Mucocutaneous Candidiasis and Thymoma
CHARLES
H. KIRKPATRICK,
M.D.
Bethesda, Maryland DOROTHY B. WINDHORST,
M.D.
Nutley, New Jersey
From the Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases. National Institutes of Health, Bethesda, Maryland: and the Department of Medical Research, Hoffmann-La Roche, Inc., Nutley, New Jersey. Requests for reprints should be addressed to Dr. Charles H. Kirkpatrick, Bldg. 10. Room llB-13, National Institutes of Health, Bethesda, Maryland 20014. Manuscript accepted January 17, 1979.
The clinical, pathologic and immunologic features of 27 patients with chronic mucocutaneous candidiasis and thymic tumors are reviewed. This form of chronic candidiasis is unique in that the infections do not occur until after the third decade and, in contrast to patients in whom candidiasis develops during infancy or childhood, it is not accompanied by failure of endocrine organs. Instead, the patients have the disorders that often accompany thymoma, such as myasthenia gravis, hypogammaglohulinemia, and abnormalities of the hone marrow and circulating blood elements. Evidence of impaired cell-mediated immunity was found in 16 of the 21 patients in whom studies were made. The pathogenesis of the immunodeficiency in these patients is unknown. Immunosuppressive activities in the plasma of four patients were found, but none of the five patients in whom the appropriate studies were made was found to have suppressor cells. The features of this disorder are unique enough that it should be considered a syndrome, and patients in whom candidiasis develops during their adult years should be studied for the presence of thymoma.
Chronic mucocutaneous candidiasis is characterized by recurrent and persistent infections of the skin, nails and mucous membranes with Candida species, usually Candida albicans. The results of investigations in several laboratories have shown that the majority of patients with mucocutaneous candidiasis have abnormalities of cell-mediated immunity [l-4]. The manifestations of the immunologic defects vary greatly from patient to patient, and clinically similar infections with C. albicans may occur in patients with disorders such as severe combined immunodeficiency [$I, thymus hypoplasia or dysplasia [6,7] and in patients whose defects are limited to impaired lymphocyte responses to antigens [l-4]. In our studies of mucocutaneous candidiasis at the National Institutes of Health, we have encountered five patients with a unique form of this disorder. None of the patients was unusually susceptible to Candida infections during infancy or childhood, but during adulthood typical, treatment-resistant candidiasis of the skin, nails and mucous membranes developed in each. Each patient also had a thymoma. In this report we describe the clinical and immunologic features of our patients. In addition, the characteristics of 22 additional patients described by others are reviewed (8-251.
June 1979 The American journal of Medicine
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939
MUCOCUTANEOUS CANDIDIASIS AND THYMOMA-KIRKPATRICK, WINDHORST
Clinical and Pathologic Data
TABLE I
At
h@(Yd Al onset of Candktiasts
At wwsls of Thymoma
Cafa No.
8sx
Tlmo ot Stsdy
1 2
F M
54 54
50 51
Patients Studted at the NIH 38 Benign lymphoid 54 Mallgnant lymphokt
3
M
63
62
49
Malignant lymphoid
4
F
55
52
55
Malignant lympho+pithelial
5
F
40
36
6
F
63
56
37 Malignant lymphoid Patients Sludied by Others 56 Not exam&
7 6
M F
45 73
34 66
40 70
9
F
41
39
38
Encapsulated “thymoma” Mixed spindle cell and lymphoid Benign reticular
10 11
F M
50 42
46 36
44 39
Benign Malignant lympho-epithelial
12 13
F F
51 71
51 69
52 71
14
F
56
58
58
15
F
71
67
71
16 17 16 19
M M F M
>35 >35 66 65
>35 >35 56 56
>35 >35 59 65
Encapsulated spindle cell Not examined (probably malignant) Benign encapsulated lymphocytic Benign lymphoid and epithelial Anaplastic malignant Anaplastic malignant “thymoma” Lymphocytic
20
F
40
38
40
21 22
M M
46 71
40 70
46 71
Malignant lymphoid and epithelial Mlxed lympho-epithelial Anaplastic
23 24 25
F M M
75 62 66
60 59 85
66 59 66
Not examined Malignant Encapsulated iymphoid
26
M
62
62
62
Encapsulated spindle cell
27
F
73
71
73
Not examined
Histotsgyst l’hymoma
MATERIAL!3 AND METHODS The five principal subjects of this report were referred to the National Institutes of Health to participate in the Clinical Center study of chronic mucocutaneous candidiasis. One patient (Case 4) had been previously described by Montes and co-workers [8]; the other four patients were not. Immunologic Studies. The general methods for assessing immune functions in our laboratory have been described in
Patients.
940
June 1979
The American Journal of Medicine
AssoclatsdDlwdsrs Myasthenia Myasthenia, chronic lymphocytic leukemia Myasthenia, chromophobe adenoma Myositis, alopecia areata None Hypogammaglobulinemia cyclic neutropenia None Pancytopenia, H. zoster Leukopenia, hypogammaglobulinemia Myasthenia Exfoliative erythroderma hepatitis Myositis None
Rd.
[61 PI [lOI [111 I121 ;r:\ ;::i
Myasthenia
1171
None
1181
None None Myasthenia Aplastic anemia, pernicious anemia Rehal lesions of SLE Myasthenia Vitiligo, myopathy, alopecia, dermatophytosis Alopecia areata None Myasthenia, deficient neutrophil bactericidal activity Red cell aplasia, pernicious anemia Hypogammaglobulinemia, agranulocytosis
,'r:; t;y 1221 v31 [231
[25]
detail elsewhere [7,26]. Delayed cutaneous hypersensitivity responses to C. albicans (Dermatophytin “0” l:lOO, Hollister-Stier Laboratories, Spokane, Washington), intermediate strdngth purified protein-derivative, streptokinase-streptodornase (SK-SD], 40/1oor 4OO/lOOU/ml (Varidase”, Lederle Laboratories, Pearl River, New York), trichophytin (permatophytin ~30, Hollister-Stier) and fluid tetanus toxoid, 10 Lf/ml. were determined by intradermal injection of 0.1 ml of
Volume 86
MUCOCUTANEOUS CANDIDIASIS AND THYMOMA-KIRKPATRICK, WINDHORST
the test solutions. Cutaneous responses were assessed at 15 minutes and 6,24 and 46 hours. Indurations of 0.5 cm or greater were scored as positive. Measurements of antigen and mitogen-induced lymphocyte transformation were made by culturing Hypaque@-Ficollseparated mononuclear cells with the appropriate stimulants and measuring incorporation of tritiated thymidine into DNA [7]. The patient’s cell suspensions, containing 60 to 90 per cent lymphocytes and 10 to 20 per cent monocytes, were cultured in both autologous and homologous group AB plasma; cells from normal Candida-reactive subjects were cultured in patient plasma to evaluate possible humoral inhibitory factors. Cellular inhibitory activities were assessed by the method of Stobo et al. {27].PeripheraI blood mononuclear cells were suspended in RPM1 1640 with 10 per cent plasma at 1 X lo6 cells/ml. After 7 to 10 days of incubation in the absence of any stimulating antigen, the cells were harvested from the culture tubes, washed, and resuspended in fresh media and serum at a density of 250,000 cells/ml. On the day that the precultured cells were collected, fresh mononuclear cells from the same patient were also prepared as already described. Three sets of cultures were established: (I] precultured cells; (2) freshlyprepared cells; and (3) 1:l mixtures of precultured cells and freshly prepared cells. Appropriate tubes were stimulated with antigens, and all tubes were incubated at 37% in a moist atmosphere of 5 per cent carbon dioxide - 95 per cent air for five to seven days, labeled with tritiated thymidine and harvested as described. Suppressor cells, if present, should inhibit antigen-induced thymidine incorporation by the freshly collected lymphocytes. and in the mixtures of fresh and precultured cells, Preculturing the cells deletes the suppressor cells [27], so the precultured cells may be responsive to antigen stimulation. Production of the lymphokines, macrophage migration inhibition factor (MIF) or leukocyte migration inhibition factor (LIF) by antigen or concanavalin-A (con A)-stimulated lymphocytes was measured as described elsewhere [26,28]. The number of E rosette-forming T-cells in the peripheral blood was measured as described previously [i’].
-
-
-
il
I! -
-
34-40 41-50 51-60-61-70
71
AGE (years)
igure 1. The age of onset of cutaneous candidiasis in 25 patients with the candidiasis-thymoma syndrome. Tvrp patients (Cases 16 and 17) were deleted because their exact age at time of onset was not given. Note that in most cases, the patients were in the sixth and seventh decades.
In 19 of the 27 patients, the onset of mucocutaneous candidiasis preceded the diagnosis of thymoma with a mean interval of three years. In four patients (Cases 1, 3, 9 and lo), thymomas were diagnosed.before candidiasis appeared, and in two [Cases 24 and 261,the t&o diagnoses were made simultaneously. The distribution of the ages at which thymomas were diagnosed is summarized in Figure 2. A variety of disorders such as myasthenia gravis, myositis, erythrqcyte aplasia, aplastic anemia, neutropenia and hypogammaglobulinemia also occur in pa-
l”r
RESULTS Clinical Features. The clinical features of our patients and of the 22 additional patients in othgr reports are presented in Table I. The sex incidence was essentially equal; there were 12 males and 15 females. The investigations of most patients occurred during the sixth decade (mean age 58.36 years); the youngest patient was 40 years old and the oldest 75 years. A unique feature of this syndrome, illustrated by the subjects of this report, is that mucocutaneous candidiasis does not appear until adulthood. None of our patients was unusually susceptible to infections with Candida or other organisms during infancy or childhood, and infections with Candida at early ages were not mentioned in the reports by others. Figure 1 shows that candidiasis did not develop in any patient before age 34 years, and the majority of the patients were in the sixth and seventh decades.
8-
1
6420
Il--Llh rl
L-L 374
-
41-50
51-60
61-70
71-73
AGE (years)
igure 2. The age at time of diagnosis of thymoma in 25 cases of the candidiasis-thymoma syndrome.
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The American Journal of Medicine
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941
MUCOCUTANEOUS
tients with thymomas [29-371. Eight of the previously described patients with the candidiasis-thymoma syndrome had myasthenia gravis and three additional patients had “myositis.” The diagnosis of myasthenia antedated the diagnosis of thymoma in four patients, was made after the diagnosis of thymoma in two, and the two diagnoses were made concurrently in two patients. In both cases in which the data were provided, the diagnosis of myositis or myopathy was made before the diagnosis of thymoma. Disorders of the bone marrow or circulating blood elements were present in eight patients. These included two patients with aplastic anemia, three with neutropenia, one each with pancytopenia and pure red cell aplasia and two with pernicious anemia. Three patients had hypogammaglobulinemia and each patient also had a leukocyte disorder; one patient each had agranulocytosis, leukopenia or cyclic neutropenia. In one patient there was evidence of impaired monocyte function, and another patient had decreased bactericidal activity of his granulocytes. Abnormalities of the integument occurred in four patients. Three patients had alopecia areata, and one also had vitiligo. The fourth patient had exfoliative erythroderma. Other than thymoma, only one other malignancy was noted-a patient who died with chronic lymphocytic leukemia (Case 2). Only six of the 27 patients did not have another disorder. Pathologic Features. Nine of the thymomas were described as benign or encapsulated. Of these, three were lymphoid, four were described as spindle-cell, reticular, epithelial or mixed, and in two cases the histology was not described. Six of the benign or encapsulated tumors occurred in females. Malignant tumors occurred in 11 patients. Four of these tumors contained mixed lymphoid and epithelial elements, three were lymphoid, three were “anaplastic,” and one was not described. Of the 12 males in this group, eight are known to have had malignant thymomas. In six patients (Cases 6,7,10, 18, 23 and 271,the histologic appearance of the tumor was not known. Immunologic Features. Some assessment of ‘cell mediated-immune responses was conducted in 21 of the patients (Table II]. Nineteen patients were skin tested with Candida extracts, and 12 patients had negative results. Twenty patients were tested with multiple antigens (including Candida), and seven failed to respond to any of the tests. Lymphocyte transformation responses to Candida were measured in 17 patients. Of the 15 patients in whom both skin tests and lymphocyte transformation tests with Candida were performed, there were concordant responses in 11 instances. Two skin test-positive patients failed to respond in the in vitro test, and two skin test-negative patients had normal lymphocyte transformation responses.
942
WINDHORST
CANDIDIASISAND THYMOMA-KIRKPATRICK,
June1979 The American Journal of Medicine
Twelve patients had lymphocyte transformation studies with antigens other than Candida and, of these, four showed no responses. These results correlated with their delayed skin tests. MIF production by Candida-stimulated lymphocytes was measured in six subjects. Three skin test-positive patients produced MIF. Of two skin test-negative patients, one did not produce MIF, and the other had normal MIF production. The sixth patient (Case 17)also did not produce MIF, but he was not skin tested. In summary, of the 21 subjects in whom cell-mediated immunity to Candida was evaluated, evidence of deficient responsiveness was found in 16.This was expressed as negative delayed skin tests in 12 patients and negative lymphocyte transformation responses in three additional patients. One patient (Case 6) was described as being anergic, but the result of testing with Candida was not specifically mentioned. Plasma factors that inhibited lymphocyte transformation were found in four patients (Cases 16,19,22 and 27). In all four, lymphocyte responses to Candida were inhibited, but in two [Cases 22 and 27) there were normal lymphocyte transformation responses to purified protein-derivative. Consistent evidence for a cellular suppressive factor was not found in any of our five patients, and such studies were not described in any of the reports from other laboratories. Serologic abnormalities were detected in 11 patients. These included seven patients with antinuclear factors, two patients with antithyroid or antithyroglobulin antibodies and one patient each with “antigamma globulin,” rheumatoid factor or antismooth muscle antibody. COMMENTS The syndromes of chronic mucocutaneous candidiasis may be divided into three general categories based on the age at which the infections begin. In the majority of patients progressive candidiasis develops during infancy or early childhood. Nearly all of these patients with “early-onset candidiasis” have impaired cell-mediated immunity to Candida, and many patients are unresponsive to all test antigens [l-4]. Because of the young age at which infections begin, it is assumed that the immunologic defects are congenital. However, with the exception of the candidiasis-endocrinopathy syndrome, and certain of the syndromes of combined immunodeficiency, there is little evidence that susceptibility to early-onset candidiasis is genetically transmitted. In a secqnd group of patients candidiasis develops during the end of the first or early in the second decade. In most of these cases there is no evidence of increased susceptibility to infectious diseases during early life. Immunologic studies of these patients have also shown deficient responses to Candida antigens [38]. In contrast to patients with the early-onset form of chronic mucocutaneous candidiasis, after adequate treatment with
Volume 66
Immunologic Data
TABLE II
C. Delaved
Case
Skiniest
NO.
km)
Tr&rsform&on 6.R.)
Antigens Lymphocyte Transform&ion (S.R.)
Other
a&cans
Lvmphocvte
Lymphskine Pr&Jctii (% inhib)
Delayed Skin Test Antigsn
(cm)
Lymphskine Productlon (% inhib)
Nftogen Response
% T Cells
AutoAntibodks
Patlents Studied at the NIH 1
0
2
1.7
1.5 14
ND
Multiple
Anergy
28
SK-SD
0.8
PPD 3 0.9 4 1.2 5 0 Normal NIH values 6 7 8 9
Not studied Negative Not studied Not studied
10 11 12 13
Not studied Negative Not studied Negative
14
Negative
15
Negative
16
ND
17 18 19
ND Negative Negative
15 2.0 1.0 4.5-20.0
ND
0
Negative 39
0.6 8 0 1.3 1.3 4.6 >4.0 >15 . Patients Studied by Others ND Multiple Anergy ND Multiple Anergy
ND
WNL
74
14
WNL
59
..
Negative
SK-SD SK-SD SK-SD
42 ND ND >15
ND
ND ND ND
. ND ND
ND ND
ND ND ,.. Antigamma globulin
ND
ND
WNL
ND
ND ... Antinuclear factor
ND ND
. Negative
pp6
“.
Negatrve
ii
ND
Pi6
Positive
Positive
WNL
ND
SK-SD Multiple
Negative Anergy
Negative Negative
ND ND
WNL
ND
WNL
ND
Multiple
Anergy
ND
ND
ND
ND
Decreased
ND
ND
..
WNL ND Negative
Decreased ND WNL
ND Multiple SK-SD
... Anergy Negative
id
id
Negative
ND
Mumps
Negative
Negative
ND
Decreased
Positive
WNL
ND
Multiple
Negative
ND
ND
ND
21
Positive
WNL
ND
ND
WNL
Negative
Decreased
ND
Positive Negative Positive
ND
22
PPD CDNB PPD
WNL
ND
Decreased
CDNB
Positive
Tricho PPD
Negative Positive
SK-SD Tricho CDNB
Negative Negative Positive
Negative
Decreased
.
Antinuclear factor Antinuclear factor Serum blocking factor
.., Decreased WNL
20
23
58 60 62 50-75
. .
. . ii
WNL WNL WNL
Rheumatoid factor Antinuclear factor Antithyroglobulin None None None
ND
Plasma inhibitory factor Monocyte defect ND Antinuclear factor Elevated Antithyroid
...
w~L
:::
WNL
Antinuclear factor Serum blocking factor . Antinuclear factor
.
.
24 25
Not studied Positive
Positive
Positive
PPD
Positive
Positive
ND
WNL
26
Positive
Negative
ND
SK-SD PPD
Positive Positive
Positive Positive
ND ND
WNL
WNL
Serum inhibitor
27
Negative
ND
ND
SK-SD Multiple
Negative Anergy
WNL
WNL
:::
Antismooth muscle ab
NOTE: S.R. = stimulation ratio; counts per minute of stimulated cultures divided by counts per minute of unstimulated cultures; WNL = within normal limits; SK-SD = streptokinase-streptodornase; PPD = tuberculin; CDNB = l-chloro-2.4 dinitrobenzene; tricho = trichophytin; ND = test not done or reported.
MUCOCUTANEOUS CANDIDIASIS AND THYMOMA-KIRKPATRICK.
antifungal antibiotics some of the patients in the second group may show spontaneous development of cellmediated responses to Candida [38,39]. The third group of patients with mucocutaneous candidiasis is the subject of this report. These patients are apparently healthy throughout childhood and young adult life. During or after the fourth decade, treatment-resistant candidiasis of the skin, nails and mucous membranes develops. A noteworthy feature of this syndrome is that the majority, if not all, of the patients have a thymoma. Abnormalities of the thymus occur in association with a variety of disorders in which there is evidence for disturbed regulation of the immune system. These include systemic lupus erythematosus (331,hypogammaglobulinemia [31,32,37] and myasthenia gravis [29,30]. The mechanisms through which the thymus participates in the pathogenesis of these disorders are not yet defined. Thymus-derived lymphocytes that are capable of suppressing immunoglobulin secretion by pokeweed mitogen-stimulated peripheral blood B-cells from normal donors have been found in patients with common variable and the Bruton-type of congenital hypogammaglobulinemia [40-421, and in patients with hypogammaglobulinemia and thymoma [43,44]. Of particular interest is the report by Litwin and Zanjani [44] which described two patients with thymoma and hypogammaglobulinemia, one of whom also had episodes of red cell agenesis. Thymus-derived Tcells from these patients suppressed both maturation qf normal B-cells into immunoglobulin-producing cells and formation of erythroid colonies by erythropoietinstimulated bone marrow cells. There is less evidence for active suppression of cellmediated immune responses. Twomey et al. [45]have reported that patients with advanced Hodgkin’s disease have blood leukocytes that suppress mixed leukocyte reactions between the patient’s lymphocytes and allogeneic leukocytes, In one case this effect was lost when the patient’s glass-wool adherent leukocytes were removed from the cultures or when protein synthesis was inhibited with cycloheximide. In several patients it waned spontaneously when they entered remissions. Stobo et al. [27]have described a similar phenomenon in four patients with chronic fungal infections. These patients had circulating leukocytes that suppressed thymidine incorporation responses by antigen and mitogen-stimulated autologous lymphocytes. The report does not mention the presence or absence of thymoma in any of the patients, but it is noteworthy that the mean age of the patients was 54 f 2 years. A reciprocal situation may exist in systemic lupus
WINDHORST
erythematosus. Abdou et al. [46]and Morimoto [47] have shown that cell cultures from these patients produce excessive amounts of antibodies and that addition of normal T-cells to the cultures reduces the antibody production towards normal. A similar abnormality in thymic regulation of antibody synthesis may be related to the presence of antinuclear and other autoantibodies in patients with the candidiasis-thymoma syndrome. Observations in younger patients with chronic mucocutaneous candidiasis strongly suggest that deficient cell-mediated immunity contributes to the pathogenesis of the progressive candidal infections. In the older patients, however, the immunologic defects are probably acquired, and they may be due to senescence of a previously normal immune system or to an active immunosuppressive influence. The plasma of four patients (Cases 1,3,5 and 20) contained normal levels of thymopoietin-like activity [48], suggesting that thymic inductive activity was not deficient. Attempts to identify a cellular suppressive activity have thus far been unsuccessful although several patients had suppressive factors in their plasmas. Although candidiasis usually antedates the diagnosis of thymoma, this may be related to the relative ease of diagnosis of the infection. It is unclear if the immune defects are secondary to the thymic tumor or if the thymic tumor represents a compensatory response to a deficient immune regulatory factor. It is conceivable that the development of thymoma in patients with defects in cell-mediated immunity may be functionally analogous to the hyperplastic nodules of B lymphocytes that occur in the intestinal tracts of certain patients with hypogammaglobulinemia [49]. Finally, neoplastic disorders occur in excessive numbers in patients with immunodeficiency syndromes [50,51]. Yet with the exception of the tumors of the thymus seen in the adult-onset group, neoplastic changes are apparently rare in immunodeficient patients with mucocutaneous candidiasis. We are aware of only two cases in which tumors other than thymoma developed and in both the patients had carcinomas of the buccal cavity [52,53]. The relationship of these tumors to the chronic inflammation of long-standing oral candidiasis is unknown. ACKNOWLEDGMENT These investigations were conducted in compliance with a protocol that had been reviewed and approved by the appropriate committees, and persons at the National Institutes of Health. We are indebted to Dr. Peter Kohler of the University of Colorado Medical Center for permission to include Case 27.
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WINDHORST
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24.
49. 50. 51. 52. 53.
Waldmann TA, Durm M, Broder S, et al.: Role of suppressor T cells in pathogenesis of common variable hypogammaglobulinemia. Lancet 2: 609, 1974. Broom BC. de la Concha IG. Webster ABD. et al.: Intracellular immunoglobulin production in vitro by lymphocytes from patients with hypogammaglobulinemia and their effect on normal lymphocytes. Chn Exp Immunol23: 73,1976. Siegal FP, Siegal M, Good RA: Suppression of B-cell differentiation by leukocytes from hypogammaglobulinemia patients. J Chn Invest 58: 109, 1976. Waldmann TA, Blaese RM. Broder S, et al.: Disorders of suppressor immunoregulatory cells in the pathogenesis of immunodeficiency and autoimmunity. Ann Intern Med 88: 226, 1978. Litwin SD, Zanjani ED: Lymphocytes suppressing both immunoglobulin production and erythroid differentiation in hypogammaglobulinemia. Nature 266: 57,1977. Twomey JJ, Laughter AH, Farrow S, et al.: Hodgkin’s disease. An immunodepleting and immunosuppressive disorder. J Chn Invest 56: 467,1975. Abdou NI, Sagawa A, Pascual E, et al.: Suppressor T-cell abnormality in idiopathic systemic lupus ervthematosus. Chn Immunol Immunopathol6: 192.1976. ” Morimoto C: Loss of suppressor T-lymphocyte function in patients with systemic lupus erythematosus (SLE). Clin Exp Immunol32: 125.1978. Kirkpatrick CH, Greenberg LE, Chapman SW, et al.: Plasma thymic hormone activity in patients with chronic mucocutaneous candidiasis. Clin Exp Immunol 31: 311, 1978. Hermans PE, Huizenga KA. Hoffman HN, et al.: Dysgammaglobulinemia associated with nodular lvmohoid hvperplasia of the small intestine. Am J Med 40: ?8,1966. Kersey JH, Spector BD, Good RA: Primary immunodeficiency diseases and cancer. The immunodeficiency-cancer registry. Int J Cancer 12: 333,1973. Waldmann TA, Strober W. Blaese RM: Immunodeficiency and malignancv. Ann Intern Med 77: 605.1972. Richman RA, Rosenthal IM, Solomon LM, et al.: Candidiasis and multiple endocrinopathv with oral sauamous cell carcinoma-comphcations. Arch Dermatol 111: 625, 1975. Richerson HB: Personal communication.
June 1979 The American Journal of Medicine
Volume 66
945
CHARLES
H. KIRKPATRICK,
M.D.
Bethesda, Maryland DOROTHY B. WINDHORST,
M.D.
Nutley, New Jersey
From the Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases. National Institutes of Health, Bethesda, Maryland: and the Department of Medical Research, Hoffmann-La Roche, Inc., Nutley, New Jersey. Requests for reprints should be addressed to Dr. Charles H. Kirkpatrick, Bldg. 10. Room llB-13, National Institutes of Health, Bethesda, Maryland 20014. Manuscript accepted January 17, 1979.
The clinical, pathologic and immunologic features of 27 patients with chronic mucocutaneous candidiasis and thymic tumors are reviewed. This form of chronic candidiasis is unique in that the infections do not occur until after the third decade and, in contrast to patients in whom candidiasis develops during infancy or childhood, it is not accompanied by failure of endocrine organs. Instead, the patients have the disorders that often accompany thymoma, such as myasthenia gravis, hypogammaglohulinemia, and abnormalities of the hone marrow and circulating blood elements. Evidence of impaired cell-mediated immunity was found in 16 of the 21 patients in whom studies were made. The pathogenesis of the immunodeficiency in these patients is unknown. Immunosuppressive activities in the plasma of four patients were found, but none of the five patients in whom the appropriate studies were made was found to have suppressor cells. The features of this disorder are unique enough that it should be considered a syndrome, and patients in whom candidiasis develops during their adult years should be studied for the presence of thymoma.
Chronic mucocutaneous candidiasis is characterized by recurrent and persistent infections of the skin, nails and mucous membranes with Candida species, usually Candida albicans. The results of investigations in several laboratories have shown that the majority of patients with mucocutaneous candidiasis have abnormalities of cell-mediated immunity [l-4]. The manifestations of the immunologic defects vary greatly from patient to patient, and clinically similar infections with C. albicans may occur in patients with disorders such as severe combined immunodeficiency [$I, thymus hypoplasia or dysplasia [6,7] and in patients whose defects are limited to impaired lymphocyte responses to antigens [l-4]. In our studies of mucocutaneous candidiasis at the National Institutes of Health, we have encountered five patients with a unique form of this disorder. None of the patients was unusually susceptible to Candida infections during infancy or childhood, but during adulthood typical, treatment-resistant candidiasis of the skin, nails and mucous membranes developed in each. Each patient also had a thymoma. In this report we describe the clinical and immunologic features of our patients. In addition, the characteristics of 22 additional patients described by others are reviewed (8-251.
June 1979 The American journal of Medicine
Volume 66
939
MUCOCUTANEOUS CANDIDIASIS AND THYMOMA-KIRKPATRICK, WINDHORST
Clinical and Pathologic Data
TABLE I
At
h@(Yd Al onset of Candktiasts
At wwsls of Thymoma
Cafa No.
8sx
Tlmo ot Stsdy
1 2
F M
54 54
50 51
Patients Studted at the NIH 38 Benign lymphoid 54 Mallgnant lymphokt
3
M
63
62
49
Malignant lymphoid
4
F
55
52
55
Malignant lympho+pithelial
5
F
40
36
6
F
63
56
37 Malignant lymphoid Patients Sludied by Others 56 Not exam&
7 6
M F
45 73
34 66
40 70
9
F
41
39
38
Encapsulated “thymoma” Mixed spindle cell and lymphoid Benign reticular
10 11
F M
50 42
46 36
44 39
Benign Malignant lympho-epithelial
12 13
F F
51 71
51 69
52 71
14
F
56
58
58
15
F
71
67
71
16 17 16 19
M M F M
>35 >35 66 65
>35 >35 56 56
>35 >35 59 65
Encapsulated spindle cell Not examined (probably malignant) Benign encapsulated lymphocytic Benign lymphoid and epithelial Anaplastic malignant Anaplastic malignant “thymoma” Lymphocytic
20
F
40
38
40
21 22
M M
46 71
40 70
46 71
Malignant lymphoid and epithelial Mlxed lympho-epithelial Anaplastic
23 24 25
F M M
75 62 66
60 59 85
66 59 66
Not examined Malignant Encapsulated iymphoid
26
M
62
62
62
Encapsulated spindle cell
27
F
73
71
73
Not examined
Histotsgyst l’hymoma
MATERIAL!3 AND METHODS The five principal subjects of this report were referred to the National Institutes of Health to participate in the Clinical Center study of chronic mucocutaneous candidiasis. One patient (Case 4) had been previously described by Montes and co-workers [8]; the other four patients were not. Immunologic Studies. The general methods for assessing immune functions in our laboratory have been described in
Patients.
940
June 1979
The American Journal of Medicine
AssoclatsdDlwdsrs Myasthenia Myasthenia, chronic lymphocytic leukemia Myasthenia, chromophobe adenoma Myositis, alopecia areata None Hypogammaglobulinemia cyclic neutropenia None Pancytopenia, H. zoster Leukopenia, hypogammaglobulinemia Myasthenia Exfoliative erythroderma hepatitis Myositis None
Rd.
[61 PI [lOI [111 I121 ;r:\ ;::i
Myasthenia
1171
None
1181
None None Myasthenia Aplastic anemia, pernicious anemia Rehal lesions of SLE Myasthenia Vitiligo, myopathy, alopecia, dermatophytosis Alopecia areata None Myasthenia, deficient neutrophil bactericidal activity Red cell aplasia, pernicious anemia Hypogammaglobulinemia, agranulocytosis
,'r:; t;y 1221 v31 [231
[25]
detail elsewhere [7,26]. Delayed cutaneous hypersensitivity responses to C. albicans (Dermatophytin “0” l:lOO, Hollister-Stier Laboratories, Spokane, Washington), intermediate strdngth purified protein-derivative, streptokinase-streptodornase (SK-SD], 40/1oor 4OO/lOOU/ml (Varidase”, Lederle Laboratories, Pearl River, New York), trichophytin (permatophytin ~30, Hollister-Stier) and fluid tetanus toxoid, 10 Lf/ml. were determined by intradermal injection of 0.1 ml of
Volume 86
MUCOCUTANEOUS CANDIDIASIS AND THYMOMA-KIRKPATRICK, WINDHORST
the test solutions. Cutaneous responses were assessed at 15 minutes and 6,24 and 46 hours. Indurations of 0.5 cm or greater were scored as positive. Measurements of antigen and mitogen-induced lymphocyte transformation were made by culturing Hypaque@-Ficollseparated mononuclear cells with the appropriate stimulants and measuring incorporation of tritiated thymidine into DNA [7]. The patient’s cell suspensions, containing 60 to 90 per cent lymphocytes and 10 to 20 per cent monocytes, were cultured in both autologous and homologous group AB plasma; cells from normal Candida-reactive subjects were cultured in patient plasma to evaluate possible humoral inhibitory factors. Cellular inhibitory activities were assessed by the method of Stobo et al. {27].PeripheraI blood mononuclear cells were suspended in RPM1 1640 with 10 per cent plasma at 1 X lo6 cells/ml. After 7 to 10 days of incubation in the absence of any stimulating antigen, the cells were harvested from the culture tubes, washed, and resuspended in fresh media and serum at a density of 250,000 cells/ml. On the day that the precultured cells were collected, fresh mononuclear cells from the same patient were also prepared as already described. Three sets of cultures were established: (I] precultured cells; (2) freshlyprepared cells; and (3) 1:l mixtures of precultured cells and freshly prepared cells. Appropriate tubes were stimulated with antigens, and all tubes were incubated at 37% in a moist atmosphere of 5 per cent carbon dioxide - 95 per cent air for five to seven days, labeled with tritiated thymidine and harvested as described. Suppressor cells, if present, should inhibit antigen-induced thymidine incorporation by the freshly collected lymphocytes. and in the mixtures of fresh and precultured cells, Preculturing the cells deletes the suppressor cells [27], so the precultured cells may be responsive to antigen stimulation. Production of the lymphokines, macrophage migration inhibition factor (MIF) or leukocyte migration inhibition factor (LIF) by antigen or concanavalin-A (con A)-stimulated lymphocytes was measured as described elsewhere [26,28]. The number of E rosette-forming T-cells in the peripheral blood was measured as described previously [i’].
-
-
-
il
I! -
-
34-40 41-50 51-60-61-70
71
AGE (years)
igure 1. The age of onset of cutaneous candidiasis in 25 patients with the candidiasis-thymoma syndrome. Tvrp patients (Cases 16 and 17) were deleted because their exact age at time of onset was not given. Note that in most cases, the patients were in the sixth and seventh decades.
In 19 of the 27 patients, the onset of mucocutaneous candidiasis preceded the diagnosis of thymoma with a mean interval of three years. In four patients (Cases 1, 3, 9 and lo), thymomas were diagnosed.before candidiasis appeared, and in two [Cases 24 and 261,the t&o diagnoses were made simultaneously. The distribution of the ages at which thymomas were diagnosed is summarized in Figure 2. A variety of disorders such as myasthenia gravis, myositis, erythrqcyte aplasia, aplastic anemia, neutropenia and hypogammaglobulinemia also occur in pa-
l”r
RESULTS Clinical Features. The clinical features of our patients and of the 22 additional patients in othgr reports are presented in Table I. The sex incidence was essentially equal; there were 12 males and 15 females. The investigations of most patients occurred during the sixth decade (mean age 58.36 years); the youngest patient was 40 years old and the oldest 75 years. A unique feature of this syndrome, illustrated by the subjects of this report, is that mucocutaneous candidiasis does not appear until adulthood. None of our patients was unusually susceptible to infections with Candida or other organisms during infancy or childhood, and infections with Candida at early ages were not mentioned in the reports by others. Figure 1 shows that candidiasis did not develop in any patient before age 34 years, and the majority of the patients were in the sixth and seventh decades.
8-
1
6420
Il--Llh rl
L-L 374
-
41-50
51-60
61-70
71-73
AGE (years)
igure 2. The age at time of diagnosis of thymoma in 25 cases of the candidiasis-thymoma syndrome.
June 1979
The American Journal of Medicine
Volume 66
941
MUCOCUTANEOUS
tients with thymomas [29-371. Eight of the previously described patients with the candidiasis-thymoma syndrome had myasthenia gravis and three additional patients had “myositis.” The diagnosis of myasthenia antedated the diagnosis of thymoma in four patients, was made after the diagnosis of thymoma in two, and the two diagnoses were made concurrently in two patients. In both cases in which the data were provided, the diagnosis of myositis or myopathy was made before the diagnosis of thymoma. Disorders of the bone marrow or circulating blood elements were present in eight patients. These included two patients with aplastic anemia, three with neutropenia, one each with pancytopenia and pure red cell aplasia and two with pernicious anemia. Three patients had hypogammaglobulinemia and each patient also had a leukocyte disorder; one patient each had agranulocytosis, leukopenia or cyclic neutropenia. In one patient there was evidence of impaired monocyte function, and another patient had decreased bactericidal activity of his granulocytes. Abnormalities of the integument occurred in four patients. Three patients had alopecia areata, and one also had vitiligo. The fourth patient had exfoliative erythroderma. Other than thymoma, only one other malignancy was noted-a patient who died with chronic lymphocytic leukemia (Case 2). Only six of the 27 patients did not have another disorder. Pathologic Features. Nine of the thymomas were described as benign or encapsulated. Of these, three were lymphoid, four were described as spindle-cell, reticular, epithelial or mixed, and in two cases the histology was not described. Six of the benign or encapsulated tumors occurred in females. Malignant tumors occurred in 11 patients. Four of these tumors contained mixed lymphoid and epithelial elements, three were lymphoid, three were “anaplastic,” and one was not described. Of the 12 males in this group, eight are known to have had malignant thymomas. In six patients (Cases 6,7,10, 18, 23 and 271,the histologic appearance of the tumor was not known. Immunologic Features. Some assessment of ‘cell mediated-immune responses was conducted in 21 of the patients (Table II]. Nineteen patients were skin tested with Candida extracts, and 12 patients had negative results. Twenty patients were tested with multiple antigens (including Candida), and seven failed to respond to any of the tests. Lymphocyte transformation responses to Candida were measured in 17 patients. Of the 15 patients in whom both skin tests and lymphocyte transformation tests with Candida were performed, there were concordant responses in 11 instances. Two skin test-positive patients failed to respond in the in vitro test, and two skin test-negative patients had normal lymphocyte transformation responses.
942
WINDHORST
CANDIDIASISAND THYMOMA-KIRKPATRICK,
June1979 The American Journal of Medicine
Twelve patients had lymphocyte transformation studies with antigens other than Candida and, of these, four showed no responses. These results correlated with their delayed skin tests. MIF production by Candida-stimulated lymphocytes was measured in six subjects. Three skin test-positive patients produced MIF. Of two skin test-negative patients, one did not produce MIF, and the other had normal MIF production. The sixth patient (Case 17)also did not produce MIF, but he was not skin tested. In summary, of the 21 subjects in whom cell-mediated immunity to Candida was evaluated, evidence of deficient responsiveness was found in 16.This was expressed as negative delayed skin tests in 12 patients and negative lymphocyte transformation responses in three additional patients. One patient (Case 6) was described as being anergic, but the result of testing with Candida was not specifically mentioned. Plasma factors that inhibited lymphocyte transformation were found in four patients (Cases 16,19,22 and 27). In all four, lymphocyte responses to Candida were inhibited, but in two [Cases 22 and 27) there were normal lymphocyte transformation responses to purified protein-derivative. Consistent evidence for a cellular suppressive factor was not found in any of our five patients, and such studies were not described in any of the reports from other laboratories. Serologic abnormalities were detected in 11 patients. These included seven patients with antinuclear factors, two patients with antithyroid or antithyroglobulin antibodies and one patient each with “antigamma globulin,” rheumatoid factor or antismooth muscle antibody. COMMENTS The syndromes of chronic mucocutaneous candidiasis may be divided into three general categories based on the age at which the infections begin. In the majority of patients progressive candidiasis develops during infancy or early childhood. Nearly all of these patients with “early-onset candidiasis” have impaired cell-mediated immunity to Candida, and many patients are unresponsive to all test antigens [l-4]. Because of the young age at which infections begin, it is assumed that the immunologic defects are congenital. However, with the exception of the candidiasis-endocrinopathy syndrome, and certain of the syndromes of combined immunodeficiency, there is little evidence that susceptibility to early-onset candidiasis is genetically transmitted. In a secqnd group of patients candidiasis develops during the end of the first or early in the second decade. In most of these cases there is no evidence of increased susceptibility to infectious diseases during early life. Immunologic studies of these patients have also shown deficient responses to Candida antigens [38]. In contrast to patients with the early-onset form of chronic mucocutaneous candidiasis, after adequate treatment with
Volume 66
Immunologic Data
TABLE II
C. Delaved
Case
Skiniest
NO.
km)
Tr&rsform&on 6.R.)
Antigens Lymphocyte Transform&ion (S.R.)
Other
a&cans
Lvmphocvte
Lymphskine Pr&Jctii (% inhib)
Delayed Skin Test Antigsn
(cm)
Lymphskine Productlon (% inhib)
Nftogen Response
% T Cells
AutoAntibodks
Patlents Studied at the NIH 1
0
2
1.7
1.5 14
ND
Multiple
Anergy
28
SK-SD
0.8
PPD 3 0.9 4 1.2 5 0 Normal NIH values 6 7 8 9
Not studied Negative Not studied Not studied
10 11 12 13
Not studied Negative Not studied Negative
14
Negative
15
Negative
16
ND
17 18 19
ND Negative Negative
15 2.0 1.0 4.5-20.0
ND
0
Negative 39
0.6 8 0 1.3 1.3 4.6 >4.0 >15 . Patients Studied by Others ND Multiple Anergy ND Multiple Anergy
ND
WNL
74
14
WNL
59
..
Negative
SK-SD SK-SD SK-SD
42 ND ND >15
ND
ND ND ND
. ND ND
ND ND
ND ND ,.. Antigamma globulin
ND
ND
WNL
ND
ND ... Antinuclear factor
ND ND
. Negative
pp6
“.
Negatrve
ii
ND
Pi6
Positive
Positive
WNL
ND
SK-SD Multiple
Negative Anergy
Negative Negative
ND ND
WNL
ND
WNL
ND
Multiple
Anergy
ND
ND
ND
ND
Decreased
ND
ND
..
WNL ND Negative
Decreased ND WNL
ND Multiple SK-SD
... Anergy Negative
id
id
Negative
ND
Mumps
Negative
Negative
ND
Decreased
Positive
WNL
ND
Multiple
Negative
ND
ND
ND
21
Positive
WNL
ND
ND
WNL
Negative
Decreased
ND
Positive Negative Positive
ND
22
PPD CDNB PPD
WNL
ND
Decreased
CDNB
Positive
Tricho PPD
Negative Positive
SK-SD Tricho CDNB
Negative Negative Positive
Negative
Decreased
.
Antinuclear factor Antinuclear factor Serum blocking factor
.., Decreased WNL
20
23
58 60 62 50-75
. .
. . ii
WNL WNL WNL
Rheumatoid factor Antinuclear factor Antithyroglobulin None None None
ND
Plasma inhibitory factor Monocyte defect ND Antinuclear factor Elevated Antithyroid
...
w~L
:::
WNL
Antinuclear factor Serum blocking factor . Antinuclear factor
.
.
24 25
Not studied Positive
Positive
Positive
PPD
Positive
Positive
ND
WNL
26
Positive
Negative
ND
SK-SD PPD
Positive Positive
Positive Positive
ND ND
WNL
WNL
Serum inhibitor
27
Negative
ND
ND
SK-SD Multiple
Negative Anergy
WNL
WNL
:::
Antismooth muscle ab
NOTE: S.R. = stimulation ratio; counts per minute of stimulated cultures divided by counts per minute of unstimulated cultures; WNL = within normal limits; SK-SD = streptokinase-streptodornase; PPD = tuberculin; CDNB = l-chloro-2.4 dinitrobenzene; tricho = trichophytin; ND = test not done or reported.
MUCOCUTANEOUS CANDIDIASIS AND THYMOMA-KIRKPATRICK.
antifungal antibiotics some of the patients in the second group may show spontaneous development of cellmediated responses to Candida [38,39]. The third group of patients with mucocutaneous candidiasis is the subject of this report. These patients are apparently healthy throughout childhood and young adult life. During or after the fourth decade, treatment-resistant candidiasis of the skin, nails and mucous membranes develops. A noteworthy feature of this syndrome is that the majority, if not all, of the patients have a thymoma. Abnormalities of the thymus occur in association with a variety of disorders in which there is evidence for disturbed regulation of the immune system. These include systemic lupus erythematosus (331,hypogammaglobulinemia [31,32,37] and myasthenia gravis [29,30]. The mechanisms through which the thymus participates in the pathogenesis of these disorders are not yet defined. Thymus-derived lymphocytes that are capable of suppressing immunoglobulin secretion by pokeweed mitogen-stimulated peripheral blood B-cells from normal donors have been found in patients with common variable and the Bruton-type of congenital hypogammaglobulinemia [40-421, and in patients with hypogammaglobulinemia and thymoma [43,44]. Of particular interest is the report by Litwin and Zanjani [44] which described two patients with thymoma and hypogammaglobulinemia, one of whom also had episodes of red cell agenesis. Thymus-derived Tcells from these patients suppressed both maturation qf normal B-cells into immunoglobulin-producing cells and formation of erythroid colonies by erythropoietinstimulated bone marrow cells. There is less evidence for active suppression of cellmediated immune responses. Twomey et al. [45]have reported that patients with advanced Hodgkin’s disease have blood leukocytes that suppress mixed leukocyte reactions between the patient’s lymphocytes and allogeneic leukocytes, In one case this effect was lost when the patient’s glass-wool adherent leukocytes were removed from the cultures or when protein synthesis was inhibited with cycloheximide. In several patients it waned spontaneously when they entered remissions. Stobo et al. [27]have described a similar phenomenon in four patients with chronic fungal infections. These patients had circulating leukocytes that suppressed thymidine incorporation responses by antigen and mitogen-stimulated autologous lymphocytes. The report does not mention the presence or absence of thymoma in any of the patients, but it is noteworthy that the mean age of the patients was 54 f 2 years. A reciprocal situation may exist in systemic lupus
WINDHORST
erythematosus. Abdou et al. [46]and Morimoto [47] have shown that cell cultures from these patients produce excessive amounts of antibodies and that addition of normal T-cells to the cultures reduces the antibody production towards normal. A similar abnormality in thymic regulation of antibody synthesis may be related to the presence of antinuclear and other autoantibodies in patients with the candidiasis-thymoma syndrome. Observations in younger patients with chronic mucocutaneous candidiasis strongly suggest that deficient cell-mediated immunity contributes to the pathogenesis of the progressive candidal infections. In the older patients, however, the immunologic defects are probably acquired, and they may be due to senescence of a previously normal immune system or to an active immunosuppressive influence. The plasma of four patients (Cases 1,3,5 and 20) contained normal levels of thymopoietin-like activity [48], suggesting that thymic inductive activity was not deficient. Attempts to identify a cellular suppressive activity have thus far been unsuccessful although several patients had suppressive factors in their plasmas. Although candidiasis usually antedates the diagnosis of thymoma, this may be related to the relative ease of diagnosis of the infection. It is unclear if the immune defects are secondary to the thymic tumor or if the thymic tumor represents a compensatory response to a deficient immune regulatory factor. It is conceivable that the development of thymoma in patients with defects in cell-mediated immunity may be functionally analogous to the hyperplastic nodules of B lymphocytes that occur in the intestinal tracts of certain patients with hypogammaglobulinemia [49]. Finally, neoplastic disorders occur in excessive numbers in patients with immunodeficiency syndromes [50,51]. Yet with the exception of the tumors of the thymus seen in the adult-onset group, neoplastic changes are apparently rare in immunodeficient patients with mucocutaneous candidiasis. We are aware of only two cases in which tumors other than thymoma developed and in both the patients had carcinomas of the buccal cavity [52,53]. The relationship of these tumors to the chronic inflammation of long-standing oral candidiasis is unknown. ACKNOWLEDGMENT These investigations were conducted in compliance with a protocol that had been reviewed and approved by the appropriate committees, and persons at the National Institutes of Health. We are indebted to Dr. Peter Kohler of the University of Colorado Medical Center for permission to include Case 27.
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June 1979
The American Journal of Medicine
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WINDHORST
D, Heller H: Idiopathic acquired agammaglobulinemia associated with thymoma. N Engl J Med 263: 536,196O. Anning ST: Myasthenia gravis and candidiasis. Br J Dermatol 74: 106, 1962. Baer RL. Bart RS, Stritzler R, et al.: Exfoliative Erythrodermie and Thymom. Hautarzt 15: 413.1964. Montes LF, Carter RE, Moreland N. et al.: Generalized cutaneous candidiasis associated with diffuse myopathy and thymoma. JAMA 204: 351,197O. Calnan CD: Chronic mucocutaneous candidiasis. Br J Dermatol 83: 423, 1970. Schoch EP: Thymic conversion of Candida albicans from commensalism to pathogenism. Arch Dermatol 163: 311, 1971. Maize JC, Lynch PJ: Chronic mucocutaneous candidiasis of the adult. A report of a patient with an associated thymoma. Arch Dermatol 105: 96, 1972. Higgs JM. Wells RS: Klassifizierung der chronischen mucocutanen Candidiasis mit Betrachtungen zum Klinischen Bild und zur Therapie. Hautarzt 25: 159, 1974 Burstein HJ: Chronic mucocutaneous candidiasis, thymoma and mvopathv. A triad. Cutis 13: 262, 1974. Twomey”JJ; Waddell CC, Krantz S, et al.: Chronic mucocutaneous candidiasis with macrophage dysfunction, a plasma inhibitor and co-existent aplastic anemia. J Lab Clin Med 85: 968, 1975. Windhorst DB, Stoitzner G: Candidiasis in Thymoma. International Conference on the Mycoses. Pan American Health Association Publication 304, Washington, DC., Pan American Health Association, 1975, p 42. Rycroft RJG. Valdimarsson H, Bannister LH, et al.: Chronic mucocutaneous candidiasis of late onset, thymoma and myopathy. A report of four cases. Clin Exp Dermatol 1: 59.
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Kirkpetrick CH, Smith TK: Chronic mucocutaneous candidiasis: immunologic and antibiotic therapy. Ann Intern Med 80: 310,1974. 39. Imperato PJ. Buckley CE, Callaway JL: Candida granuloma: a clinical and immunologic study. Arch Dermato197: 139, 1974
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June 1979 The American Journal of Medicine
Volume 66
945
