1978).
establish an organic basis for the chronic illness,
and of the almost irresistible recommendation of TREATMENT OF CHRONIC
psychiatric therapy. CANDIDIASIS
Attention in the history should be directed to the Chronic antigenemia, occurring naturally or
influence of repeated pregnancies, birth-control induced experimentally, may result in im-
pills, antibiotics, and cortisone and other munologic unresponsiveness to specific
immunosuppressants. The onset of local antigens, including those of infectious origin.
symptoms of yeast infection in relation to the use Antigens that evoke a normal immune response
of these drugs is especially significant and usually initially may induce immunologic tolerance
precedes the systemic response. Repeated courses when antigenic exposure becomes of the
of antibiotics and birth-control pills, often quantity and duration critical to its
punctuated with multiple pregnancies, lead to establishment. With its immunologic defenses
ever-increasing symptoms of mucosal infections neutralized, the host becomes incapable of
in the vagina and gastrointestinal tract. Ac- eliminating from its tissues the source of
companying these are manifestations of tissue tolerizing antigen, insuring perpetuation of the
injury based on immunologic and possibly toxic compromised immune response and persistence
responses to yeast products released into the in the tissues of the infectious agent.
systemic circulation. Many infections are Total loss of immune capability is suggested
secondary to allergic responses of the mucous by the terms "immunologic paralysis" and
membranes of the respiratory tract, urethra, and "immunologic unresponsiveness"; "immunologic
bladder, necessitating increasingly frequent tolerance" may perhaps better describe a
antibiotic therapy that simultaneously aggravates continuing but ineffectual immune response that
and perpetuates the underlying cause of the al- "tolerates" rather than rejects the organism. The
lergic membrane that allowed the infection. "ebb and flow" in the opposing forces of foreign
Depression is common, often associated with invasion and immune rejection is reflected
difficulty in memory, reasoning and clinically in the remissions and exacerbations
concentration. These symptoms are especially characteristic of many chronic illnesses. The
severe in women, who in addition have great incompleteness of "paralysis" is suggested by
difficulty with the explosive irritability, crying, fluctuations both in clinical manifestations and
and loss of self-confidence that are so in such simple tests of normal immune activity
characteristic of abnormal function of the ovarian as the white blood cell count, skin test response,
hormones. Poor end-organ response to these body temperature, and antibody titer, as well as
sex hormones is confirmed by the common by the inconstancy of indicators of abnormal
association of acne, impairment or total loss of immunologic activity, e.g., immune complex
libido, and the whole range of abnormalities of deposition, RA factor, LE cell, ANA. The
menstrual bleeding and cramps, as well as a very pattern of the clinical response may undergo
high incidence of endometriosis in those who constant change as the immune system reacts
have undergone hysterectomy. both normally and abnormally to the qualitative
Many of these patients also start developing and quantitative variations in antigenic
multiple intolerances to foods and chemicals, stimulation.
making it increasingly difficult for them to live in Persistence of Candida albicans in the tissues
a normal environment. Many or all of these for prolonged periods typifies these principles.
intolerances disappear as the yeast problem is Chronic symptoms representing systemic
brought under control. responses to soluble yeast products accompany
The purpose of this paper is to outline ex- manifestations referable to the infected sites.
periences in the treatment of chronic candidiasis Both fluctuate according to the effectiveness of a
by measures designed to restore immunologic weakened immune response that is often
competence to this yeast. Detailed discussion of influenced by factors directly favorable to yeast
the manifestations and diagnosis has been growth.
289RESTORATION OF IMMUNOLOGIC COMPETENCE
An analysis of such factors allows a logical manifestations.
approach to therapy, with each aspect designed This preference for carbohydrate has been
either to retard the rate of yeast proliferation or to documented objectively in a strain of Candida
strengthen the immune response to its presence. albicans reported in Japan; this strain has the
Acting together, these measures interrupt the self- unique ability to ferment carbohydrate to ethyl
perpetuating cycle of tissue invasion and alcohol within the intestinal tract. A rapidly
tolerance-inducing antigenemia. In time both rising level of alcohol is measurable in the
local and systemic manifestations cease with bloodstream following the ingestion of a
eradication of yeast from the tissues—the measured amount of glucose or other
ultimate goal of therapy. carbohydrate. Other strains apparently lack the
A program that has proved effective in restoring enzymes necessary to complete the conversion
immunologic competence to Candida albicans is to alcohol.
summarized in Table 1 and described in the In addition to limiting total carbohydrate
section following. of carbohydrate, often intake, avoidance of foods with a high yeast
accompanied by exacerbation of their systemic
TABLE 1
TREATMENT OF CHRONIC CANDIDIASIS
I. Non-immunologic measures that retard yeast proliferation
A. Passive: measures of avoidance
1. Diet: low in carbohydrates and in foods with high yeast or mold content
2. Antibiotics
3. Contraceptive hormones
4. Environments characterized by high mold-spore exposure
B. Active: therapy with anti-fungal drugs: nystatin, amphotericin-B, flucytosine, ketoconazole
II. Measures to strengthen the immune response of the host
A. Passive (avoidance): immunosuppressant drugs
B. Active
1. Diet: adequate nutrients for proper immune response
2. Correction of unrelated conditions that impair the immune response, e.g., hypothyroidism
3. Use of extracts of Candida albicans
a. Extracts
b. Testing
c. Treatment
or mold content is helpful. The most important
I. Non-immunologic Measures that Retard of these include breads and pastries with yeast
Yeast Proliferation (which should be avoided in any event as part of
A. Passive: Measures of Avoidance the carbohydrate restriction), mushroom (a
1. Diet fungus), aged cheeses, and alcoholic beverages
The first component of the "avoidance" aspect of with their high yeast content.
yeast control embodies certain modifications of It is difficult to evaluate the benefit from these
the diet. Of the three classes of foods, yeasts dietary restrictions when other measures are
ferment fat and protein poorly, but thrive on simultaneously alleviating symptoms. But in
carbohydrate. Limiting the intake of sweets and theory as well as practice, diet is important,
starches deprives Candida of the nutrient that especially early in treatment. Occasional
allows its maximum multiplication. Most patients departures seem not to aggravate symptoms
have observed increased intestinal gas and "bloat- noticeably, in contrast to the continuous high
ing" following the intake of large quantities intake of these foods.
290ORTHOMOLECULAR PSYCHIATRY, VOLUME 9, NUMBER 4, 1980, Pp. 287-301
Additional benefits may derive from control pills", whether used for contraception,
carbohydrate restriction. Many patients are allergic prevention of menstrual cramps, or regulation
to the cereal grains, while others exhibit an of menstrual irregularity. Avoidance of these
abnormal response to carbohydrate in the glucose hormones is mandatory if chronic candidiasis
tolerance test. Carbohydrate restriction may is to be successfully controlled.
eliminate such food allergens from the diet, and Their use is associated with acute vaginal
also may correct the excessive insulin response candidiasis in approximately thirty-five percent
that results in hypoglycemia. of women; it is quite probable that in the
remainder, subtle changes occur in those
2. Antibiotics immunologic responses appropriate for control
The use of antibiotics should be limited to the of this yeast. Chronic yeast vaginitis tends to
fullest possible extent, avoiding in particular the be at its worst when progesterone levels are
"broad-spectrum" drugs that destroy the gram- high, as in pregnancy and the luteal phase of
negative intestinal and vaginal bacteria. At those the menstrual cycle; therefore the progesterone
times when their use is dictated by culture and component of contraceptive hormones may
sensitivity studies, stimulation of the yeast may be well be responsible for their adverse effect.
countered with concomitant nystatin therapy, with The more severe cases of vaginitis often are
discontinuation of the antibiotic as soon as pos- associated with depression, emotional lability,
sible. For a limited time overt symptoms of and an explosive irritability, suggesting that an
increased yeast growth can often be prevented in abnormal vaginal epithelium is but part of a
this way, although they may erupt in fulminant general inadequacy in the response to these
form if the antibiotic therapy is too prolonged. hormones.
(This was illustrated in a highly sensitive patient This association of yeast vaginitis and "em-
who was protected by sixteen nystatin tablets daily
otional" symptoms is worthy of special com-
during eight days of unavoidable Ampicillin ment. They frequently appear for the first time
therapy. On the ninth day explosive diarrhea,
in healthy young women soon after their first
pruritis ani, and intense vaginitis erupted
use of these contraceptive hormones. That they
simultaneously and persisted long after the
are symptoms of poor hormone function rather
Ampicillin was discontinued.)
than "neurotic" or "psychiatric" in origin is
The long-term use of tetracycline for the clearly indicated by their absence before the
treatment of acne is particularly insidious and must use of these hormones and their disappearance
be discontinued in these patients. Another soon after their use is discontinued. In this
condition in which antibiotics are often needlessly situation no physician would doubt the relation
used is in the treatment of urethritis. Although due of these symptoms to improper hormone
to the generalized Candida infection in the vulvo- function. Yet the same symptoms in a young
vaginal area, because of the dysuria and frequency woman not taking hormones are almost always
it is often misdiagnosed as cystitis and treated with considered "psychoneurotic" in origin, leading
antibiotics for weeks or months, despite the to a futile psychiatric approach to therapy. The
absence of a clinical response. This serves only to recognition of these as symptoms resulting
aggravate further the yeast infection that is the from interference with hormone function is
actual cause of the discomfort. Finally, viral vital in recognizing this syndrome.
illnesses are often treated with antibiotics; a great
reduction in the use of these drugs would result
4. Environments Characterized by High
from the careful differentiation of these from bact-
Mold-Spore Exposure
erial infections.
Many molds that do not exist within the body
3. Contraceptive Hormones have some degree of cross-antigen-icity with
Rivaling antibiotics in impact on the immune Candida albicans. Patients often
containment of Candida have been the “birth
291RESTORATION OF IMMUNOLOGIC COMPETENCE
notice aggravation of their symptoms in en- demonstrated that Candida albicans penetrates
vironments characterized by a high content of the epithelial cells of the mucous membranes, to
mold spores; basement apartments and homes persist therein as an intracellular organism.
with a chronic moisture problem are frequently Thus even this limited absorption into the
seen examples. Homes near poorly-drained areas bloodstream may extend the effectiveness of
or bodies of water are likely to have a high count nystatin to the more protected intra-epithelial
of mold spores. Correction of drainage problems cell sites and may account for the additional
is helpful, as is proper control of the level of benefit noted in certain patients with higher
humidity in the home. Occasionally it is necessary doses. Even without penetration of the epithelial
to change homes. cell itself, the drug should encounter yeast cells
in transit to this ultimate intra-epithelial dest-
B. Active: Therapy with Anti-fungal Drugs ination. Also theoretically it is possible that
Drugs that kill or suppress the growth of yeast cell destruction in these deeper tissues is
Candida albicans in vivo are of great benefit; only accomplished by lower doses in that this drug is
nystatin will be considered in detail. Other drugs fixed by the yeast cell wall, and perhaps could
are available but heretofore their toxicity has accumulate slowly therein until of sufficient
limited their use to life threatening Candida concentration to initiate cell leakage and death.
infections. Indications for their use should widen Immunologic tolerance results from long-term
with increased understanding of the relation of exposure to an antigen either in low or high
yeast to systemic illness, both physical and amounts. Interruption or reduction of such
mental. Drugs not presently available may serve chronic antigenemia is essential in the
better than nystatin to eradicate yeast from deeper restoration of the capacity of the immune
sites within the tissues; ketocona-zole is a system to respond competently to the antigen.
promising example. To achieve maximum reduction in the antigenic
Nystatin is valuable both diagnostically and load, nystatin must be brought into contact with
therapeutically in human candidiasis. It is ab- the greatest possible number of yeast cells,
sorbed poorly from the intestinal tract, and is hence the necessity for these various
generally considered ineffective for other than preparations. Candida lives predominantly in
yeast infections of mucosal and skin surfaces, the gastrointestinal tract and vagina. A negative
where it may be brought into contact with the culture for yeast does not establish its absence
organism. As a suspension, it contacts yeast on the in a given location. For reasons that at present
oral and esophageal mucous membranes; in tablet are obscure, it frequently fails to grow with
form it reaches the remainder of the intestinal present culture methods, even though it may do
mucosa. Suppositories are necessary for vaginal so after stimulation with tetracycline for two to
yeast suppression, and occasionally the cream or three days.
ointment is helpful for yeast infections of the
For these reasons nystatin in several forms
vulva, skin, or nails.
simultaneously is used even if cultures are not
Nystatin is fixed in the wall of yeast cells; this
positive from each site. This is particularly
leads to increased permeability with efflux of vital
important initially when attempting to confirm
cellular components and ultimate cell death.
the diagnosis by therapeutic trial. The
Absorption from the gastrointestinal tract is poor;
combination may subsequently be modified in
a dose of approximately eight million units
each patient according to the location of
(sixteen tablets) results in low plasma levels in the
mucosal symptoms. The preparations and
range of 1 to 2.5 micrograms per mililiter
dosages that have proved useful may be
(Goodman and Gilman, 1975). Even this low level
summarized as follows:
may be of some benefit, however, since in vitro
(a) Oral suspension: Since the tablet passes
concentrations between 1.5 and 6.5 micrograms
immediately into the stomachy the liquid must
per milliliter may be toxic to Candida albicans
be used to coat the mucous
(Goodman and Gilman, 1975). This is an
important point. Electron microscopy has
292ORTHOMOLECULAR PSYCHIATRY, VOLUME 9, NUMBER 4,1980, Pp. 287-301
membrane from mouth through esophagus. One (c) Vaginal suppositories are important in the
teaspoon four times daily is adequate. The initial treatment and are required intermittently in
patient is instructed to use it as a mouthwash for most women. This is especially true from puberty
one to two minutes, attempting to achieve to menopause; the high progesterone levels
contact with the maximum area of mucous following ovulation and during pregnancy often
membrane. As it is then swallowed, the are associated with an increase in yeast
esophageal mucosa becomes coated with the symptoms. The use of vaginal suppositories
drug. The patient is advised to avoid food or should be continued during the menstrual period,
drink for one to two hours after each dose in blood being an excellent nutrient for yeast.
order to obtain maximum benefit. Use of the (d) Nystatin as a cream or ointment is pre-
liquid is important since the lower part of the scribed when there are symptoms or signs of
esophagus is a favorite site of yeast growth. In external yeast growth. In practical terms this is
addition to reducing the release of yeast antigens usually limited to the vulvar area, although
from this area, nystatin administered in this way occasionally infection may be noted on nails, at
will often relieve symptoms of "heartburn," the corners of the mouth, or as a "diaper rash."
"indigestion," etc. that may have been present These, then, are the various preparations of
for years. nystatin that have been so valuable both in
(b) Nystatin tablets are less expensive than the therapeutic trials and in the ultimate restoration
liquid and are used in its place to the fullest of immune competence to Candida albicans.
possible extent, although both are used initially. Other more toxic drugs are available, but the
One tablet four times daily is a suitable starting indication for their use must be weighed against
dose. An increase to two tablets four times daily their greater toxicity. Additional drugs of low
is recommended after three to six weeks except toxicity are available for vaginal yeast infections
when the initial dose proves adequate for and they can be tried if vaginal symptoms
effective control of symptoms. After three to six respond poorly to nystatin. Development of
weeks at this level, further increases to twelve or Candida albicans resistance to nystatin is said to
sixteen tablets in divided doses may be tried. If be rare, but this should be reevaluated.
no additional benefit is derived; the dose is One phenomenon deserving emphasis is seen
reduced to the least number that achieves occasionally when therapy is initiated. It suggests
maximum symptomatic relief. Nystatin is well- the Herxheimer reaction, originally described
tolerated by most patients. Nausea or mild when syphilis was treated with the arsenicals, and
diarrhea may occur with higher doses. One consisting of a febrile reaction thought to result
patient complained of leg cramps accociated from the massive absorption of dead spirochetes
with nystatin therapy. Slight skin rash has been as well as to activation of foci of syphilitic
seen twice after long-term use. All such infection (Herxheimer and Martin, 1926). It is
intolerances have cleared within several days important to recognize and distinguish this trans-
after reduction of the dose or discontinuation of ient occurrence; otherwise it will appear to be
the drug; no serious toxicity has ever been en- allergy or intolerance to nystatin and the patient
countered. will be deprived of the benefit of this valuable
A special problem may occur when initiating drug. The reaction is usually limited to a flu-like
therapy in the patient with multiple food and syndrome of mild generalized aching and low-
chemical intolerances. The different grade fever, but may also encompass an
preparations may be tried individually in small exacerbation of the patient's allergic
initial doses. For example, the liquid may be manifestations. This was exemplified by a patient
tolerated by a patient who reacts to excipients in who developed a temperature of 101 degrees
the tablet. Once a starting point is achieved, orally with associated generalized aching,
increased tolerance to these preparations will beginning the first twenty-four
coincide with general improvement in the
intolerances to foods, drugs, and chemicals.
293RESTORATION OF IMMUNOLOGIC COMPETENCE
hours of nystatin therapy. Within three days he improved by these valuable drugs. Symptoms in
exhibited a recurrence of the acute agitation such autoimmune
typical of his long-standing mental illness and allergic conditions result largely from in-
considered to be "schizophrenia." If indeed this flammation induced by some type of abnormal
was an example of the Herxheimer immune response. Suppression of these abnormal
phenomenon, it established the relation of yeast immune responses cannot be achieved without at
products to this patient's chronic mental once suppressing normal immune mechanisms
symptoms. The simultaneous diminution of vital to the containment of yeast. With the
multiple "mush/' stools in this patient indicates etiologic agent in these cases an organism living
their relation to yeast infection of the bowel and within the body, steroid therapy actually con-
further strengthens the concept that Candida is stitutes an obstacle to the ultimate goal of clearing
etiologically related to his symptoms. the tissues of the source of the incriminated
Thus, when symptoms follow immediately antigen.
the institution of nystatin therapy, it is. unlikely Judicious use of this type therapy is essential in
that a drug allergy is the cause. If such a many situations. Minimal doses with strict
reaction aggravates or reproduces the patient's indications, perhaps in short courses rather than
previous chronic symptoms, it is confirmatory continuously, should minimize the impact of these
of their relation to Candida. This type of drugs on immune competence to Candida.
reaction to treatment will only be seen initially, Meanwhile more specific measures for control of
and is not at all common. The possibility of this yeast should gradually obviate the need for the
occurrence, however, suggests the wisdom of continued use of these drugs in conditions caused
initiating therapy with a low dose of nystatin in by Candida.
patients whose symptoms would be particularly Similar reasoning is applicable to other forms of
unpleasant if aggravated. immunosuppressive therapy. When used in
conjunction with organ transplantation, treatment
II. Measures to Strengthen the Immune Re- of autoimmune disorders, etc., the underlying
sponse A. Passive: avoidance indication for immunosuppression will almost
Immunosuppressants comprise a third class of always override all other considerations. When
drugs associated with a breakdown in the Candida albicans is not etiologically related to the
immune response to yeast. By definition these condition requiring this type therapy, induced
are certain to enhance yeast growth by their exacerbation of candidiasis is of little
non-specific suppression of the immune consequence other than for increasing the risk of
response. fatal septicemic spread in patients often already
The most widely used drugs in this category debilitated and often immunocompromised.
are the adrenocorticosteroids. Their.
effectiveness in suppressing the immune re- B. Active 1. Diet
sponse has led to their extensive use in allergic
and autoimmune disorders. Suppression of an Malnutrition may prohibit the normal immune
abnormal immunologic phenomenon is response; therefore it is mandatory to detect and
beneficial with respect to the patient's correct deficiencies in those nutrients essential for
symptoms as long as therapy is continued. But the proper function of cells of the immune system.
if the abnormal immunological response in
question represents a response to Candida 2. Correction of Unrelated Conditions
antigens, as suggested previously, (Truss, Similarly, endocrine or other metabolic ab-
1978), the immunosuppression induced by the normalities may impair the immune response,
steroid allows increased growth of yeast, even hypothyroidism being a common example. These
as the patient's condition is temporarily should be identified and corrected when possible.
294ORTHOMOLECULAR PSYCHIATRY, VOLUME 9, NUMBER 4, 1980, Pp. 287-301
3. Use of Extracts of Candida Albicans upon the batch used, the same patient will,
A rational approach to the use of antigenic according to skin test, vary from non-allergic to
stimulation (vaccine therapy) in the restoration highly allergic, with an immune response ranging
of immunologic competence to Candida from strongly positive to totally absent. The fact
albicans in humans must be based primarily that these two types of skin response may vary
upon experiments in animals in the induction independently suggests the possibility that
and termination of immunologic tolerance, different antigens are involved.
supplemented by observations in humans of the (b) Testing: Testing normally begins with .1 cc
natural history of diseases that eventuate in the intracutaneously of the 1:1,000 dilution of the
state of tolerance. 1:10 concentrate. This is observed for immediate
Immunologic mechanisms responsible for hypersensitivity, Arthus, and twenty-four and
"unresponsiveness" to "foreign" antigens appear forty-eight hour delayed immune responses. If
to be similar to those involved in the the immediate hypersensitivity reaction is
maintenance of tolerance to "self" antigens. negative and the delayed no more than
Evidence suggests that both depend upon the moderately positive, the test is repeated using the
continued presence of thymus-derived 1:100 dilution, again to evaluate the patient for an
suppressor cells which specifically prevent an allergic response. However, if the twenty-four or
immunologic response that in their absence forty-eight hour delayed response is strongly
would otherwise occur. Thus tolerance, even to positive to the 1:1,000 dilution, testing with the
"self antigens, seems to be an active rather than 1:100 strength is omitted because of the
passive process. probability of an excessively large and painful
Consideration of the experimental manip- delayed reaction. In any event, a positive test for
ulations that first cause loss of and then re- immediate hypersensitivity is not essential for the
storation of responsiveness to an antigen diagnosis. A negative test reflects only a lack of
suggests that the basic requirements for tol- response to the antigens in the particular extract.
erance induction are met by chronic exposure to A word of caution is in order regarding testing.
Candida antigens when clinical conditions are The 1:10 undiluted concentrate should not be
suitable for its continued presence in the tissues. used. Too large an amount of antigen may lead to
Similarly, experimental techniques for the immune-complex deposition. A severe Arthus
"breaking" of tolerance illustrate principles reaction beginning at two to four hours,
applicable in the use of vaccines as an aid in the consisting of a diffuse, indurated, itching,
restoration of immunologic competence to erythematous area several inches in diameter,
Candida albicans in the human. may evolve into ulceration. This may be
(a) Extracts: Because of the marked variation accompanied by a systemic allergic reaction such
and irreproducability in the complement of as occurred in one patient tested in this way by
antigens among strains of Candida, each new her physician; a very large Arthus reaction
batch (lot number) should be tested for skin occurred, and within forty-eight hours she
reactivity on known reactors. This applies developed severe tinnitus and vertigo which
equally to successive batches whether from the required fully two years to subside completely.
same or different companies. The importance of Using this protocol, there have been no
this "bio-assay" was illustrated recently when problems testing in this manner. Many allergists
fresh extracts obtained from four different use different techniques for testing. Three
suppliers were tested simultaneously in a patients described severe systemic responses to
number of patients with previously sub-lingual testing, and two patients told of
demonstrated reactivity. Immediate similar reactions when tested by the serial-
hypersensitivity reactions ranged from 0 to dilution "neutralizing" technique. These cases
++++. This same inconsistency applied as well may be exceptions, and it would be helpful to
to the delayed skin test, considered indicative of know the experience of allergists who use these
the cellular immune response. Thus, depending techniques in the
295RESTORATION OF IMMUNOLOGIC COMPETENCE
diagnosis of Candida albicans sensitivity. or predicts in any way the response of the patient
Interpretation of test results: Despite the to treatment.
inconsistencies in extracts and the large number Likewise thus far unsuccessful has been the
of healthy individuals exhibiting positive tests, attempt to choose, based on skin test, the
efforts are continuing to find correlations of test particular batch of vaccine to which an individual
results to aid both diagnosis and treatment. At patient might best respond. Efforts along this line
the present time, however, tests do not are continuing, because in theory a patient should
distinguish between the symptomatic and respond differently therapeutically to two
asymptomatic individual with respect to vaccines that elicit sharply differing immediate
Candida; neither are they of help in the choice and/or delayed skin reactions.
of extract strength with which to treat; and they Also unrewarding has been the steady increase
offer no clue as to the speed or degree of in extract strength that is often successful with
response to therapy. Thus, at the present time conventional injection therapy for inhalant
they are of no help in the diagnosis, treatment, allergy. Although the patient may improve with
or prognosis. each increment in dose, symptoms soon return
(c) Treatment: The injection of an extract of and a further increase is required; eventually the
Candida albicans constitutes an attempt to maximum available concentration is reached and
strengthen the immune response to the yeast in no further increase is possible. The immune sys-
a patient who is actively infected by the tem seems to adjust to each level of stimulation if
organism. Symptoms, both infectious and given time. In most patients, therefore, changes in
allergic in nature, exist in a setting of an extract strength are made infrequently, and only
impaired immunologic capability. Marked when no response is apparent at the previous
variation is exhibited among patients in the level.
pattern of their allergic responses. It is not Extensive experience with concentrations from
surprising, therefore, that in this unique sit- 10-2 to 10-30 has led to the choice of extracts in
uation it has proved impossible to standardize a the 10-5 to 10_15 range, although occasionally
program of injection therapy. The strength of concentrations outside of this range are
the extract and the interval between injections employed. One-tenth milliliter (.1 ml)
varies not only among patients, but also in the subcutaneously twice weekly is a suitable starting
same patient at different stages of recovery; it is point, but the interval may be varied in either
as though the strength of antigenic stimulus direction. One departure from this basic schedule
must be matched roughly to the status of the im- has frequently proved useful, often affording
mune response. Immunologic techniques may dramatic relief of acute symptoms. This consists
someday aid in explaining these variations and of dividing the dose into several injections given
in establishing for each patient the optimal at thirty to forty-five-minute intervals. Although
protocol for immunization; at present this must the total dose may be virtually unchanged, the
necessarily be based on empirical observations. patient's response may be quite different. For
The presentation to follow summarizes example, ten doses of .1 ml each of the 10~15
experiences and present methods of applying strength contain the same total amount of antigen
immuno-therapy in an overall program aimed at as .1 ml of the 10-14 strength—still an extremely
restoring to its maximum the immune capability small amount. Administration of two to four in-
with which an individual is genetically jections spaced this way will often afford relief
endowed. not provided by a single injection of either of the
Perhaps the best way to begin is to emphasize two adjacent dilutions. This technique has proved
several principles that have not proved useful. It very valuable diagnostically as well as in
has already been pointed out that the choice of conjunction with efforts to alleviate such acute
extract strength cannot be established by skin problems as migraine headache, bladder or
reactions, and that no combination of immediate urethral
and delayed skin tests indicates whether to treat,
296ORTHOMOLECULAR PSYCHIATRY, VOLUME 9, NUMBER 4, 1980, Pp. 287-301
spasm, or joint manifestations. either antigen or antibody excess. (The immune
A tendency to overdo this departure from the response comprises much more than the antigen-
regular schedule should be resisted because of its antibody relationship, and it is highly improbable
effect on the long-range immune response. that this explanation is more than a useful
Patience is essential to allow the immune system framework for necessary adjustments in response
time to adapt to and begin its response to to a changing immunologic picture.)
antigenic stimulation at the chosen concentration In certain patients an additional modification of
and interval. the basic schedule is occasionally necessary, and
One pattern of response occurs sufficiently again, an explanation based on immunologic
often to merit special discussion. Marked, often evidence is not possible. Certain patients will
dramatic improvement may occur in the first few notice complete relief of symptoms following the
weeks of treatment using the same dilution of antigen injection. However, if they are still
antigen. Then the patient may report a symptom asymptomatic at the time of the next injection,
occurring as a result of the injection, often within symptoms may recur within a few minutes of the
thirty minutes or so; it may be a "stopped-up injection. Such cases are better managed by de-
nose,” or “extreme sleepiness." Such a symptom laying their injection until symptoms have started
will clear almost immediately if the identical to return, at which point relief rather than
dose is repeated as soon as the symptom occurs. aggravation will occur. (Using the same immune-
Thus the dose to which the patient has responded complex hypothesis, the asymptomatic state
with steady improvement suddenly results in a represents the absence of significant antigen or
symptom that is relieved by giving more antigen. antibody excess, at which point antigen
At that point the amount of antigen given rout- administration results in antigen excess and onset
inely should be increased until this minor side of symptoms. On the other hand, the return of
effect ceases. A change to the next stronger symptoms signals the beginning of antibody
concentration is usually effective. (Example: .1 excess and injection of antigen, if delayed until
ml of 10~15 twice weekly leads to steady this time, again restores antigen-antibody
improvement. After eight to ten weeks the above balance.)
phenomenon occurs and the symptom is cleared In summary, immune therapy with Candida
by repeating the .1 ml of 10-15. Thereafter treat albicans extracts consists of arbitrarily choosing a
with .1 ml of the 10~14 strength twice weekly.) starting dilution and observing the patient's
This unusual reaction is never serious, and response over a period of a few weeks, adjusting
usually occurs only once in a given patient, most the strength and interval of extract accordingly. It
often after the first few weeks of treatment. Since is important to explain to the patient that
it is seen in the clinical setting of a much symptoms will recur frequently, but that with
improved patient, it seem logical that it is patience and time, as the resistance to yeast
occurring in a setting of an improving im- gradually increases, relapses will become less
munologic response to the vaccine. Speculation frequent and less severe. The situation is unique.
concerning the responsible immunologic An effort is being made to rekindle the immune
mechanism is futile. Since more antigen relieves response to an organism that is actively infecting
the symptom, it is useful to think in terms of the the patient. It is both an infection and a systemic
balance between antigens and antibodies in the allergic and/or toxic response to metabolites of an
serum; as the antibody response becomes organism that has been able to perpetuate its
stronger, symptoms result because an imbalance presence in the tissues by effectively neutralizing
in the direction of antibody excess perhaps leads host defenses.
to immune-complex deposition. The injection of
more antigen returns the antigen-antibody DISCUSSION
balance to the zone of equivalence. One method for the experimental induction
Experimentally immune complexes are
much more damaging if given in the zones of
297RESTORATION OF IMMUNOLOGIC COMPETENCE
of immunologic tolerance is to expose an animal ing antigen, which may be defined as a protein
repeatedly to soluble protein antigen below the with determinants that are shared with the
threshold dose that is immunogenic (Benacerraf tolerated protein as well as others that are
and Unanue, 1979). This "low zone" tolerance is specific to itself. For maximum effectiveness the
usually restricted to the T-cell, the B-cell degree of antigenic identity should be at least 15
retaining or recovering the ability to respond percent but not more than 75 percent. Current
with antibody production. theoretical explanations for this phenomenon
Colonization of tissues by Candida albicans have been presented in a recent concise review
provides in the human the counterpart of this (Benacerraf and Unanue, 1979). T-helper cells
experimental protocol for the induction of T-cell that are tolerant and unresponsive to shared
tolerance. The presence in human sera of 79 determinants will respond to those determinants
immunologically distinct antibodies to Candida specific to the cross-reacting protein. If there are
indicates the chronic release of a complex B-cells capable of cooperating with these
mixture of soluble proteins, thus simulating the stimulated T-helper cells, they will produce
conditions for experimental tolerance induction antibodies that are effective in terminating
by chronic exposure to low doses of antigen. tolerance.
Studies reported by Budtz-Jorgensen in children An exception that has been described to this
with advanced chronic mucocutaneous general principle could well be important in the
candidiasis demonstrated that in this condition clinical setting of candidiasis. If the tolerated
tolerance is primarily in the T-cell. When the protein is injected simultaneously, the cross-
fungus was suppressed by am-photeracin-B reacting protein fails to terminate tolerance, the
therapy, the ensuing reduction in antigenic load theory being that the shared determinants
led to conversion from negative to positive of in temporarily toler-ize the B-cells, rendering them
vitro tests of the T-cell response without incapable of responding to the new T-helper
detectable change in antibody titers. Upon cells. In patients the various factors that stimulate
withdrawal of amphot-eracin-B, these in vitro yeast growth should result in the increased re-
tests reverted to negative with relapse and spread lease or "injection" of the tolerated protein. By
of the fungous infection, again with no analogy, this should decrease or prevent the
detectable change in antibody levels. Further desired response to the cross-reacting protein,
confirmation that B-cells may remain functional which in this case has been extracted from
in the presence of tolerized T-cells is suggested Candida albicans and administered as a
by experiments in monkeys with induced "vaccine." The clinician endeavoring to restore a
Candida infections of the palate (Budtz- patient's competence to respond to the antigens of
Jorgensen, 1973). Without suppression of the T- this yeast is not so fortunate as the experimentor,
cells by azothiaprine, an early T-cell response who may arbitrarily withhold further exposure to
preceded by several weeks the onset of detect- the tolerated protein. Surges of yeast growth as-
able antibody. Prior treatment with this im- sociated with high carbohydrate availability,
munosuppressant prevented the T-cell response contraceptive hormones, antibiotics and im-
and resulted in a stronger and much earlier munosuppressant drugs, and characteristic of the
antibody response, suggesting that T-suppressor luteal phase of the menstrual cycle and pregnancy
cells were more susceptible than T-helper cells may account in large measure for inconsistencies
to inhibition by azothiaprine. in the response of patients, particularly in the
The importance of retained B-cell function in early months of treatment. The pre-menstrual
association with T-cell tolerance to Candida period is characteristically the time of greatest
antigens relates to experimental techniques for intensity of yeast vaginitis for most women; the
the termination of specific immunologic sudden return of symptoms at this time is the
unresponsiveness. Provided that B-cells remain most frequent example of this fluctuation in re-
functional, T-cell tolerance may be "broken" by sponse.
the injection of a cross-react-
298ORTHOMOLECULAR PSYCHIATRY, VOLUME 9, NUMBER 4, 1980, Pp. 287-301
Recovery from immunologic tolerance may also in many cases. The rapidity and degree of
occur spontaneously, i.e., without the influence recovery may well reflect the speed of recovery
of cross-reacting antigens. Since this is greatly from the yeast antigenemia which in turn is
influenced by the presence of residual antigen influenced by the sensitivity of the specific strain
capable of tol-erizing new cells arising from the of yeast to nystatin, by the degree and speed of
stem cell pool (Benacerraf and Unanue, 1979), all response to yeast vaccine by the immune system,
aspects of therapy other than active immunization and by the extent to which the patient is able to
with extracts are designed to minimize the avoid those factors that favor yeast proliferation.
"tolerogenic" load. If total elimination were The suggestion is made that one of the adverse
possible, presumably spontaneous recovery from effects of chronic candidiasis is to alter the
the tolerant state would co-' incide with the adaptability to environmental contacts. Probably
emergence of young competent cells in the everyone would react to any chemical if exposed
absence of tolerogen. to a sufficiently high concentration. Therefore it
Of the greatest importance to many patients appears to be the threshold at which an individual
with chronic candidiasis is the development of reacts that is altered by the chronic exposure to
intolerance to foods, drugs, and chemicals. A yeast products. When this alteration is minimal,
careful history often reveals the earliest of these environmental intolerances are minimal. But in a
intolerances occurring in the first several years patient who is highly susceptible to this
after the symptoms of chronic yeast infection. particular effect of Candida, the number and
Thereafter occurs a rapidly accelerating inability severity of intolerances may be completely
to tolerate environmental chemicals, whether they incapacitating. Even the slightest exposure to
be known as "foods," "drugs," or "chemicals." cosmetics, foods, drugs, and almost any other
These patients may literally become unable to class of "chemicals" may lead to severe physical
live in normal environments, resorting for relief symptoms, including those arising from the
to the most dramatic measures of environmental central nervous system and so frequently er-
control. They are unable to work, and may even roneously considered "psychoneurotic" in origin.
move to remote areas in their attempt to minimize The relation of Candida albicans to the de-
the total load of chemicals contacted in their daily velopment of drug allergies is of particular
lives. importance. Intolerance develops to a rapidly
Dr. Theron Randolph (1962) called attention to expanding number of drugs. This often is one of
this developing problem beginning in the early the earlier manifestations of chemical
1950's and discussed the problem at length in intolerance. It suggests the possibility that either
1962. His pioneering efforts have enabled many Candida antigens, or antibodies directed at these
patients to be helped by a program of maximum antigens, are acting as carrier proteins,
avoidance of the offending chemicals, including combining with the drug ("hapten") to form an
contaminants in both food and air. It is of great allergic complex.
interest and potential significance that his Finally, it cannot be emphasized too strongly
observations and publications in this field that the treatment of this condition is unique.
coincided with the tremendous proliferation of Each patient requires close attention and ready
articles delineating the increasing prevalence of access to the physician. When symptoms recur,
chronic yeast problems in the population, the associated depression and anxiety may be
attributable to the advent and wide-spread use of severe, accompanied by a destructive loss of self-
the broad-spectrum antibiotics. confidence and nope. Together with the lethargy
Disappearance of such chemical intolerances and excessive sleepiness that often coincide with
often occurs when the candidiasis clears. Patients the physical manifestations characterized for
may begin to note improvement in the first few each patient, these "emotional" symptoms,
weeks of treatment; within six to twelve months, actually referable to the
most or all of the intolerances will be gone
299RESTORATION OF IMMUNOLOGIC COMPETENCE
effect of yeast on the central nervous system and what to both family and physician had seemed so
on hormone function, may render a patient surely to be psychiatric in cause.
unable to cope with the simplest daily problem.
This may be devastating in women during the
child-bearing years, almost certainly due to SUMMARY AND CONCLUSIONS
interference in the response to hormones so Chronic infection with Candida albicans results
characteristic of this condition. when a state of impaired immunity prevents the
Marital problems are often acute. If most normal immunologic responses necessary for
physicians are so quick to relegate these patients eradication of the yeast from the tissues.
to the psychoneurotic category, one can only Symptoms usually occur at the sites of fungous
imagine how difficult it is for a husband to accept colonization. More importantly, symptoms
that this is not willful behavior, and absolutely frequently result from responses in uninfected
cannot be controlled voluntarily any more than tissues to yeast metabolites released
other conditions that adversely affect brain systemically; these may represent an allergic or
physiology. His interpretation of his wife's other abnormal immunologic response, but
behavior is profoundly reinforced by her often theoretically could also result from toxins acting
total loss of libido and aversion to marital through non-immunologic mechanisms.
relations. The patient herself feels hopelessly A program has been described that is designed
isolated, with no place to turn as she sees her life to achieve the maximal possible reduction in the
disintegrating. Faithful adherence to medical quantity of yeast products entering the
recommendations (including psychiatric bloodstream, together with a program of active
treatment) by many specialists for many years therapy with extracts of Candida albicans
has not stopped the deterioration of her health designed to terminate the state of immunologic
and her life. In fact, often the combined tolerance. The rationale presented is based on
undesirable effects of many well-intentioned current theory of mechanisms involved in the
medications have only served to depress further induction and termination of tolerance.
the involved physiologic processes, with The goal set forth in the title of this paper is at
minimum benefit symptomatica! ly. Careful once ambitious and unattainable except in a
explanation to a husband is of great value to him, relative sense. Its universal presence in humans
to the marital status, and to the woman struggling indicates an inherent weakness of the immune
to escape from this disaster during the time response to this yeast.
necessary for her to begin to improve. Once More properly stated, the goal of therapy
improvement begins, it becomes easier for all becomes the restoration of the maximal immune
concerned to accept that all along this has been a capability with which each individual is
physiological and not a psychiatric problem, and genetically endowed, whereby is achieved the
to believe that finally there is a justifiable basis maximum possible reduction in the chronic
for renewed hope. exposure to this organism and its metabolites.
When these patients have the sudden recurrence
of symptoms, it has proved most valuable to have References
them stay in the office and receive the yeast
extract at twenty to thirty-minute intervals for BENACERRAF, B. and UNANUE, E.: Textbook of Immunology.
one and a half to two hours. This is almost "Tolerance." Baltimore: Williams and Wilkins Co.; 166-177,1979.
always effective in alleviating the acute BUDTZ-JORGENSEN, E.: Cellular Immunity in Acquired
symptoms, both physical and mental. Of even Candidiasis of the Palate. Scand. J. Dent. Res. 81; 372-383.1973.
greater value is the benefit to patient and family BUDTZ-JORGENSEN. E.: Immune Response to Candida Albicans
of seeing this reversal of these unbearable in Monkeys with Experimental Candidiasis in the Palate. Scan. J.
Dent. Res. 81;360-371,1973.
symptoms. Even though cautioned that relief by
this method lasts only a few hours to a few days, GOODMAN, S. and GILMAN, A.: The Pharmaceutical Basis of
they now have evidence from their own therapeutics, 5th ed. New York: MacMillan; 1235-1236.1975.
experience that there truly is a physical reason for
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