TISSUE INJURY INDUCED by CANDIDA ALBICANS Menstrual Period Occurring on the 26Th Day of "She's More Active," "Doesn't Sit and Hold Her Treatment

Tissue Injury

Induced By Candida Albicans

Mental and Neurologic Manifestations

C. Orian Truss, M.D.I

Introduction body complexes or the presence of "auto- Medical research of the past several decades antibodies" to one's own tissues are but two has greatly expanded our knowledge of the examples. deranged chemistry and physiology that The same "dead end" is reached, however, characterize many individual disease states. Yet when the search for a virus or other antigenic most diseases have stubbornly resisted the agent is unfruitful. The evidence indicates that massive effort to unlock the secret of their an immunologic response is taking place and etiologies. We learn more and more about the is in some way involved in the disease abnormalities of function that result in clinical process, but the antigenic agent continues to symptoms and signs, but continue to be frustrated elude discovery. in our effort to discover the identity of the factor Or we may postulate that the immunologic initiating the departure from normal function. It is process occurs secondary to toxic damage to a unfortunate that the list of such diseases is headed tissue, leading to autoantibodies and perhaps by those that are the most frequent cause of to antigen-antibody complex deposition. But disability and death. Among them would be again, such a toxin escapes detection, if it atherosclerosis, most often clinically expressed as exists. hypertension, heart attacks, and strokes; In presenting selected, cases treated during malignancies, "auto-immune" diseases, arthritis, the past 16 years, I hope to call attention to muscle-wasting diseases, mental and neurologic Candida Albicans as a possible candidate for disorders, and many others. the role of etiologic agent in diseases that Frequently the evidence suggests that seem to have an immunologic or toxic basis, immunologic mechanisms of tissue injury are but for which no such factor has been involved. The deposition of antigen-anti- discovered. This yeast probably exists in all humans as well as in many animal species. Anti-Candida antibodies are present in 100 percent of humans, as will be discussed later. 2614 Highland Avenue, Birmingham, Alabama 35205. If studied serially, a high percentage also will Presented at the eighth annual Scientific Symposium of the Academy of Orthomolecular Psychiatry held in Toronto yield a positive culture of mucous membrane April 30 • May 1,1977. surfaces, as well as a positive delayed skin test to Candida. 17 ORTHOMOLECULAR PSYCHIATRY, VOLUME 7, NUMBER 1, 1978, Pp. 17-37

The very fact of its universal presence probably tension. accounts in large part for the neglect in My interest then evolved to depression and attempting to relate this yeast to serious disease. anxiety not limited to the premenstrual period, Instead, it is today relegated to the role of an and to their relationship to the chronic allergic aggravating nuisance when it infects mucous state and to Candida in particular. I noted that membranes, skin, and nails; the one exception is in certain women the premenstrual depression the rare septicemic dissemination to internal would become so intense that in appearance organs in the chronically ill, often immuno- and response they brought to mind patients compromised host. Since culture, skin test, and with catatonic schizophrenia. I remember serology fail to distinguish between a well person remarking at the time that I would like to treat and one in whom Candida is causing illness, there the yeast infection in a schizophrenic patient has been no reason to suspect that it may, by an to see whether there would be any entirely different mechanism, play a far more improvement in the mental status if the yeast important role as an agent of tissue injury. By problem could be brought under control. Four treating yeast infection and yeast allergy years after the initial incident this opportunity intensively where found, it has been possible to was afforded me, and this patient is presented demonstrate the relationship between mucous as Case No. 1. membrane infection and abnormal function in organs distant to the yeast infection and not Case #1 actually themselves infected. The cases selected In 1965 a 36-year-old woman with allergic for presentation also demonstrate the variety of sinus headaches was brought to see me. tissues that may be injured by this mechanism, as However, her case was distinctive in that for judged by the diversity of symptoms and signs six years she had been treated for schizo- that ceased when the mucous membrane infection phrenia. After many courses of drug and cleared. electroshock therapy, her condition had deteriorated to the point that permanent Case Presentations commitment to the state mental hospital had been recommended by her psychiatrist. On An incident that occurred in 1961 was the first checking with him regarding any objection he indication that this organism perhaps is capable might have to my treating her headache of causing disorders much more severe than problem, I was told to go right ahead—that conventionally attributed to it. A 40-year-old nothing could aggravate her already grave woman whom I was treating for allergic rhinitis mental condition. and migraine headaches walked into the office The patient was withdrawn, managing a yes with one of her severe headaches. It was readily or no answer to questions only after much apparent that she was also quite depressed, which effort and hesitation, so that the history was was characteristic of the severe premenstrual obtained from her neighbor and long-time symptoms that she experienced for one week friend. Two weeks after the first injection of each month. Candida Albicans was one of her extract of Candida Albicans, she was more allergens, and chronic yeast vaginitis worse alert and better able to answer questions. The premenstrually was a prominent complaint. A second injection resulted in marked small dose of Candida extract relieved the improvement, such that four weeks after headache, but the most startling result of the beginning treatment she was doing her own injection was the rapid and complete housework, was cheerful, and "even able to disappearance of the depression. Her initial get mad again." At seven weeks she stated unsmiling, agitated manner was suddenly "I'm myself again"—an appraisal to which her replaced by a relaxed, smiling countenance. In husband acquiesced. Chronic yeast vaginitis subsequent months it was possible to duplicate and menstrual spotting had stopped with the this experience, both in her and in other similar first injection, a normal cases of severe premenstrual depression and

18 TISSUE INJURY INDUCED BY CANDIDA ALBICANS menstrual period occurring on the 26th day of "she's more active," "doesn't sit and hold her treatment. Stelazine and Elavil had been hands—not as clumsy; before her period she discontinued at five weeks, the only remaining drops almost everything she picks up." "After medication being one Librium capsule in the her period starts it is easier to rouse her." morning, "but not every day." She had returned to "When I fuss at her, I think she hears me." her church activities, and stated that "I'm looking Physical symptoms by this time included pain for a job." She was totally asymptomatic except in the left shoulder and back, episodes of for mild, mid-morning "nervousness" for which marked abdominal distention, sore throat and she used the Librium capsule when needed. headaches, fungus infection between the Normal menstrual cycles continued. At 12 weeks fingers, chronic nausea and puffiness of the she was "taking in ironing" to supplement the eyelids, and the chronic yeast vaginitis. family income, in addition to her housework and The next two years saw progression of these church activities. Her husband stated "she's sassy mental and physical symptoms. Shock now." treatment would seem to help for three to four A careful history led to the choice of treatment weeks only. One month before her first visit to that resulted in this rapid recovery after six years me eight shock treatments helped "for a few of progressing, chronic mental illness. hours—then right back down." At this point Her health had been remarkably good until age they were discontinued. Premarin, because of 25 years. At that time her second pregnancy was three months of menstrual spotting, Stelazine, complicated by hypertension and urinary Elavil, and Librium were the prescribed frequency and burning. Following delivery, she medications at the time her allergy treatment developed vaginal discharge and a fungus was begun. infection between the fingers of both hands, both This woman was treated for one year with conditions recurring repeatedly thereafter. nothing other than the Candida Albicans extract. Follow up 10 years later found her well. Between ages 25 and 30 years she remained Three years after her Candida treatment was active and well, and "very energetic." During this discontinued, she had a transient episode of interval she continued to have the vaginal mild depression which cleared quickly when discharge and itching and the fungus infection her psychiatrist gave her three shock between the fingers. She also began to note treatments as an outpatient. She had remained repeated sore throat and postnasal drainage. well for the next seven years. Developing hormone problems were signaled by This case will be discussed further later. It is the onset of excessive menstruation and cramps, of note that vaginitis and fungus infections of loss of libido, and seven to 10 days of the fingers, both following her second premenstrual anxiety and depression. These pregnancy, were the earliest indicators of a symptoms would typically abate once her period change from her previously normal started and gradually increase as she moved farther physiologic state, and heralded 10 years of into the next cycle. steady deterioration in hormone function and At age 30 years pain and tenderness in one breast mental status. were associated with increasing nervousness. By age 31 years she was under the regular care of a Review of Conventional Role psychiatrist. On tablets prescribed by him she Candida Albicans enters and colonizes remained active, but with occasional "quiet spells." newborn infants during or soon after birth. The premenstrual tension progressed both in This event may be evidenced clinically as oral severity and duration. By age 33 years the thrush, but in the vast majority of cases it depression was severe. She stopped church escapes clinical detection. Nevertheless, that it activities. Headaches and back pain began. occurs is apparent from the fact that by age six Even as her overall condition became worse, she months, 90 percent of babies have developed a would still improve for seven to 10 days once her positive delayed skin test. period started. Her friend stated "her face clears," 19 ORTHOMOLECULAR PSYCHIATRY, VOLUME 7, NUMBER 1, 1978, Pp. 17 - 37

This, together with the simultaneous development presentation, suggests the existence of an of humoral antibodies, indicates that T- as well as additional mechanism by which Candida may B-lymphocytes have participated in the lead to symptoms. These may range from mild immunologic response to this yeast. to severe and may represent disturbed function Thus soon after birth the stage is set for a lifelong in a variety of tissues. In terms of human dis- battle between this yeast and the human body. That ability, both mental and physical, symptoms this continues throughout life is confirmed by the induced by this mechanism far outweigh the presence at any age of the same high incidence of minor nuisance of mucous membrane immunologic response, as well as by the frequency colonization by yeast. of recurring clinical yeast infections. If we consider The distinguishing feature of this type the fluctuating levels of humoral antibody together symptom is its origin in a tissue remote from with the alternating pattern of positive and negative actual yeast colonization. Abnormal function cultures of the mucosal surfaces in a given in a tissue results rather from the release of individual, the ebb and flow of the host-parasite yeast products into the bloodstream of the struggle is evident. Many factors favor the yeast in host. That at least some of these factors are its attempt to extend its total area of mucosal antigenic is evidenced by the response of both involvement. We may have had its growth under T- and B-lymphocytes; however, there is no reasonably good immunologic control, only to have reason to assume that all are antigenic, or that such a factor (e.g., antibiotic therapy) lead to a the resulting abnormal function is necessarily breakdown in this control. This may be mild or mediated by immune mechanisms. The im- severe and may be easy or difficult to reverse. Few portant distinction is that chronic colonization if any individuals over a lifetime escape repeated of mucous membranes may lead to serious encounters of this type. From what is known about illness apart from the purely local symptoms the genetic control of the immune response, we of soreness, itching, discharge, or diarrhea. might predict wide variation among individuals in Possible ways in which yeast products may their ability to keep yeast growth under control; and lead to such a result will be considered indeed, this prediction is borne out by clinical following the case presentations. Conceding experience. for the moment the existence of such a The next point for consideration is the effect that mechanism, it becomes apparent that the such yeast growth has on the host. Turning to the proper approach to terminating such a most recent edition of the standard textbooks of situation is to drive the yeast out of the tissues medicine, we find Candida Albicans described as a wherever it has been able to establish itself. fungus of widespread occurrence, usually of no im- Although anti-yeast drug therapy and possibly portance other than for the discomfort it causes on diet help accomplish this, ultimate success mucosal surfaces (and occasionally the skin and must depend on immunological techniques nails), chief of which are soreness of the mouth, designed to reestablish a competent defense diarrhea or rectal itching, and vaginal discharge or against this infectious agent. The antigenic itching. The one exception to this assigned role as a nature of Candida Albicans and the relatively minor nuisance is Candida septicemia, immunologic response of the human to it will whereby the yeast may be disseminated throughout be discussed in detail later. At this time, since the body, leading to serious or fatal consequences. it is an integral part of the postulated This occurrence is usually ascribed to a con- mechanism, a brief description will be given comitant severe illness, often one associated with of the phenomenon of immunologic tolerance, general immunosuppression, e.g., leukemia. or unresponsiveness, as it may apply in this Hypothesis instance. The response to an anti-Candida therapeutic It is possible to render an animal program, as illustrated by the cases selected for 20 TISSUE INJURY INDUCED BY CANDIDA ALBICANS unresponsive to an antigen by exposing it more or its own products, antigenic or otherwise, into less continually to this antigen. This may be carried the bloodstream. If indeed such yeast products out with very high doses of antigen—called "high- have the capacity to injure tissues in the zone tolerance"—or with very low doses, "low- various organs of the body, the requisites for zone tolerance." High-zone tolerance tends to chronic disease are present. The continued render unresponsive both T- and B-cells, whereas elaboration of the injurious agent is assured by low-zone tolerance weakens or blocks the T-cell an impairment of the immune response, which response only. Thus the cellular immune response in turn is perpetuated by the organism (T-cell) is more easily blocked, and such blockage elaborating the injurious factor. The clinical is easier to sustain than is the humoral (B-cell) manifestations of chronic illness will reflect response. Furthermore, unresponsiveness (or the abnormal function in the particular tissues "tolerance") is easier to induce with soluble than involved. Genetic factors may be of primary with aggregated antigens. importance in determining which tissues will Thus immunologic tolerance is most readily react in a given individual. achieved by more or less continual exposure to a The cases selected for presentation soluble antigen, with T-cell paralysis being much demonstrate the wide range of tissues and easier to achieve and sustain. organs that may be involved, either in a given When mucous membranes are chronically infected patient or among a group of patients. by yeast, cells of the immune system are exposed This hypothesis allows the seemingly continually to Candida antigens, thus satisfying the unrelated conditions represented by these conditions for tolerance induction. This weakened cases to be tied together by a common immunologic response allows the yeast to thrive in mechanism. We have only to keep in mind the tissues, and a vicious cycle is established. An that perhaps no tissue or organ is safe from analagous situation has been reported in such injury in order to understand how lepromatous leprosy. In this, the widely symptoms related to such diverse areas of the disseminated form of leprosy, impairment of the body as brain, skin, muscles and joints, and immune response has been demonstrated in vivo by internal organs can respond to the same form reversion to negative of the lepromin skin test, and of treatment. in vitro both by impairment of the lymphocyte transformation test on exposure to the leprosy Case#1 bacillus or phytohemagglu-tinin, and release of the The case presented at the beginning of this migration inhibitory factor on exposure to the paper illustrated the severity that symptoms bacillus. In the tuberculoid form of leprosy, may reach in this syndrome. It will be however, this does not occur. This is the localized discussed in more detail later, but first I would form of the disease, which carries a good like to present a less complicated case that prognosis. Thus widespread involvement is demonstrates the principles outlined in the associated with impairment of the immune previously presented hypothesis. response. With Candida infection, as with leprosy, there Case #2 may be for each individual a critical point beyond This young white woman was relatively free which the total area of involvement is such that the of health problems until 24 years of age. The antigenic stimulus paralyzes rather than stimulates one exception was hay fever present since the immune system, particularly the T-cell com- childhood, nonseasonal, and aggravated by partment. Until this state of immunologic windy or damp weather and damp, musty unresponsiveness is broken, drug therapy of the places. yeast infection will be less than fully effective. This She and two other healthy young women chronic state of depressed immunity allows the working in the same office became ill with infectious agent to thrive and to continue to release vomiting and diarrhea. Her two fellow-

21 ORTHOMOLECULAR PSYCHIATRY, VOLUME 7, NUMBER 1, 1978, Pp. 17 - 37 workers recovered in the usual two to three days, possible with nystatin alone, and if it were, but when I first saw her three years later, the whether the central nervous system symptoms patient had never returned to her former state of of anxiety and depression would clear. She good health. Unlike her two friends, she had responded quickly to this therapy; in 10 days consulted her physician, who had prescribed she was totally free of all symptoms and tetracycline for the intestinal flu symptoms. She having normal bowel movements. I promptly developed yeast vaginitis which recurred discontinued treatment and within two days intermittently during the next three years. Within all symptoms returned, only to cease quickly six months she developed severe constipation. X- on resumption of treatment. After three weeks rays showed "megacolon." She began to have without symptoms, I halved the dose from 16 episodes of marked abdominal distention, to eight tablets per day. She again relapsed associated with anxiety and depression. She also and again quickly cleared on return to the had noted the onset of premenstrual tension of original dose. After another six weeks of three days' duration; this had never been a problem symptom-free therapy with four tablets four for her prior to the present illness. This is an im- times a day and one vaginal suppository twice portant point which will be considered later. daily, she remained well when treatment was Proctoscopic examination and colon x-ray were stopped. At the time of my last contact with unremarkable at the time of her initial work-up her one year later, she was well. Her follow- with the exception of internal and external up letter to me at that time concluded with the hemorrhoids. following statement, "I personally feel that I In order to test the idea that her three-year have had a complete recovery since I no illness was due to Candida Albicans, and because longer have any problem with waste with injection therapy there is always the elimination and my nerves and hay fever have possibility of nonspecific stimulation of the caused me no trouble since I finished taking immune system, I chose to treat this patient only the pill which you prescribed." with nystatin. The sole effect of this drug is to suppress yeast growth; it is the most widely used Discussion of Case #2 drug for this purpose. It is used in tablet form for Because of her remarkable freedom from intestinal, suppository for vaginal, and suspension illness of any kind until age 24 years, except for oral yeast infections; in addition, it may be for her mild hay fever, we may assume a well- used topically for skin and nail involvement. It is functioning immunologic system, and a absorbed from the intestine in such small amount genetically determined ability to contain yeast that it is of no value for treating Candida in an effective way. The stimulation by infections of the internal organs. In fact, if it were tetracycline enabled the yeast to initiate the absorbed in the small intestine, it would not reach colonization of her mucous membranes and the large intestine and would therefore be thus begin releasing its products into her ineffective in treating yeast growth in the bowel. bloodstream. That she soon became unable to Since pharmacologically this drug has no effect mount an effective immunologic response to other than to suppress yeast growth on mucosal the yeast is indicated by increasing and skin surfaces, any symptoms that are cleared colonization in the colon and vagina. Whether by its administration may be presumed to have or not skin and in vitro tests are adequate to been caused by yeast. This would apply not only document it, we must assume that her immune to symptoms and signs related to the skin and response to yeast had been impaired to a mucous membrane colonization, but more degree sufficient to prevent her from regaining importantly to those arising in an organ itself not her previous control of this infectious agent. infected by this fungus. Also illustrated in this case are the two In this young woman I hoped to determine mechanisms of symptom induction. She suf- whether clearing the mucous membrane fered from conventional local symptoms involvement in the colon and vagina would be

22 TISSUE INJURY INDUCED BY CANDIDA ALBICANS due to mucous membrane infection (constipation, smoked. Examination and x-rays revealed no abdominal distention, vaginal discharge, and cause. His exercise tolerance had previously itching) as well as central nervous system been exceptionally good. symptoms of depression and anxiety. Indeed, she Finally, three years earlier and now four could tolerate the symptoms of local infection much years after the skin lesion had appeared, he better than the anxiety and depression, of which she developed what was diagnosed as "mucous complained bitterly. colitis." A gluten-free diet helped only The recurrence of symptoms when the nystatin slightly. No cause could be found. was discontinued prematurely and again when the Thus over a seven-year period he had the dose was halved indicate that relief of both local sequential appearance of a skin lesion un- and remote symptoms depends upon an adequate diagnosable by three different pathologists on dose administered for a sufficient length of time. biopsy; dyspnea and wheezing; and the This woman remained well as of the last follow alternating diarrhea and constipation of up one year after treatment was discontinued. It is mucous colitis. unusual to achieve this result with nystatin alone. Nystatin was started in a dose of four Usually immunotherapy with Candida vaccine is tablets four times daily. He reported that required. But this case does illustrate in an uncom- within 24 hours there was dramatic relief of plicated way the manner in which a healthy person the intestinal symptoms and within three to may become chronically ill when some factor leads four days "25 percent improvement in the to a breakdown in yeast control; how the shortness of breath." The skin lesion became involvement may be local or at sites distant to the much less intense in color and less elevated. yeast growth; and how the patient's immune control Two weeks later it was smaller, the stools of the infection may be re-established, if given the were normal, and the dyspnea much better. opportunity, by adequate suppression of the yeast After 10 weeks of nystatin therapy, still on a for a sufficient length of time. dose of four tablets four times a day, the skin lesion had disappeared and the bowel Case #3 movements remained normal. The wheezing The next case is chosen to illustrate an in- had ceased, and the exertional dyspnea was flammatory response in tissue distant to the site of "75 percent gone." yeast colonization. This 66-year-old man had been After 12 weeks of therapy with nystatin, in excellent health until seven years before his first weekly infections of Candida extract were visit. At that time a skin lesion developed on the added because of the residual dyspnea. Six inner aspect of the left forearm just below the weeks later he stated that the respiratory dif- elbow. It was purple, about two inches long, one ficulty had ceased. Treatment was continued inch wide, raised one-half inch above the skin for one year with no further recurrence of any surface, and very firm. During these seven years it symptom. had not varied, and had been biopsied three times. There was no precipitating incident to ac- The first was read as "lupus erythematosus"; the count for the onset of the present illness. The second as "an intense lymphocytic infiltrate"; the only antibiotic therapy he could recall had third "about like the first." I was able to secure the been three years before the appearance of the pathology report only of the second biopsy. It tumor. There was no history of allergy except described "perivascular lymphocytosis, marked— for a penicillin reaction 20 years earlier. suggest absolute lymphocyte count of blood and lymph node to rule out leukemia. The perivascular Although this patient had no symptoms to collections are quite prominent." implicate the central nervous system, he did Five years earlier, which was two years after the have involvement of two areas distant to the appearance of the skin lesion, he developed yeast infection. The immediate response to exertional dyspnea with wheezing. He had never nystatin indicates that the "mucous colitis"

23 ORTHOMOLECULAR PSYCHIATRY, VOLUME 7, NUMBER 1, 1978, Pp. 17 - 37 was probably chronic yeast growth in the colon. 140 pounds to 193 pounds. One year after Participation of the skin and the respiratory system delivery her weight was down to 125 pounds in the response to the yeast infection illustrates and she felt fairly well. These evidences of tissue changes resulting not from yeast severe hormone dysfunction are significant colonization, but from a different mechanism. This and will be considered in detail later. conclusion seems inescapable since the nystatin, Past allergies were limited to mild allergic due to its negligible absorption from the intestinal rhinitis in the fall and winter and multiple drug tract, would not be available in the skin and lungs. allergies. Resolution of the inflammation in these tissues, Detailed questioning concerning problems therefore, must have been secondary to the clearing with yeast revealed the following: At nine of the infection in the intestine. years of age she had oral thrush requiring treatment, during which two permanent teeth "just came out." At this same age she began to Case #4 have three to four bowel movements almost The next is a case in which the central nervous daily. A history of "colitis" as an infant may system was involved. It illustrates the severity of be significant. Within the year after her symptoms that may result when it is the tissue of pregnancy she developed yeast vaginitis from the brain that is reacting, since this young woman antibiotics. shot herself three times in the chest. She survived Her own description of herself at the time after weeks in intensive care following surgery to of her first visit was as follows: "My memory remove a bullet that had lodged in her heart. has become very poor in the past four months; I first heard of this 36-year-old registered nurse it used to be excellent." "I despise my husband from her sister, a physician's wife who was already and child when I'm like this; as soon as they under my care, who told me over a period of come in the door I scream at them over just months of the family's increasing concern for her anything; I don't appreciate anything." sister's steadily progressing mental depression. She Her initial skin tests were just slightly was seeing a psychiatrist regularly. At the request positive to molds, dust, and grass. Treatment of the family, and after securing her psychiatrist's was started immediately with Candida permission, I agreed to see her with the stipulation Albicans extract. Her second visit was two that she miss none of her appointments with her weeks later. She and her husband reported psychiatrist. "great improvement" in mood; also of great The initial history revealed four months of interest was the fact that the kidney symptoms rapidly progressing depression. Preceding by ceased and the urinalysis became clear of several weeks the onset of the depression was gross blood for 11 days after beginning the urinary bleeding with clots. Over the next few injections. Four weeks after treatment was weeks she passed several kidney stones and begun, she reported "10 perfect days; then exhibited gross or microscopic hematuria almost slight wheezing the past three to four days." continually. Wide fluctuations of weight—as much Now we come to an incredible occurrence. as 20 pounds—would occur over a several-day It is difficult to see how such a thing could period. She had first passed kidney stones at age 25 happen, but for two months she did not return. years when six weeks pregnant. She passed several Since she was feeling so well when last seen, more stones in the ensuing six years. and lived 220 miles away, I assumed from Past history revealed grossly abnormal week to week that she was just postponing her menstrual cycles from age 14 years, with next visit. The unbelievable fact was that no irregularity, clots, cramps, and premenstrual one in her family realized that she was no tension. An 11-month period of amenorrhea longer coming. preceded her only pregnancy, which was marked One day my phone rang. It was the by pre-eclampsia at three months with hypertension, albuminuria, and gain in weight from 24 TISSUE INJURY INDUCED BY CANDIDA ALBICANS patient's sister, informing me of the near-fatal dysmenorrhea. Periods may be too close suicide attempt. After heroic surgical measures had together, or too far apart. The vaginal smear saved her life, I was asked to resume her treatment. often reveals poor cor-nification, and vaginal Again I left it up to her psychiatrist, and again he candidiasis is present on a chronic recurring approved. basis in most patients. But by far the most She lost 13 pounds with the first injection of devastating to the unfortunate woman with Candida Albicans extract, and her depression this problem are the irritability, emotional cleared. During the next six weeks she felt lability, mental depression, and general extremely well, complaining only of "hot flashes" inability to function. Total loss of libido is (remember the lifelong hormone problems). The particularly prominent, often adding strained extent of her improvement was indicated when her marital relations to the rest of her problems. psychiatrist told her "you don't need me anymore," The typical woman who has reached this point and to my amazement, dismissed her. Some four has been referred to a psychiatrist with the months after the suicide attempt, she was working belief that the mental problem is primary. In regularly and soon became administrator of a 300- reality, the mental symptoms are merely the bed nursing home. It is now 11 years later. She has manifestation of aberrant function within the been treated without interruption, receiving Can- central nervous system, just as the bleeding dida injections weekly. After nine years on Candida disorders are indicators of abnormal uterine vaccine alone, I added dust, pollen, and airborne function. This interference with hormone mold extracts because of some trouble with hay function in the chronically allergic patient will fever, which was in itself mild, but caused her to be discussed in detail later. It is presented have hot flashes that were more troublesome than briefly at this point so that it may be pointed the hay fever. During these 11 years we really have out as these cases are discussed. had no significant problems. She has worked Returning now to the last case presented, throughout, never feeling any indication of the old we recall the history of colitis as an infant and symptoms returning. oral thrush at age nine years with the onset of Before considering this case further, I would like several bowel movements per day. It is at this point to discuss briefly one of the probable, therefore, that chronic yeast mechanisms that seems to be involved in the infection preceded the onset of her hormone production of these symptoms of brain dysfunction. cycle at age 14 years. Her cycles were never This consists of interference with sex hormone normal, and finally a hysterectomy was function, particularly in women. In the cases performed at age 32 years. Her only presented thus far, I have stressed premenstrual ten- pregnancy occurred following 11 months sion and abnormalities of hormone function as without a period. Severe pre-eclampsia manifested by disturbances in the menstrual cycle. complicated her pregnancy from the third In almost every case I have treated, symptoms month. Hot flashes have occurred from time to referrable to poor hormone function are among the time when she was troubled with hay fever. most prominent and most intolerable to the female It is not possible to say what precipitated patient. the final plunge into severe depression. I have There is no interference with hormone production been unable to ascertain whether antibiotics by the ovaries. The serum level and 24-hour urinary were given when the stones and hematuria output of estrogen are normal, but there is much were such problems about the time the evidence that the tissues are not responding to this depression began to progress. It is of interest estrogen in the usual way. Skin becomes rough, that the kidney symptoms and hematuria dry, scaly, and prone to acne. Decreased fullness of ceased when Candida therapy was initiated, the breasts frequently is noted, with loss of and that this same phenomenon occurred later sensitivity of the nipples. Improper in her father (Case #5). stimulation of the endometrium is manifested by This patient's psychiatrist had diagnosed menorrhagia, metrorrhagia, clots, and 25 ORTHOMOLECULAR PSYCHIATRY, VOLUME 7, NUMBER 1,1978, Pp. 17 - 37

"manic depression and schizophrenia." The case daughter. This was Case #4, the 36-year-old presented at the beginning of the paper had been depressed woman who shot herself in the chest. diagnosed "schizophrenia." Other psychiatrists She had passed kidney stones intermittently might have given different names to the illnesses starting at 26 years of age. Gross urinary that nearly wrecked the lives of these two women. bleeding of several weeks' duration, with the It doesn't seem too important what name we give to passage of several stones, preceded the onset of these groupings of symptoms that indicate mental depression. As the depression deepened, advanced deterioration in brain physiology. What is her urinary problem continued unabated, and important is that such symptoms cleared completely this was the situation when treatment with when Candida immunotherapy was instituted, and Candida extract was begun. The urinary in one of the two recurred to the point of a nearly symptoms and signs ceased within the first fatal suicide attempt when treatment was month of treatment and have not recurred interrupted, again to clear quickly and completely during the ensuing 11 years of excellent health. when therapy was reinstituted. The abrupt, sustained cessation of the formation and passage of renal stones with the Case #5 associated infection and hematuria, in this This 60-year-old man developed severe chronic father-daughter pair, is intriguing. The inflammation of the eye that resisted all forms of probability of this occurring coincidentalfy treatment. This had its onset following Declomycin rather than as a result of anti-Candida therapy therapy and had been present for three months seems remote. More likely is that the condition when oral nystatin therapy was begun. Within three in each one was in some way related to their days there was marked diminution of the long-standing battle with Candida, and that inflammation; it had cleared completely after eight genetic factors were decisive in determining weeks of therapy. that this particular organ-system would be Severe constipation and lethargy that had been involved. present at the time nystatin was begun were relieved almost immediately. He has continued two Discussion of Case #5 to four nystatin tablets daily for 12 years and In this case we again see demonstrated the remained well. Efforts to discontinue therapy clearing of a chronic inflammatory response by invariably resulted in return of the lethargy and oral nystatin therapy. The conjunctivitis had constipation, although not the conjunctivitis. proved intractable to antibiotic and steroid History in this man revealed 20 years of therapy. Since the involved tissue was the eye, intermittent antibiotic therapy for chronic urinary we had another opportunity to actually see a tract infection in association with multiple kidney tissue that by some mechanism was responding stones. Stones had been removed from each kidney, to Candida products as had been true of the and many stones had been passed. The urine was lymphoid tumor of the arm in Case #3. In both reported as "4+ for pus cells" during the three years instances resolution of the inflammation began preceding the administration of nystatin, often with almost at once following suppression of concomitant gross or microscopic hematuria. intestinal yeast by oral nystatin. Once again a Three months after beginning anti-yeast therapy, return to normal colon function coincided with the urinalysis was normal. There has been no clearing an inflammatory response in a tissue recurrence of kidney infection or stones during inaccessible to nystatin in the form given. these 12 years on nystatin. There is no clue as to This man did not demonstrate symptoms to why this longstanding renal problem cleared so indicate a reaction in brain tissue. His case was abruptly. Speculation that this unexpected develop- included because of the location of the ment was indeed related to bringing the inflamed tissue on the surface of the body. The chronic yeast infection under control is conjunctivitis in this man and the lymphoid strengthened by an almost identical result in his tumor in Case#3 were visible

ORTHOMOLECULAR PSYCHIATRY, VOLUME 7, NUMBER 1, 1978, Pp. 17 - 37 numbness and tingling. There was a history of local membrane symptoms again occurred blood in the stools intermittently as a teen-ager. quickly. Paresthesias had begun to decrease at Colon x-ray at age 21 years was normal. A vaginal the time of this writing, which was eight weeks yeast infection occurred 10 months before onset of after reinstitution of nystatin therapy. the paresthesias (two months after the initial visual field defect). She also could recall episodes of Discussion of Host-Parasite Relationships vaginal discharge in childhood. Except for occasional intra-uterine infection, Again the total picture is one of lifelong allergy, colonization of the human body by Candida chronic intestinal and vaginal symptoms, and poor Albicans begins during passage through the hormone function. Many courses of antibiotic vagina and increases very rapidly during the were administered from childhood on. The initial ensuing four weeks. In a study of 140 full-term neurological symptom occurred during massive normal babies, Russell and Lay (1973) found antibiotic therapy over a four-month period for the positive oral cultures in 5.7 percent of babies severe lung infection. on the day of birth; by four weeks this had Therapy with oral and vaginal nystatin was increased to 82 percent and by one year had begun three months after onset of the paresthesias, decreased to 50 percent. These figures are which was 15 months after the visual field defect. probably low, since it is known that repeated Improvement in energy was apparent early in cultures in the same individual may be treatment. It was 10 weeks before the bowel alternately positive and negative. movements became normal. During the next two By six months of age the immunologic years of almost continuous nystatin therapy im- response to first contact with this yeast has provement was steady. The visual field defect resulted in the development of a positive cleared completely on examination, but recurred delayed skin test in 90 percent of infants. Many later. studies indicate that this test of cellular After two years of nystatin therapy neurological immunity remains positive throughout life in examination was "entirely normal." The nystatin approximately this same percent of individuals. was discontinued. Within three to four months the Antibody formation has begun by three menstrual periods, which had become normal at months of age in 9 percent of normal infants. 29-32 day intervals, again increased to as much as This rises to 80 percent by the school years 50-day intervals. The next two cycles were (Winner and Hurley, 1964). These studies were associated with paresthesias for about four days done before the much more sensitive premenstrually. Also two days of vaginal bleeding immunologic techniques available today. Thus and itching occurred around ovulation time in each Axelsen (1976), using quantitative of the last two cycles. There have been no acute immunoelectrophoresis to Candida antigen 78, attacks as severe as before nystatin treatment was found antibody in 163 of 169 "normal controls" begun. Mild exacerbations were noted when in unconcentrated sera. Chew and Theus (1967) symptoms of vaginal or colon candidiasis had found precipitins to the mannan cell-wall increased. antigen of Candida in 48 percent of Next she noted intermittent loose bowel unconcentrated sera from healthy adults. When movements; a definite decrease in energy was the immunoglobulins were concentrated 15 noted; and most important, numbness and tingling times, precipitins were found in 100 percent of of all extremities and in the eyeball reappeared. sera from these adults. Axelsen suggests that This time she also noted soreness of the gums and these findings indicate that differences in small white spots on the gums. Nystatin therapy antibody response of candidiasis patients and was started with tablets, vaginal suppositories, and controls may be quantitative rather than oral suspension (to be used as a qualitative, and support the common belief that mouthwash). Improvement both in energy and all, or practically all, humans have

28 TISSUE INJURY INDUCED BY CANDIDA ALBICANS responded to antigens of Candida Albicans by phase contains at least one antigen not virtue of contact with this microorganism. demonstrated in the yeast form. Fourteen of Candida vaginitis was shown by Stanley and these antigens have been found to have Hurley (Budtz-Jorgensen, 1973) to stimulate the enzymatic activity, while nothing is known of production of Candida precipitins. Waldman the function of the remainder. Only mannan (Bach, 1971) showed that intravaginal application and a few of the cytoplasmic antigens have of Candida vaccine resulted in a rise in serum been purified. Most studies have used water precipitin levels and in IgA precipitins in vaginal extracts of the disrupted yeast phase, containing secretions. in some instances approximately 30 of the Thus, whether we look at antibody levels, known Candida antigens. cutlures of mucosal surfaces, or the cellular Immunologic Response to Candida Anti- immune response as represented by the delayed gens skin test, a picture begins to emerge of early and With an organism of such antigenic com- lifelong contact with this yeast. As the total plexity, it is not surprising that the precipitin exposure to yeast varies from time to time, so too response is equally complex. The pattern of will these parameters of the body's immunologic response will vary among individuals, both in response. Modifying factors that enhance yeast the rabbit and in the human. Antibodies of IgG, growth in the body result in an increased antigenic IgA, and IgE classes have been demonstrated. load reaching the cells of the immune system. In The pattern of antibody response will vary as response to this stimulus, cells in both com- the antigen load changes qualitatively and partments of the immune system proliferate, and quantitatively. The role of antibody in defense each is capable of modifying the response of the against Candida invasion is uncertain. other. Depending on whether suppressor or helper Many types of evidence indicate that the effects predominate, the T-cells may inhibit or cellular immune response is the more important stimulate antibody formation. In turn, by such in resistance to Candida. In syndromes phenomena as immunologic enhancement, characterized by deficiency of the thymus, antibodies may influence the cellular immune yeast infection is prevalent. In conditions response. characterized by inability to form antibodies, Cultures will become negative or remain yeast is not a problem (e.g., positive, depending upon whether the net effect of agammaglobulinemia). If a previously healthy the responses has resulted in immunity or individual develops a disease that compromises tolerance. Undoubtedly important in determining the cellular immune response, there is a strong which outcome prevails are the immunologic likelihood of a yeast infection which is usually status of the host, the nature of the antigens, and resistant to anti-fungal therapy. In the limited the manner in which they are presented to the number of cases in which it has been possible immune system. to repair the defect in cellular immunity with transplants of thymus or bone marrow, or ad- Immunology of Candida Albicans Candida ministration of transfer factor, the yeast in- Antigens fection has cleared. This subject has been recently reviewed by Budtz-Jorgensen (1973) studied the serum Axelsen (1976). Seventy-nine distinct, agglutinins in 180 subjects, as well as the immunologically definable antigenic determinants cellular immune response as measured in vitro have been demonstrated for Candida; this is the by the production of the migration inhibitors largest number yet found in any organism. The factory (MIF). In addition to normal controls, cell wall contains one principal antigen, mannan, 55 patients had Candida-induced denture which is a polymer of the sugar, mannose; water- stomatitis while others had traumatic (non- soluble extracts of the yeast phase yield the Candida) stomatitis. Others had Candida 77 cytoplasmic antigens. In addition, the mycelial vaginitis, dermatitis, Candida

29 ORTHOMOLECULAR PSYCHIATRY, VOLUME 7, NUMBER 1,1978, Pp. 17 - 37 leukoplakia, and chronic mucocutaneous returned in the cases of chronic mucocutaneous candidiasis. Candida-induced denture stomatitis candidiasis, once therapy was stopped, the exists in two forms, termed simple and granular. cellular immune response again ceased as The simple is characterized by a general erythema measured by the MIF test. and inflammatory response. The granular type is In an effort to clarify the sequence and more extensive and shows less inflammation. The relationship of the humoral and cellular percentage of patients in each group exhibiting a response to Candida, Budtz-Jorgensen (1973) positive cellular immune response as measured by induced candidiasis of the palate in monkeys the MIF test was as follows: normal controls, 50 both with and without prior treatment with percent; traumatic (non-Candidal) stomatitis, 94 azathioprine, an inhibitor of the T-cell percent; Candida vaginitis, 80 percent; Candida response. dermatitis, 67 percent; simple Candida stomatitis, In the untreated monkeys, migration 76 percent; granular Candida stomatitis, 28 per- inhibition was significant in one week and cent; leukoplakia and chronic mucocutaneous lasted five months, indicating an early and candidiasis, 0 percent. persistent response within the T-cell com- Antibody response increased as the level of partment. In two weeks the Candidal lesions cellular response decreased in the various groups. had healed. Antibody could not be detected In other words, in the syndromes characterized by until four weeks, after which the antibody level impairment of cellular immunity, antibody titers continued to rise for eight months (at which are much higher, so that in patients with chronic time the experiment was terminated). As the mucocutaneous candidiasis, levels are as high as antibody level rose, the MJF response those reached in rabbits during the production of decreased. At the end of eight months the MIF Candida antisera. response was back to the pre-infection level, In 12 patients the palatal candidiasis was treated but the antibody titer was at its peak. topically for one week with am-photeracin B. In Palatal smears during the two-week infec- all 12 cases, marked inhibition of leucocyte tion showed acute inflammation and a moderate migration was found after treatment, indicating number of hyphae of Candida. By culture as that suppression of yeast growth resulted in well as biopsy, the lesions were healed in two restoration of the cellular immune response. weeks, which was a full two weeks before the Showing the greatest increase were those in whom antibody response was first detectable. the cellular immunity was most depressed prior to When a similar group of monkeys was treatment. pretreated with azathioprine, a different Several important aspects of the immune response ensued. It should be noted that response to Candida are illustrated in this study. It azathioprine acts selectively on T-lymphocytes appears that up to a point the T-cells respond to while having no effect on antibody formation. Candida; as the antigenic load increases (or This effect is transient, the immunosuppression perhaps changes-qualitatively) there is a decreasing by 75 percent within 12 hours after progressive impairment of cellular immunity, administration (Bach, 1971; Bach and associated with an increase in antibody response. Dardenne, 1971; Bach etal., 1972). This reaches its peak in chronic mucocutaneous In this group of monkeys the antibody candidiasis, as evidenced by high antibody levels response was earlier and strong, beginning at together with total absence of in vitro MIF two weeks (while the animals were still production. receiving azathioprine), reaching a maximum Following suppression of yeast by topical titer in three to four weeks, and declining therapy for denture stomatitis, and by systemic as thereafter. (This titer had been reached only well as topical treatment in chronic after eight months in the normal monkeys.) The mucocutaneous candidiasis, the MIF response onset of MIF production was delayed three to returned to normal. As the yeast growth gradually six weeks; in each case

30 TISSUE INJURY INDUCED BY CANDIDA ALBICANS it did not occur until one week after cessation of system able to mount an effective response. As immunosuppressive therapy. Thus the reciprocal this becomes progressively stronger, the palatal response of T-and B-cells is again demonstrated; lesions begin to heal concomitantly with a when the T-cell response is suppressed, the B-cell falling antibody titer. response occurs in two rather than four weeks. The These findings in general support the fin- B-cell response declines rapidly as the T-cell dings in humans with candidiasis in various response begins (three to six weeks). In contrast, sites of the body. In the syndromes with the in the normal monkeys the T-cell response most extensive yeast colonization (chronic occurred early and the B-cell response began only mucocutaneous candidiasis) we find the as the T-cell response started to subside. association of high antibody levels with poor The findings on histologic examination of cellular immune response, as measured in vitro biopsy specimens of the Candidal lesions are by the MIF and lymphocyte transformation equally significant. In the monkeys not given tests, and in vivo by the delayed skin test. (The azathioprine, a strong inflammatory response MIF test is the most consistently abnormal. In occurred with an atrophic appearance of the certain instances a positive transformation test palatal mucosa and absence of hyphae (in contrast or delayed skin test may be found despite the to those seen on the palatal smear). There was absence of MIF production.) complete healing in two weeks' time. This may be In clinical conditions that are characterized considered the "normal" response. by intermittency, e.g., vaginitis, lower humoral In the monkeys receiving azathioprine, thrush- and higher cellular immunity is found. As long like lesions were produced. These were different as this immunologic pattern persists, the host on microscopic examination in that little seems to be able to eradicate the infection. inflammatory response was present and invasion When one of the factors favoring yeast growth by hyphae was pronounced. Healing of the palatal again exerts its influence, the cycle repeats yeast infection did not occur until after the itself. azathioprine had been discontinued and MIF At such point that the colonization of the production had begun. tissues becomes sufficiently extensive to These studies indicate that thrush-like lesions produce a state of tolerance in the T-cell do not ensue when the immunologic response is response, the situation becomes analagous to primarily cellular rather than humoral. Hyphae, that in the azathioprine-treated monkeys. The indicative of the invasive or mycelial form of yeast transforms to the mycelial phase, and the Candida, are seen on smears, but not on biopsy. lesions become thrush-like. As the area of Healing is rapid and complete well before the colonization increases, so will the antigenic antibody response is detectable. This is the pattern load. In addition, antigens characteristic of the that might be considered the normal response in a mycelial phase increasingly exert their healthy individual. influence on the immune response. Assuming When, however, the initial response is one of rapid that as the condition progresses, cells still in the and strong antibody formation without a detectable yeast phase begin to rupture, then the large response of the cellular immune system, thrush- number of soluble cytoplasmic antigens like infection occurs, characterized histologically heretofore shielded within the yeast membrane by marked depression of the normal influx of enter the blood stream to further stimulate or inflammatory cells. The finding of hyphae compromise the immune response of the host. indicates a transition from the yeast to the mycelial Thus is the immune system presented with phase, typically seen with invasive candidiasis. an antigenic load of great complexity that is The infection is able to persist and spread despite subject to wide fluctuation, both quantitatively high antibody levels. and qualitatively. Among the better known Only when the suppressive influence of factors that favor yeast growth azathioprine is removed is the cellular immune

31 ORTHOMOLECULAR PSYCHIATRY, VOLUME 7, NUMBER 1, 1978, Pp. 17 - 37 in the body and therefore alter the pattern of infection, and it was possible to control other Candida antigens presented to the immune system variables (e.g., nutrition) that might in humans of the host are antibiotics, birth control pills, account for the variation of antibody response. pregnancy, and steroids. Further, any congenital or Immune-response (IR) genes, found in acquired condition that results in general association with the major histocom-patability impairment of the T-cell response of the host locus, determine the extent to which a given favors the yeast in the continuing host-parasite en- individual is able to respond to an antigen. counter. Well-known examples of such conditions When this capability is absent genetically, are Hodgkin's disease, Boeck's sarcoid, nothing can cause that individual to respond lymphoma, and Di George syndrome. (except, theoretically, a gene transplant). On the Immunosuppressive therapy, for whatever reason other hand, the genetically determined ability to administered, leads to a similar result. respond may be greatly influenced by other factors. Adjuvants may cause a greater than natural response. A response less than the genetic capability may result for many reasons Genetic Factors (states of immune tolerance, immunosup- Thus Candida Albicans is demonstrably an pressive agents, and diseases characterized by infectious agent of great antigenic complexity. The immunosuppression). extent and form of its colonization of human tissue Familial susceptibility to yeast is frequently are influenced greatly by extrinsic factors seen. Mother-daughter combinations are (antibiotics, steroids, pregnancy, contraceptive common wherein the daughter may suffer from hormones, etc.). Antigens of the yeast cell wall, of oral and/or vaginal yeast infection from early the mycelial phase, and of the yeast cytoplasm are childhood. (An example in this paper is the presented to the immune system in a constantly father with the chronically inflamed eye, one changing spectrum, its pattern at any given daughter who attempted suicide, and another moment determined largely by the extent of daughter with severe chronic yeast vaginitis.) mucous membrane involvement, the relative It seems probable that an individual en- amounts of yeast and mycelial phase in the tissues, dowed genetically with a limited ability to and the rate of rupture of yeast cells with release respond to Candida antigens will be more of cytoplasmic antigens into the host. susceptible to the yeast-stimulating influence of The state of the immune defenses of the host at such extrinsic factors as antibiotics, steroids, the time this array of antigens is presented to it and hormones. A sudden increase in antigenic will be critical in determining the outcome of the load can more easily upset the state of limited encounter. While the overall condition of the control of yeast growth that has previously immune system is influential, of greater concern is prevailed, and allow progressive tissue the degree to which the host is capable of penetration by Candida and a chronic state of mounting an effective response specifically to paralysis of the immune response. The Candidal antigens. The single most important continuation of the yeast presence in the tissues factor in determining this capability is the genetic allows the release into the host of products, make-up of the individual. Axelsen (1976) has antigenic or otherwise, on a chronic basis that pointed out the variability in the extent to which may last for years. Accepting for the moment given individual members of the species (human the capacity of such products to produce tissue or rabbit) respond to the different antigens of injury in the host at sites distant to the actual Candida. This observation in rabbits, noted during infection, we have the ingredients of chronic the raising of an-tisera for investigational use, is of illness. By such a mechanism we can explain special significance since stimulation was with the variety of otherwise unrelated symptoms Candida extracts in the absence of actual yeast represented in these case reports.

32 TISSUE INJURY INDUCED BY CANDIDA ALBICANS

Discussion one rather than three "diseases." Recalling Case As we attempt to interpret the meaning of these #3, the tumor on the arm had been suggestive cases, two facts stand out. All responded to of lupus erythematosus to two different treatment of Candida Albicans with clearing of pathologists by biopsy, and of "leukemia" to their symptoms and signs, and symptoms and yet another pathologist. Two years after the signs reflected involvement of a variety of tissues appearance of the tumor, he developed in the body. Follow up of at least three years in "bronchial asthma" and again two years later each instance has indicated that the benefits have "mucous colitis." Since nystatin by mouth persisted. What diseases, then, have been cleared all three conditions, Candida Albicans controlled or "cured" by this approach? was apparently causing tissue abnormalities in Most diseases were first described many years the skin, bronchial tubes, and colon. Thus a ago. When a new condition was first described, common etiology may cut across conventional rarely was there any indication of the cause of the diagnostic lines and explain the common disease. As a result, the name given to the response of such diverse "diseases" as condition was of necessity descriptive of the "schizophrenia," "multiple sclerosis," "asthma," symptoms (e.g., schizophrenia, manic depressive), and "mucous colitis." of the signs (e.g., rheumatoid arthritis, lupus Great care must be exercised in attempting to erythematosus), or of the name of the person define the "diseases" that responded to this credited with its recognition (e.g. Hodgkin's anti-yeast approach. Even though diagnosed by disease, Reiter's syndrome, Bechef s disease). competent specialists, were these truly cases of Therefore the name of the disease usually reflected schizophrenia or multiple sclerosis? As stated the tissue or tissues involved rather than its earlier, whether they were or not doesn't alter etiology. Usually no one patient would have all of the fact that symptoms of central nervous the reported symptoms or signs, indicating that the system involvement were profound and same combination of tissue involvement was not prolonged, indicating that brain tissue was found in every case. Thus a "new disease" might functioning abnormally even though be nothing more than a different combination of manifesting this dysfunction differently in each involved tissues. When a common etiologic basis individual. These cases were chosen to has later emerged, a new designation denoting this illustrate how a variety of "diseases" may have common factor has replaced the original individual a common cause. names. For example, once the basic cause linking The mechanism by which yeast produced them was discovered, "atherosclerosis" replaced these tissue abnormalities, and the factors that the various names for "stroke" and "heart attack." determined which tissues reacted in each Or, "myxedema" is now "hypothyroidism," instance, must remain speculative at this stage. "Graves' disease" is "hyperthyroidism," etc. Endotoxin activity has been attributed to The importance of this discussion becomes Candida Albicans, and this is one possibility. apparent if we look at the "diseases" represented in Immunologic mechanisms of tissue injury, any these cases. Taken together, involvement is seen one of which may be applicable, are being of the tissues of the eye, skin, sinuses, vagina, investigated in many diseases. Evidence for uterus, colon, bronchial tubes, kidney, and central impairment of the immune response to Candida nervous system. Case #1 was the woman was presented earlier. This in itself results in an diagnosed by several psychiatrists as increased susceptibility to the penetration of "schizophrenia." Her gynecologist was treating tissues by yeast, so that tissue injury may result "metrorrhagia," and her allergist would have been from the immunologic response of the host. dealing with "allergic sinusitis." The common Cellular damage initiating auto-immune response to Candida extract of all three responses is suggested by the frequent finding conditions surely of auto-antibodies to various tissues in patients suggests a common etiology. Different tissues with widespread were reacting in the same individual; yet it was 33 ORTHOMOLECULAR PSYCHIATRY, VOLUME 7, NUMBER 1, 1978, Pp. 17 - 37 yeast growth (as in chronic mucocutaneous of the host. To be avoided, then, are those candidiasis). A cross-reaction between Candida factors that strengthen the parasite and antibodies and tissue cell-surface antigens is compromise the host. another possibility. Candida antibodies have been The incidence of overt yeast infection in found to cross-react with human blood Group A humans increases sharply with the use of an- antigens. Research should be initiated to determine tibodies, birth control pills, cortisone-type whether certain of the 79 Candida antigens, given steroid hormones, and other immunosup- the right combination of conditions in the parasite pressant drugs. Even in those who escape and in the host, may stimulate antibodies which symptomatic infection there is the strong will react with human tissue antigens. In view of probability that the yeast is able to expand its the array of available Candida antigens as well as antigenic influence in varying degree. The the genetically determined variability in cell- reported incidence of overt yeast infection for surface antigens in the different tissues of the host, each of these four types of drugs is the same 35 immunologic techniques more sophisticated than percent known to be characteristic of presently available may be required to demonstrate pregnancy; this may represent that portion of such a cross-reaction if it exists. One aspect of the the population with the greatest genetic mechanism that does seem clear is that the yeast is susceptibility. It will be recalled that these able to release into the host a factor that ultimately forms of therapy appeared on the scene in the results in tissue injury. Nystatin is able to suppress late 1940's with the advent of aureomycin. the release of this factor; and the tissues are then Cortisone, birth control pills, and additional able to recover, both functionally and immunosuppressants came into general use histologically. Alternately, suppression of the during the next 10 years. Frequently two or yeast may be achieved immunologically by more would be used simultaneously, often with injections of Candida extract. Why this is effective pregnancy an additional factor. is again speculative. Selective suppression of the I have often thought of the young adult of T-cell response is known as immune deviation. the 1970's as belonging to "the antibiotic Breaking such a state of immune deviation or generation." I would like to describe a tolerance by injecting a cross-reacting antigen hypothetical young person 16 years of age in might be an example of how such injection 1977, and show how these factors that can so therapy could lead to the suppression of yeast profoundly alter the yeast host-parasite growth, since cellular immunity is the chief relationship may have come into play during defense against fungus infections. his lifetime. Thus treatment at this time consists of Typically, his mother would have used birth suppression of yeast growth either directly with control pills for a year or more prior to antifungal drugs, or immunologically by restoring conception. Already weakened in her response a state of competence to the immune response in to yeast, she enters the yeast-associated the compromised host. Irrespective of the basic condition of pregnancy. Any of the 79 yeast mechanism of tissue injury, driving the yeast out antigens that cross the placental barrier will of the tissues, wherever it may have succeeded in result in intra-uterine exposure with its establishing a colony, must remain the ultimate tolerance-inducing influence on the unborn goal of treatment. child. It is almost a certainty that antibiotics There are, however, additional measures to be would have been prescribed intermittently taken. Whereas antifungal therapy and during these years of pregnancy and "the pill." immunotherapy are active forms of treatment, Should she have had asthma, arthritis, or any much help in controlling this condition is available one of a number of other conditions, cortisone through passive treatment in the form of or other immunosuppressant drugs might have avoidance. To state the obvious, our goal is to added their influence. weaken the parasite and strengthen the resistance Soon after birth, yeast enters the

34 TISSUE JNJURY INDUCED BY CANDIDA ALBICANS newborn child, establishes itself permanently, and Better drugs and better extracts should perpetuates the state of partial tolerance increase the effectiveness of active therapy of established in utero. If his immune response (IR) yeast infections. Nystatin is effective and genes dictate a reasonably strong resistance, he virtually free of side effects. Extracts, however, may overcome this situation as his immune are crude and variable in antigenic content. system matures. If on the other hand he has This has been a problem in the laboratories of inherited genes that allow him a limited defense the most skilled investigators, and is not a at best against Candida, he has little chance of reflection on commercial sources. Frequently a overcoming the state of unresponsiveness. given batch will not produce a positive skin test Antibiotics soon after birth and intermittently in an individual who reacted positively to a thereafter continue to stimulate the yeast. Allergic previous lot. Studies are badly needed com- membranes with frequent infections are common, paring the cell wall, cytoplasmic, and mycelial increasing the need for antibiotics. antigens as to their ability to induce immunity Had this hypothetical young person been born as opposed to tolerance. One might well be 25 years earlier, his genetically determined ability much more effective in stimulating the cellular to control yeast growth in his tissues would have immune system, while another might be been influenced only by the pregnant state. If, as I tolerance-inducing. believe and as I think the cases presented This variability in extracts may in part ac- illustrate, there are mechanisms whereby yeast count for the difficulty in arriving at one dose may cause serious illness, it is apparent that many schedule suitable for all patients, although individuals are being done much harm by these variation in the immune response genes is drugs. probably equally important. Candida Albicans A particular case in point is the widespread use extract may be ordered as a 10,000 protein of tetracycline for the treatment of acne. As many nitrogen unit/cc concentrate. Serial 1:10 as four capsules daily for many years without dilutions are made down to a strength of 10"8 interruption are used. This is deeply disturbing to PNU/cc. Either alum precipitated or aqueous me, because I have seen a number of patients extracts may be used. who were in a state of chronic illness as a result. Most patients will respond to .1 cc doses Widespread mucous membrane involvement, subcutaneously at intervals of three to four days lethargy, depression, and chronic aching are or longer of the weakest strengths (10" 8, 10"7, among the numerous complaints. etc.), or to doses one to two times per week of Birth control pills are almost predictably 100-500 PNU. However, it is not possible to poorly tolerated by a woman with a history of a determine in advance the strength at which the yeast problem, or inhalant mold allergy. Their use patient will first begin to show a response as is usually associated with depression, emotional indicated by the relief of symptoms. Further, as lability, yeast infections, and general lethargy. the patient begins to improve, the strength may One additional "passive" treatment that may have to be increased somewhat. Close attention well be beneficial is a low-carbohydrate diet. to each patient is required; we are trying to Carbohydrate is the chief nutrient of Candida; its activate an immune response to an organism at restriction in the diet may slow down the rate of the same time that it is actually infecting the growth and division of yeast and thereby reduce tissues. This is not a form of extract treatment the antigenic load reaching the host. The reported that lends itself to a predetermined schedule of benefit of such carbohydrate restriction in certain injections administered by the nurse. schizophrenics is of interest in this connection, as It is preferable to determine the maximum is the fact that lithium in relatively low benefit from antifungal therapy before adding concentration halts yeast growth in vitro. extract treatment. If nystatin

35 ORTHOMOLECULAR PSYCHIATRY, VOLUME 7, NUMBER 1, 1978, Pp. 17 - 37 quickly alleviates symptoms of poor colon host on a chronic basis. Until elucidation of the function or of oral or vaginal yeast infection, it is process by which tissue injury occurs leads better to persist with drug therapy for several perhaps to a laboratory method of diagnosis, weeks before adding immunotherapy. patient selection must remain on clinical The selection of patients who may be grounds. manifesting this type of tissue reaction to Candida Albicans rests at present entirely on clinical grounds. Neither skin tests, antibody studies, nor Summary and Conclusions culture techniques distinguish these patients from Sensitive immunologic techniques indicate normal, since such a high incidence of positive that probably everyone has responded to the tests is found in asymptomatic individuals. If a antigens of the yeast, Candida Albicans. patient is having symptoms of mucous membrane Evidence from the literature indicates a lifelong infection, nystatin therapy is justified. The aim of host-parasite struggle in which many factors treatment should be the suppression of growth favor the parasite. The resulting fluctuations in wherever it is accessible to nystatin. Close yeast growth and phase lead to variation in the observation of the response of other symptoms pattern of stimulation by the 79 known will enable an evaluation of their possible antigens. Under the proper conditions, perhaps relationship to the yeast infection. dictated largely by the nature of genetically Colon function frequently becomes normal determined tissue antigens, the immunologic within several days after nystatin therapy is response of the host results in tissue injury. It is started. Therefore diarrhea, constipation, or possible that no tissue is insulated from such diagnoses such as "spastic colon" or "mucous injury, hence the great variety of symptoms and colitis" are frequent indications of underlying signs that may result from the same underlying yeast growth in the colon. Oral and vaginal mechanism. infections are usually clearly indicated by the A close look at "diseases" and "syndromes" familiar symptoms of infection in these areas. of unknown cause is indicated, to detect a Thus far treatment has been limited to patients relationship to yeast growth if it exists. with such symptoms of mucosal involvement, but Conditions that seem to be on an immunologic Case#3 demonstrated that the remote tissue basis deserve special attention. Candida reaction may antedate symptoms of mucosal Albicans is only one of many antigenic agents involvement by several years. The lymphoid confronting the immune system. It is certainly tumor of the arm actually preceded the "mucous one of the most complex, and it is probably colitis" by four years, during which time there with each of us at all times. Much work is would have been nothing to suggest the needed to determine whether the conditions relationship to yeast indicated by the rapid described herein, all of which responded to an regression of the tumor with nystatin therapy. anti-Candida program, are representative of The purpose of this paper is not to report the many more patients with chronic disorders or treatment of a group of patients with one merely represent isolated occurrences. diagnosis, but rather to show that a variety of In view of the complexity and chronicity of tissues may show this response. Controlled studies antigenic stimulation by this fungus, it would of patients with the same diagnosis are needed to not be surprising to find this a mechanism of determine the importance of Candida as an tissue injury in many diseases. In fact, should it etiologic agent in a given disease. If tissue injury prove to be so, the surprising thing would be is by an immunologic mechanism, Candida may that for so long it should have been considered be just one of many antigenic substances capable possible for the human body to tolerate such an of initiating such a response. Yet its position incessant immunologic stimulus without is unique, both in its antigenic complexity and its frequent harm to the tissues. opportunity to disseminate these antigens into the

36 TISSUE INJURY INDUCED BY CANDIDA ALBICANS

REFERENCES

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WINNER, H.I., and HURLEY, R.: Candida Albicans. J. and A. Churchill, Ltt. 1964.

AXELSEN, N.H.: Scand. J. Immunol. Vol. 5, 177-190, 1976.

CHEW, W.H., and THEUS. T.L.: Candida precipitins. J. Immunol. 98, 220, 1967.

BUDT2-JORGENSEN, E.: Scand. J. Dent. Res. 81:360-371, 1973.

BACH, J.F.: Antigen recognition by T-cells and its suppression. Ann. Rheum. Dis. 30, 565- 573, 1971.

BACH, J.F., and DARDENNE, M.: Activities of immunosuppressive agents in vitro. I. Rosette inhibition by azathioprine. Rev. Europe Etudes Clin. Biol. 16,770-777, 1971.

BACH, J.F., DARDENNE, M., and BACH, A.A.: Dosage Metabolitics Actifs Des Immunosuppresseurs dans le Serum. Application a I'azath-ioprine. Nouv. Presse Med. 1:2293-2298,1972.