Host Factors in Defense of Fungal Infections Dr. Charles Krikpatrick The immune system contains multiple components that provide
protection against specific groups of microorganisms. The degree
of specialization of function is clearly illustrated in patients with
immunodeficiency syndromes in whom the nature of the defect determines the sites of the infections and the susceptibility to certain
organisms. Chronic mucocutaneous candidiasis is an especially
dramatic illustration of the role of the T-lymphocyte system in de-
fense against opportunistic fungal infections, especially of the skin
and mucous membranes. There is considerable heterogeneity of the
immune abnormalities in patients with chronic mucocutaneous can-
didiasis. The most consistent defects involve subnormal production
of lymphokines by T-cells in response to Candida antigens. How-
ever, some patients have more global defects and are unresponsive
to all antigens and may have reduced responsiveness to mitogens
as well. Successful therapy of this infection requires a combination
of treatments, including such antifungal drugs as clotrimazole, ke-
toconazole, or amphotericin B and correction of the underlying
immune defect with such agents as transfer factor.
.Chronic oral candidiasis (group a) involves the mucosa of the tongue, lips, and
buccal cavity. In most cases, there is perleche, a chronic
infection of the mucocutaneous junctions at the corners of
the mouth. The skin and nails are not affected. The dis-
order may begin at any age and affects both sexes, al-
though it is somewhat more frequent in female patients.
There is no recognized genetic component. Chronic Candidiasis with Endocrinopathy. The candidiasis and endocrinopathy syndrome (group b) [10,11] usually begins in childhood as mucous membrane, un- gual, and/or cutaneous candidiasis. It often affects sib- lings but does not affect members of successive genera- tions. Family studies suggest that it is transmitted as an autosomal recessive trait. The most frequently observed endocrinopathies are hypoadrenalism, hypoparathyroid- ism, and hypothyroidism; many patients have polyen- docrinopathies. Endocrine failure usually occurs within a few years of the onset of mucocutaneous candidiasis, but it may not appear until the third or fourth decade. For this reason, we recommend that patients with chronic candidi- asis have detailed endocrine evaluations at least annu- ally. Little is known about the pathogenesis of the endocri- nopathies in these patients. Chronic Localized Mucocutaneous Candidiasis. The syndrome of chronic localized mucocutaneous candidia- sis (group c) also usually begins during childhood. The distribution of the Candida infections is similar to the can- didiasis and endocrincpathy syndrome, and some of these patients may have endocrinopathies. The cutane- ous lesions are characterized by marked hyperkeratosis and cutaneous horn formation (Figure 2) that has been designated "Candida granuloma." Both sexes are af- fected, and there is no recognized genetic component to this syndrome. Chronic Diffuse Candidiasis. Chronic diffuse candidiasis (group d) is associated with widespread candidiasis of the skin, nails, and mucous membranes. In contrast to Candida granuloma, the lesions have an erythematous, serpiginous appearance, with only modest hyperkeratosis (Figure 3). The syndrome usually begins in childhood, and the patients do not have endocrine disorders. None of our patients with chronic diffuse candidiasis has had af fected relatives. However, Wells et al [12] described eight pedigrees in which there was strong evidence for auto- somal recessive inheritance and designated this disorder familial chronic mucocutaneous candidiasis. There is a subset of patients with chronic diffuse can- didiasis who do not develop the disorder until adolescent years. Some of these patients had repeated courses of antibiotics for such disorders as acne, furunculosis, or uri- nary tract infections. lt is possible that antibiotic therapy upsets the balance of flora in the gastrointestinal tract and allows overgrowth with C. albicans. It is not known why these patients progress to chronic diffuse candidiasis. Candidiasis with Thymoma. Lehner [13] described
chronic diffuse candidiasis as a syndrome of cutaneous,
ungual, and mucous membrane candidiasis that usually
occurs in older men; he makes no mention of thymomas in
his patients. Although our experience with candidiasis that
begins after the third decade is limited, each of the pa-
tients also had a thymoma (group e). A recent review de-
scribed 27 patients with adult-onset candidiasis and thy-
moma [14]. This syndrome, like chronic diffuse
candidiasis, is characterized by treatment-resistant can-
didiasis of the nails, mucous membranes, and skin. In
addition, the patients have such disorders as myasthenia
gravis, aplastic anemia, neutropenia, or hypogammaglob-
ulinemia, which often accompany thymomas.
lt is our opinion that the association of adult-onset
mucocutaneous candidiasis with thymoma establishes this
as a separate syndrome. Other Syndromes. In addition to the two syndromes of chronic candidiasis that appear to be transmitted as auto- somal recessive traits, there are a few families in which members of two or more successive generations are af- fected. Canales et al [15] described a family in which a brother and sister and the child of the sister had chronic candidiasis. Okamoto et al [16] described a mother and two daughters with candidiasis, alopecia universalis, and chronic keratoconjunctivitis. The mother’s father may have had a similar disorder. Sams and associates [17] reported a family in which nine persons in three genera- tions had chronic candidiasis, and we have seen two fami- lies in which the mother and a child were affected. Other families in which chronic mucocutaneous candidiasis oc- curred in association with defects in leukocyte chemotaxis were reported by Van Scoy et al [18] and Djawari et al [19]. These findings suggest additional genetically determined syndromes of mucocutaneous candidiasis (group f). We have conducted a study of the frequency of HLA antigens in 49 patients with chronic mucocutaneous can- didiasis. There was a significant increase (40.8 percent versus 25.0 percent; p = 0.02) in the frequency of HLA- B7 in candidiasis patients, but the antigen excess was not limited to patients with any one of the candidiasis syn- dromes. IMMUNOLOGlC FEATURES OF CHRONIC MUCOCUTANEOUS CANDIDIASIS The possibility that chronic mucocutaneous candidiasis is an opportunistic process in patients with defective de- fense mechanisms is suggested by the occurrence of clin- ically similar disorders in patients with a variety of well-de- fined immunodeficiency syndromes. In most instances, the immunologic defects were either limited to the T-cell system or involved both the T-cell and B-ceIl systems (re- viewed by Kirkpatrick and Sohnle [7]). In contrast, muco- cutaneous candidiasis essentially never occurs in patients whose immunologic defects are limited to the immuno globulin·producing system. Assessment of immunologic functions in patients with chronic rnucocutaneous candidiasis has revealed several patterns of immunologic dysfunction. The classification given in Table III is based on evaluation of T-lymphocyte functions in vivo and in vitro.
LYMPHOCYTE-MEDIATED FUNCTIONS Patients in group 1 have the most severe defects. They
have marked deficiencies in the numbers of T-cells (or
both T- and B-cells), and this is accompanied by virtually
complete unresponsiveness to T-cell mitogens as well as
to antigens and allogeneic cells. This immunologic profile
is seen in patients with the DiGeorge syndrome, the thy-
mus dysplasias, some forms of severe combined immu-
nodeficiency, and in the acquired immune deficiency syn-
drome. The patients in group 2 have some thymus-dependent responses. They have normal numbers of rosette-forming T-ceIls, and stimulation of their cells with such mitogens as phytohemagglutinin or concanavalin A causes marked increases in DNA synthesis and production of lympho- kines, the inflammatory mediators of cellular immunity. ln contrast, stimulation of their lymphocytes with antigens, including Candida, does not cause either increased DNA synthesis or Iymphokine production. Thus, the patients have cells that are potentially capable of producing inflam- matory mediators in response to certain signals (mito- gens) but not to specific signals (antigens). This implies that the basic problem in these patients is at the level of antigen recognition or antigen processing, with failure to integrate antigenic signals into mediator production. The in vivo expression of the defect is cutaneous anergy: the failure to develop delayed cutaneous re- sponses to any test antigen. Because this immunologic profile is often found in patients with early-onset candidia- sis, it is assumed that the defect is congenital rather than acquired. The patients in group 3 are also anergic, but in vitro studies show variable cell-mediated immune responses, T-lymphocytes from these patients respond to some com- mon antigens with normal increments of DNA synthesis, but the same stimuli fail to evoke mediator production. These data are in concert with the concept that different subpopulations of T-celIs participate in DNA synthesis and lymphokine production, and indicate that the immuno- logic lesion is limited to one of the subsets. They also imply that the mechanisms of antigen processing are in- tact. Groups 4 and 5 contain patients who are able to de- velop and express cell-mediated immune responses to some antigens, such as streptococcal proteins (streptoki— nase-streptodornase [SK-SD]), tuberculin, or tetanus tox- oid, but not to Candida, The members of group 5 differ from group 4 in that they have Candida-responsive cells in the lymphocyte transformation test; neither group has cells that produce Iymphokines in response to Candida antigen. Delayed-type skin tests with Candida antigen give negative results, but responses to other antigens are intact. The pathogenesis of this selective immunologic defect is unclear. Some patients develop candidiasis early in life, but others are healthy during the first decade. In the latter group are the patients who developed mucocutaneous candidiasis in association with antibiotic therapy, and it is possible that the immunologic defects are acquired through suppressive effects of chronic antigenic expo- sure. This possibility is supported by the reports that ade- quate therapy with antifungal antibiotics has been accom- panied by normalization of immune responses to Candida antigen [20,21]. The patients in group 6 are similar to those of group 3 of Valdimarsson et al [22] and have very provocative immu· nologic profiles. They do not develop delayed cutaneous reactions to Candida antigen, and stimulation of their cells with Candida antigen in vitro does not result in increased DNA synthesis. However, the same stimulus causes mi- gration inhibiting factor production. This immunologic de- fect is the converse of that found in groups 3 and 5. Holt [23] stated that this immunologic abnormality is found in chronic granulomatous candidiasis. Our experience has not confirmed this, but it is an intriguing notion because of the possibility that exposure to Candida antigens induces production of a Iymphokine that causes the epidermal pro· liferation and hyperkeratosis that characterizes Candida granuloma. These patients also illustrate the limits of our knowledge of the roles of the individual lymphokines in production of immunologically based inflammation. Most studies have shown concordance between anergy and failure to pro- duce lymphokines, but Chapman and Kirkpatrick [24] found poor correlation between production of leukocyte migration inhibitory factor and cutaneous reactivity to Candida antigen in patients with mucocutaneous candidi- asis. Studies of production of other Iymphokines, espe- cially chemotactic factors, may provide important informa- tion concerning the roles of individual Iymphokines in defense mechanisms and inflammation. The final group (group 7) is composed of those patients in whom no immunologic defects are recognized. This may be related to the limitations of the methods of evalua- tion of host defenses rather than normal responses by the patients. Relatively little attention has been devoted to cytotoxic activities by lymphocytes from candidiasis patients. Leh- ner et al [25] studied 15 patients with various syndromes of mucocutaneous candidiasis; in no case did Candida- stimulated lymphocytes Iyse51Cr-labeled chicken erythro- cytes as well as the normal controls. Valdimarsson et al [22] measured cytotoxicity of phytohemagglutinin-acti- vated lymphocytes from candidiasis patients. All patients had normal cytotoxic activity. Thus, T-cell mediated cyto- toxicity activity is similar to lymphokine production in that activation by nonspecific lectins is intact, but activation by Candida is deficient. ln spite of the obvious diversity of lymphocyte-mediated responses in mucocutaneous candidiasis, there are cer- tain features that characterize the majority of patients. Most have normal levels of thymopoietin-like activity in their serum [26] and normal numbers of rosette—forming T-cells [7]. In most patients, stimulation of lymphocytes with nonspecific mitogens evokes normal responses in the lymphocyte transformation, lymphokine production, and cytotoxicity assays, findings that indicate that the lymphoid cells in the patients are potentially able to differ- entiate into effector cells. The most consistent abnormali- ties are unresponsiveness in delayed cutaneous skin tests and failure to produce Iymphokines in response to antigenic stimulation. ln addition, the majority (approxi- mately 80 percent) of patients with negative delayed skin tests do not have antigen-responsive cells by the T-cell proliferation assay. ln our experience, about 50 percent of the Candida patients with negative skin tests are com- pletely anergic, and the remainder react to antigens other than Candida. REGULATORY ABNORMALITIES Abnormalities of suppressor cells have been associated with a variety of immunologic and hematologic disorders [27]. Of particular relevance to mucocutaneous candidia- sis is the report by Stobo etal [28] that some patients with chronic fungal infections, such as disseminated histopIas— mosis or cryptoccccosis, have cells with immunosuppres- sive activities. The suppressive influence could be re- moved by culturing the patients’ cells for several days before stimulating them with antigens. On the other hand, Arulanantham et al [29] described a family with the can- didiasis and endocrinopathy syndrome in which three members had deficient suppressor cell activity. We have conducted similar experiments in 14 patients with child- hood·onset chronic mucocutaneous candidiasis and have not identified significant suppressive activity in any pa- tient. Failure to find suppressive activities may be addi- tional evidence that the immunologic defects in childhood- onset candidiasis are due to defects in differentiation of antigen—responsive cells rather than to secondary abnor- malities in regulation of T-cell functions. Late-onset cases. such as those described by Stobo el al [28], may be asso- ciated with disturbances in immunoregulation. ANTIBODY PRODUCTION The results of studies in several laboratories (reviewed by Kirkpatrick and Sohnle [7]) indicate that most patients with chronic mucocutaneous candidiasis have normal concen- trations of immunoglobulins in the serum and salivary fluids, and normal or elevated concentrations of Candida antibodies. The immediate—type wheal-and-flare re- sponses to Candida antigen indicate the presence of IgE antibodies to Candida. Production of antibody responses involving all classes of immunoglobulins suggests that the afferent compo- nents and cell cooperations in the B-cell system are usu- ally intact in candidiasis patients. It is not known if the antibodies provide any protective immunity, but Axelsen et al [30] suggested that they may prevent dissemination of mucocutaneous infections to parenchymal organs. There are two sets of observations that suggest that regulation of antibody synthesis may be abnormal in some patients. Chilgren etal [31] described two candidiasis pa- tients who had deficient concentrations of Candida anti- body in the lgA of their parotid fluids. Lehner et al [25], in a study of 1,5 patients, found deficient salivary IgA anti- Candida activity in all four patients with chronic oral can- didiasis and in seven of eight patients with mucocutane- ous candidiasis. The second abnormality of antibody production is the excessive concentration of anti-tissue antibodies in pa- tients with the candidiasis-endocrinopathy syndrome [10,1 1]. Synthesis of these antibodies may be the conse- quence of impaired regulation of T-ceIl functions similar to that noted by Arulanantham et al [29]. Fischer et al [33] identified an inhibitory substance in the serum of six of 23 children with chronic mucocutane· ous candidiasis. Each patient had a negative delayed skin response to Candida, but four responded to streptoki- nase-streptodornase or purified protein derivative. The patients’ lymphocytes did not respond to Candida in the lymphocyte proliferation assay, but the three patients who were studied had normal streptokinase-streptodornase or purified protein derivative. Additional studies provided evi- dence that the inhibitory substance in the plasma was a polysaccharide antigen from C. albicans. Five of the sera also contained antibodies to Candida, a finding similar to that reported by Axelsen and Kirkpatrick [34], It is not known if circulating Candida antigens explain every in- stance of serum suppressive activity or if additional sub- stances such as prostaglandins will be identified. PHAGOCYTIC CELL FUNCTION Diamond and associates [35,36] have described the mechanisms of injury to C. albicans by neutrophils. Rec- ognition of C. albicans by these phagocytes involves a chymotrypsin-sensitive component of the pseudohyphal phase of the organism and trypsinand chymotrypsin- sensitive "receptor" on the neutrophil. lnjury to the orga- nism is mediated through oxidative mechanisms, includ- ing superoxide and hydrogen peroxide. In spite of this evi- dence for candidacidal activity by neutrophils, there is little evidence that phagocyte dysfunction is common in pa- tients with chronic mucocutaneous candidiasis. Five of our candidiasis patients had deficient neutrophil and mon- ocyte chemotactic responses to endotoxin-activated human serum (C5a); responses to sodium caseinate were normal. Each of these patients also had recurrent pyo- genic infections of the skin or the respiratory system or both, and three patients had the hyperimmunoglobulin E syndrome [37]. Djawari et al [19] reported five cases of mucocutaneous candidiasis with defective granulocyte chemotactic responses to mussel glycogen; three of their patients were members of the same family. The report did not mention problems with recurrent pyogenic infections or serum IgE values. Another family was described by Van Scoy et al [18]. The mother and daughter had recurrent pyogenic infections, chronic mucocutaneous candidiasis, impaired granulocyte chemotaxis, and hyperim- munoglobulin E. In addition, the chiId's father and paternal grandfather had hyperimmunoglobulin E and moderate impairments of chemotaxis; they were apparently healthy, Snyderman et at [38] reported on a 9·year-old girl with chronic mucocutaneous candidiasis who had impaired monocyte chemotaxis; IgE values were not given. After administration of transfer factor to this patient, a marked improvement in her responses to chemotactic factors oc- curred. A similar effect of transfer factor was noted in the patient reported by Lawton et al`[39] but not in the patient of Kirkpatrick and Gallin [40]. A different immunologic defect was found in the patient studied by Twomey et al [41]. This patient, in addition to chronic mucocutaneous candidiasis, had a thymoma, a plasma inhibitor of lymphocyte transformation, and aplas- tic anemia. His monocytes were apparently unable to process or present antigens to his lymphocytes. It must be recognized that these patients are excep- tional, and the majority of patients with chronic mucocuta- neous candidiasis do not have defects in chemotactic re~ sponses, microbicidal activities, or monocyte functions.
The role of the late complement components in resist- ance to epicutaneous and intraepidermal challenges with Candida species has been studied by Ray and Weupper [46]. Only C. albicans and Candida stellatoidea invaded the stratum corneum and the underlying stratum mal- pighii, and Candida tropicalis invaded the stratum mal- pighii but not the stratum corneum of normal mice. When mice were depleted of late complement components with cobra venom factor or when C5-deficient B10.D2/oSn _ mice were infected, the infections extended into the sub- cutaneous fat. Histologic examination of the infected areas showed marked reduction of the inflammatory re- sponses in complement depleted animals. Their studies defined three factors that constituted the defense system of mice against acute cutaneous candidi- asis. First, the stratum corneum must be intact. Second, the animals must be able to generate complement-de- pendent chemotactic factors, and, finally, the inflamma- tory cells, predominantly neutrophils, must confine the in- fection. Sohnle and Kirkpatrick [47] have shown that a fourth factor, epidermal proliferation, is also important for clearing cutaneous candidiasis. MECHANISMS OF CUTANEOUS INFLAMMATION Biopsies of cutaneous and mucous membrane lesions from patients with chronic mucocutaneous candidiasis show the infecting organisms in the superficial tissues and an intense infiltration with inflammatory cells in the under- lying areas (Figure 4). The immunologic components of these inflammatory responses have been defined. Sohnle et al [48] performed immunofluorescent studies on biop- sies of normal and lesional skin from six candidiasis pa- tients. None of the specimens contained deposits of immunoglobulins, and only one sample contained detect- able Candida antigen. On the other hand, three speci- mens of lesional skin contained deposits of C3 and pro- perdin along the basement membrane zone; C4 was not found. These findings suggested that the inflammatory pathway was independent of cell-mediated or antibody- mediated immunologic mechanisms, but the reaction was related to direct activation of the alternative complement pathway. Subsequent experiments in which C2-deficient human serum was incubated with a soluble Candida ex- tract or yeast-phase organisms showed that components of Candida were capable of converting properdin factor B to E [48]. ln addition, components of the organism have direct chemotactic activity [49] and react with complement components to produce chemotactic factors [50]. Sohnle et al [49] and Ftay and Weupper [50] also stud- ied the pathogenesis of inflammatory responses in acute cutaneous candidiasis of guinea pigs and mice. In both models production of inflammatory mediators was shown to be associated with direct activation of the alternative complement pathway, but not to demonstrable cellular or humoral immune mechanisms. These data and the abnormalities of cellular immunity previously described permit construction of a model for the pathogenesis of chronic mucocutaneous candidiasis. The cellular immune defects predispose the patients to acquisition of mucocutaneous infections with this oppor- tunistic organism. Production of the inflammatory lesions involves another immunologic process, generation of in- flammatory mediators through direct interaction between components of the organism and the alternative comple- ment pathway. TREATMENT OF CHRONIC MUCOCUTANEOUS CANDIDIASIS The most effective protocols for attaining long-term remis- sions in patients with chronic mucocutaneous candidiasis have employed combinations of antifungal antibiotics and immunologic treatments that correct the associated im- munodeficiency.
Immunologic Therapy. Thymus transplantation, injec- tions of thymic extracts, infusions of lymphocytes from immunocompetent donors, and transfer factor have been employed in attempts to correct the immunologic detects in patients with chronic mucocutaneous candidiasis [7]. After thymus transplantation, the spontaneous clearing of oral and cutaneous lesions occurred in the DiGeorge syn- drome patient of Cleveland et al [51]. Levy et al [52] ad- ministered two fetal thymuses to a 17-year-old boy with the candidiasis and endocrinopathy syndrome. Both clini- cal and immunologic responses were noted. The candidi- asis patients treated [53,54] had subnormal numbers of circulating T-lymphocytes and subnormal in vitro lympho- cyte responses to T-cell mitogens. injections of transfer factor did not produce either immunologic or clinical ef- fects in either patient. After transplantation of fetal thymus tissue, both patients had marked increases in the num- bers of circulating T-cells and the cells were responsive to T-cell mitogens. Of particular interest was the finding that, following thymus transplantation, the patients were able to express delayed hypersensitivity after injections of trans- fer factor. The patient reported by Ballow and Hyman [54], had a clinical response, but the patient of Kirkpatrick et al [53] did not. Wara and Ammann [55] gave multiple injections of thymosin traction 5 to four patients with chronic mucocu- taneous candidiasis. One patient, a 13·year-old girl with a modest T-cell defect, had both clinical and immunologic responses. A second patient, a 49-year-old man with sub- normal Iymphocyte responses to phytohemagglutinin, also had a clinical response. Other attempts to reconstitute candidiasis patients have involved transfusions of peripheral blood leukocytes from Candida-sensitive donors. Valdimarsson et al [56] trans- fused cells from an,HLA-identical, mixed leukocyte reac- tion-nonreactive brother. The recipient acquired cell me- diated reactivity to Candida, and at the time of their report (17 months after initiating treatment) the patient was in excellent health. One of the patients of Kirkpatrick et al [57] received four daily transfusions of cells from his fa- ther. He, too, became responsive to Candida and his cu- taneous Iesions cleared within a few days. The remission lasted for 8 months; at the time of relapse his Candida skin test had reverted to negative. A second patient did not become reactive to Candida, but had gradual clearing of the Candida lesions over several months. By current standards, procedures such as leukocyte transfusions may seem crude. However at the time the studies were done, they provided useful information. For example, it was not known if candidiasis patients could be passively sensitized by any immunologic manipulations, or if their immunologic deficits were due to suppressive or inhibitory activities that would prevent reconstitution. Moreover, it was not known if immunotherapy would pro- vide clinical benefits. The observations in these experi- ments with living cells prompted use of other forms of immunotherapy, such as transfer factor. There are at least 60 reported instances in which can- didiasis patients have been treated with transfer factor [58]. In 16 cases transfer factor was the only treatment given. Four patients were described as receiving at least temporary clinical benefit, and in three instances dramatic results were reported. Fifteen patients had deficient cell- mediated immunity, and 14 of these patients showed im- proved immunologic responses after receiving transfer factor. ln 13 cases it is stated that the transfer factor do- nors were sensitive to Candida; in two reports this infor- mation is not provided. Thus, administration of transfer factor improved the immunologic defects in the patients, but in most cases they were still unable to clear established mucocutaneous infections. Antifungal Antibiotics. Until recently, the most widely employed systemic therapy for chronic mucocutaneous candidiasis was amphotericin B [21]. Adequate doses of amphotericin B regularly induced remissions of cutaneous and mucous membrane lesions and in some patients good responses were also seen in the nails. Unfortunately, unless the underlying immune defect is corrected, the patients usually relapsed within a few weeks after ces- sation of treatment. Recently, ketoconazole has become a widely used sys- temic drug for treating chronic mucocutaneous candidia- sis. Its efficacy has been established in clinical trials [59], and tolerance of long-term treatment has been reported [60]. The major adverse effect is hepatotoxicity, which, although uncommon, can be severe. There are a few in- stances in which ketoconazole-resistant isolates of C. albicans may have developed, but it is not known if these putative resistant organisms represent artifacts of the method for determining sensitivity, or are truly resistant strains. For candidiasis of the buccal cavity, pharynx, and, in some cases, the esophagus, topical therapy with troches containing clotrimazole has been effective [61]. This for mulation was evaluated in a clinical trial in which troches, containing either clotrimazole or placebo, were used five times each day for 14 days (Table IV). A representative response is shown in Figure 5. No adverse effects were observed. _ _ After completion of the blind phase of the trial, 15 pa- tients entered an open study with clotrimaiole troches. One to three troches per day were found adequate to maintain remissions. Some of these patients have used the troches for four or five years and have remained in remission; none has had adverse effects. Combination Therapy. One of the first attempts to treat mucocutaneous candidiasis with immunologic interven- tion was reported by Buckley et al [62]. Their patient was a 10-year—old girl who developed candidiasis at age 14 months. Multiple courses of amphotericin B produced ' clearing of the infections, but relapse repeatedly occurred approximately two months after cessation of treatment. Her immunologic defect was severe and was character- ized by cutaneous anergy, prolonged survival of skin, allo- grafts, and impaired in vitro responses of lymphocytes to phytohemagglutinin; After first clearing the active lesions with amphotericin B, she was transfused with paternal bone marrow cells. The post-transplantation immunologic studies showed that she had acquired delayed hypersen- sitivity to three of the six reactivities possessed by the marrow donor, and her in vitro lymphocyte responses to phytohemagglutinin were essentially normal. Her clinical remission had lasted more than six months when the case was reported.
In 18 other cases, antifungal chemotherapy was used in conjunction with transfer factor from Candida-sensitive donors (reviewed by Kirkpatrick et al [58]). Improvements in immunologic responses were noted in 16 recipients but were only temporary in three patients. Thirteen patients showed clinical improvements, but they were only partial in one patient and transient in another. It is of interest that the temporary clinical and immunologic responses oc- curred in the same patients. Three reports compare the results of transfer factor therapy with material from Candida-insensitive and Can- dida-sensitive donors. The patients reported by Benz et al [63] and Littman et al [64] failed to show either clinical or immunologic responses to transfer factor from Candida- insensitive donors. Both patients subsequently became reactive to Candida and had clinical responses when they were given transfer factor from Candida-sensitive donors. We have compared transfer factor from Candida-sensitive and Candida-insensitive donors in 12 patients with chronic mucocutaneous candidiasis [65]. All patients were treated with antifungal chemotherapy before starting transfer factor. Transfer factor was given monthly and later reduced to every three to four months. All seven re- cipients of transfer factor from Candida—sensitive donors became reactive to Candida; none of the five recipients of transfer factor from Candida-negative donors became reactive to Candida, although four became responsive to other donor reactivities, such as streptokinase-streptodor- nase or tetanus toxoid. Four recipients of "Candida-posi- tive" transfer factor have remained reactive to Candida, and these four patients were still in remission after 27, 47, 87, and 93 months. Three other recipients of Candida- positive transfer factor reverted to insensitivity to Candida, and these patients relapsed at five, seven, and 12 months, respectively. Even though they are still unreactive to Candida, three of the recipients of Candida—negative transfer factor were in remission at 22, 31, and 36 months. Two other patients had a relapse at nine and 16 months. These results indicate that transfer factor may have
both specific and nonspecific effects on the clinical
courses of patients with mucocutaneous candidiasis.
Long-term remissions are achieved in patients who ac-
quire and maintain cellular immunity to Candida. How-
ever, even in the absence of reactivity to Candida, some
patients have sustained remissions after combination
treatment with antifungal chemotherapy and transfer fac-
tor from Candida-negative donors. In conclusion, the ex-
perience that has accumulated thus far indicates that the
combination of antifungal chemotherapy and transfer fac-
tor from Candida-sensitive donors provides a safe and ef-
fective therapeutic schedule for these patients. REFERENCES
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