CLINICAL STUDIES
Histoplasmosis in lmmunosuppressed Patients
CAROL A. KAUFFMAN,
M.D.*
Cincinnati, Ohio KAREN S. ISRAEL, M.D.+ Indianapolis,
Indiana
JAMES W. SMITH, M.D. Indianapolis,
Indiana
ARTHUR C. WHITE, M.D. Indianapolis, Indiana JAN SCHWARZ,
M.D.
Cincinnati, Ohio GEORGE F. BROOKS, M.D.t Indianapolis,
Indiana
From the Division of Infectious Diseases, Cincinnati Veterans Administration Hospital and University of Cincinnati Medical Center; the Department of Pathology, Jewish Hospital and University of Cincinnati Medical Center, Cincinnati, Ohio: Division of Infectious Diseases, Indiana University Medical Center; and Department of Pathology, Indianapolis Veterans Administration Hospital and Indiana University Medical Center, Indianapolis, Indiana. Requests for reprints should be addressed to Dr. Carol A. Kauffman. Manuscript accepted November 11, 1977. Present address: Infectious Disease Service, Veterans Administration Hospital, Ann Arbor, Michigan 48105. + Present address: Lilly Research Laboratories, Indianapolis, Indiana 46202. t Present address: Infectious Disease Service, Veterans Administration Hospital, Martinez, California. l
Infection with Hi&plasma capsulatum in 58 patients whose immune responses were suppressed (Immunosuppressed patients) (18 from the present series and 42 described previously) was analyzed. The most common underlying diseases were Hodgkin’s dtsease (29 per cent), chronic lymphocytlc leukemia (19 per cent) and acute lymphocytic leukemia (17 per cent). Sixty-three per cent of the pattents had received cytotoxlc drugs, and 57 per cent had taken corticosteroids. Widely disseminated Infection occurred In 88 per cent of the patients, with predominant involvement of lungs and organs of the retlculoendothelial system. Localized pulmonary infection was present in the remaining patients. The most useful diagnostic method was bone marrow biopsy with microscopic examination for the intracellular yeast form of H. capsulatum. Biopsy of oral lesions, lung, liver and lymph noUe also proved diagnostically helpful. Growth of H. capsulatum In culture was frequently too stow to be beneftcial in dtagnoskq htstopl&mosts in ill patients. Serologic methods were of ltttle dlagnostlc help In this population of immunosuppressed patients. The response to amphoterlcln B therapy was excellent (8.7 per cent mortality rate) In those patients in whom the dlagnosts was established early and in whom a full course of antlfungal therapy could be given. In contrast, the mortality rate in patlents who recelved no antifungal therapy or less than 1 g of amphotericin B was 100 per cent. Fungal infections have become an increasingly severe problem in the immunologically compromised host [ 1,2]. The pathogenesis of infections due to opportunists such as Aspergillus [3], Candida [4] and the phycomycetes [5] has been extensively studied in many patients who are immunosuppressed. However, infections with usually pathogenic fungi have only recently been studied in the immunologically compromised patient [6]. The natural history of histoplasmosis in immunosuppressed patients is not well-documented; most reports are single case studies [7-361; the largest series consists of six children with acute leukemia [ 131. We report here our observations of active histoplasmosis in 16 immunologically compromised adult patients and review the English literature dealing with histoplasmosis in the immunologically compromised host. METHODS The medical records of 16 immunologically compromised adult patients with
histoplasmosis were reviewed. The patients were seen between September 1953 and December 1975 at the Indiana University Medical Center (12 pa-
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HISTOPLASMOSIS
IN IMMUNOSUPPRESSED PATIENTS-KAUFFMAN
ET AL.
tients) and the University of Cincinnati Medical Center (four patients). Eight of the 16 cases occurred between 1970 and 1975. Immunologically compromised patients were those who met one or both of the following criteria: (1) patients with a hematologic malignancy, (2) patients treated with immunosuppressive drugs (corticosteroids and/or cytotoxic drugs) and/or radiation therapy for at least three months prior to the diagnosis of histoplasmosis. The diagnosis of histoplasmosis was made if patients had a clinical illness compatible with active disease and at least one of the following: (1) a positive culture from any site for H. capsulatum, (2) a biopsy specimen showing the characteristic intracellular yeast form of H. capsulatum. RESULTS
General
Characteristics
and Underlying
Diseases.
The 16 patients with histoplasmosis ranged in age from
23 to 76 years (Table I). Nine were men and seven women. Six patients had stage IV Hodgkin’s disease, and five had chronic lymphocytic leukemia. In nine of these 11 patients, the underlying disease was present from one to seven years (mean 4.3 years) prior to the recognition of histoplasmosis. In one patient (Case 5), chronic lymphocytic leukemia and histoplasmosis were diagnosed concomitantly just prior to death. Another patient (Case 14) had chronic cavitary pulmonary histoplasmosis at least nine months before the diagnosis of chronic lymphocytic leukemia was established. The other five patients had received immunosuppressive therapy for systemic lupus erythematosus (three patients), sarcoidosis (one patient) and following renal transplantation (one patient). These five patients had their underlying disease for 0.3 to seven years (mean 1.8 years) before the onset of histoplasmosis. Immunosuppressive Therapy. Fourteen of 15 patients had received immunosuppressive drugs and/or radiation therapy prior to the development of histoplasmosis. (Case 14 is excluded from this analysis because the initial episode of histoplasmosis occurred before chronic lymphocytic leukemia developed). Three patients (Cases 1,2 and 12) had not received any immunosuppressive therapy for five months to three years prior to the development of histoplasmosis.
TABLE I
Characteristics
of Hlstoplasmosls
Thirteen patients were treated with corticosteroids; most received moderately large doses (20 to 60 mg prednisone daily). Two patients (Cases 4 and 9) received only corticosteroids prior to the development of histoplasmosis. Although some patients received corticosteroids intermittently as part of intensive combined chemotherapy (MOPP, COPP) for lymphoma or leukemia, seven patients received continuous therapy for three to 24 months (mean eight months) prior to the diagnosis of histoplasmosis. Twelve patients received cytotoxic agents. The patients with Hodgkin’s disease generally received combination chemotherapy, such as MOPP or COPP. All but one of the patients with nonmalignant disease received azathioprine, vinblastine or 6-mercaptopurine in addition to corticosteroids. The renal allograft recipient also received antilymphocyte globulin. Radiation therapy was administered to five patients. One patient (Case 1) received high-dosage extended field radiation therapy four years before the development of histoplasmosis; four patients (Case 2, 3, 6 and 12) received only low-dosage local radiation therapy nine to 36 months preceding the onset of histoplasmosis. Dissemlnated Histoplasmosis. Eleven of the 16 patients had disseminated infection-seven of these had Hodgkin’s disease or chronic lymphocytic leukemia, three had systemic lupus erythematosus, and one had sarcoidosis (group I, Table I). Eight were receiving immunosuppressive drugs when the diagnosis of histoplasmosis was made. All 11 patients were febrile (from 1Ol’F to 104’F) and had weight loss, weakness and fatigue. Symptoms pointing to specific organ involvement included cough and/or dyspnea in eight and painful mouth ulcerations or sore throat in three. One patient with central nervous system involvement had seizures and another with central nervous system histoplasmosis presented with headache and confusion. Splenomegaly and lymphadenopathy were described in five and six patients, respectively, and three patients had hepatomegaly. Rales were detected in three patients. The extent of dissemination of H. capsulatum was
in lmmunosuppressed
Patients lnitlal
Ca=
W (yr)
No.
and Sex
Undsrlying Disease
lmmunosuppresslve Therapy
Prsssntlng Symptoms
Organ Involvement
Method of Dlagnorls
Treatment
Outcome
Group I: Dlaeemlnrtod 1
28, F
Hodgkln’s disease
Extended field radlatlon, MOPP
2
54, M
Hodgkin’s disease
Local radlatlon
Hletoplaatnosls Fever, malaise, Bone marrow, cough, dyspnea liver Fever, welght Spleen, lungs, loss, confuslon, adrenals, braln, headache menlnges l
Continued 924
June 1978
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Bone marrow blopsy Necropsy
Amphotericln B (1.8 9) None
Survived
Died
HISTDPLA8MOSIS IN IMMUNOSUPPREGSEDPATIENTS-KAUFFMAN ET AL.
TABLE I (Cont’d.)
Case No.
AC (Y) and Sex
Chsracteristlcs of HistoplasmoslsIn ImmunosuppressedPatlents
Werfykrg Wssass
ImmunorupprOSSiVO
Prsssfltlng
TM+rspy
8rmptsms
Local radiation, MOPP, cyclophosphamide, vinblastine
Fever, dyspnea, cough, weakness
3
23, M
Hodgkin’s disease
4
51, F
5
66, M
Hodgkin’s Corticosteroids disease dose) Chronic lym- None phocytic leukemia
6
56. M
Organ Involvsrnsnl Bone marrow, liver, lungs, nodes, kidneys, adrenals, pancreas Spleen, nodes heart* Bone marrow, spleen, liver, lungs, adrenals, kidneys, brain, meninges’ Lungs, pharynx
lnftlal Mstflsd of DlsglOsfS
Tnstmsel
&lfcsms
Necropsy
None
Died
Necropsy
None
Died
Bone marrow culture
None
Died
l
7
50, F
8
65, M
9
23, F
10
35, M
11
41, F
Chronic lymphocytic leukemia Chronic lymphocytic leukemia Systemic lupus erythernatosus Systemic lupus erythematosus Systemic lupus erythematosus Sarcoidosis
(low
Local radiation, COPP, corticosteroids (low dose) COP, chlorambucil, corticosteroids (high dose)
Fever, fatigue, dyspnea Fever, malaise, weight loss
Fever, cough, fatigue, sore throat
Pharyngeal mass biopsy
Amphotericin B
survived
(2.6 g)
Fever, weakness, Lungs, adrenals, cough, dyspnea bone marrow (probable)?
Blood culturet
6_mercaptopurine, corticosteroids (high dose)
Fever, fatigue, dyspnea
Bone marrow, spleen, liver, lungs, kidneys’
Bone marrow biopsy
Corticosteroids (high dose)
Fever, malaise, weight loss
Bone marrow, liver, lungs
Liver biopsy
None
Amphotericin B
Died
Died
(39 mg) Amphotericin B
Survived
(1.5 9) 6-mercaptopurine, corticosteroids (high dose)
Fever, malaise, weight loss, dyspnea
Azathioprine, vincristine, vinblastine, corticosteroids (low dose)
Fever, fatigue, Lung, liver, bone dyspnea, mouth marrow ulcers
Lungs, kidneys, brain*
l
Necropsy
None
Lung biopsy, bone Amphomarrow biopsy tericin B
Died
Died
(440 mg)
GroupII: Pulmonary Histoplasmosls 12
48, M
Hodgkin’s disease
13
24, F
Hodgkin’s disease Chronic Chlorambucil lymphocytic leukemia Chronic Chlorambucil, lymphocytic corticosteroids leukemia (low dose) Renal Azathioprine, transplant corticosteroids (high dose), antilymphocyte globulin
14
46, M
15
76, M
16
54, F
Local radiation, nitrogen mustard, corticosteroids (low dose) MOPP, vinblastine
None
Fever, weakness, dyspnea
Lungs-diffuse*
Necropsy
Cough, weight loss Cough
Lungs-LUL
Lung biopsy
Amphotericin
Survived
Sputum culture
B (1.7 g) Amphotericin
Survived
Lungs-RUL
cavitary
Died
B (1.9 g) Fever, cough
Mediastinal nodes, lungs’
Necropsy
Fever, cough, dyspnea
Lungs-diffuse
Lung biopsy, transtracheal aspirate
None
Amphotericin
Died
Survived
B(t.4g)
NOTE: MOPP = nitrogen mustard, oncovin, prednisone, procarbazine; COPP = cytoxan. oncovin, prednlsone, procarbarine; COP = cytoxan, oncovin, prednisone. *Confirmed at necropsy. 7 No necropsy performed to conflrm adrenal and bone marrow involvement. t Positive culture reported after patient had died.
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HISTOPLASMOSIS IN IMMUNOSUPPRESSEDPATIENTS-KAWFMAN
ET AL.
demonstrated in the seven patients in whom necropsies were performed-extensive multiplication of organisms in the bone marrow, spleen, liver and lungs was found in almost all patients. Additionally, four patients had renal involvement, three had adrenal involvement, three had H. capsulatum demonstrated in the brain and/or meninges, and one each had organisms in the pancreas and myocardium. Pulmonary Histoplasmosis. In five patients-two each with Hodgkin’s disease and chronic lymphocytic leukemia and one who had received a renal allografthistoplasmosis was clinically confined to the respiratory tract (group II, Table I). Four of these five patients had received immunosuppressive therapy before the onset of histoplasmosis. One patient (Case 14) differed in that he had a previous history of treated chronic cavitary pulmonary histoplasmosis and the relapse of histoplasmosis occurred after the onset of chronic lymphocytic leukemia. The symptoms manifested by these patients were predominantly fever, cough and dyspnea. Pulmonary symptoms in three patients (Case 12, 13 and 14) led to their hospitalization but were never considered severe. One patient (Case 16) had acute respiratory distress secondary to diffuse pulmonary histoplasmosis. The initial clinical diagnosis in this patient was Pneumocystis carinii pneumonitis. One patient (Case 15) died of Pseudomonas pneumonia and septicemia, and pulmonary histoplasmosis was discovered at necropsy. It is unclear which, if any, symptoms were due to histoplasmosis in this patient. Objective findings of lung disease in these patients were not prominent. Rales were present in three patients, and signs of consolidation were not apparent in any case. Clubbing and cyanosis did not occur. Laboratory Findings. Chest roentgenograms were abnormal in 13 of the 16 patients. The most common roentgenographic manifestation of histoplasmosis was the occurrence of diffuse interstitial infiltrates in eight patients. Nodular lesions of varying sizes and patchy infiltrates were found in another five patients; in two patients cavities developed within the infiltrate. Significant anemia was common (12 patients), but it was present before the development of infection in at least seven patients. Three patients had granulocytopenia (< 1,500 neutrophils/mm3): two with chronic lymphocytic leukemia and one with systemic lupus erythematosus. One of the three patients with granulocytopenia had localized pulmonary histoplasmosis, whereas the other two had disseminated disease. Lymphocytopenia ( 16 mg/
kg. t One patient who survived received saramycetin in addition to sulfonamides.
ture are often necessary for initial diagnosis in very ill patients. Direct pathologic examination of infected tissue is the most useful procedure. Several investigators have emphasized the value of bone marrow aspiration in patients with disseminated histoplasmosis [ 12,17,32]. This proved to be the most useful test in the 34 patients in whom histoplasmosis was found antemortem (Table V). In 12 patients, the presence of typical intracellular yeast forms of H. capsulatum in bone marrow specimens stained with Giemsa or methenamine silver stains led to the diagnosis of histoplasmosis. Cultures of bone marrow were positive in six additional patients in whom morphologic examination failed to reveal H. capsulatum. Biopsy of other tissues (lung, liver, lymph nodes, skin, oral tissues and blood smears) yielded the diagnosis in another 11 patients. Serologic methods, using either the standard complement fixation test or precipitin tests have been very helpful in the diagnosis of histoplasmosis in the normal host. However, in immunosuppressed patients, serologic studies proved to be of little value. Only 11 of 26 (42 per cent) patients in whom serum complement fixation tests were performed had titers 11:16. This contrasts with the data of Deresinski and Stevens [6] who found that serology was usually positive in immunosuppressed patients with coccidioidomycosis. Histoplasmin skin testing, although a useful epide-
miologic tool, is of limited value in the diagnosis of individual cases of histoplasmosis in an endemic area. In immunosuppressed patients with histoplasmosis, skin testing appears to be of even less value. Only three of 22 patients, all of whom had disseminated disease, showed a positive reaction. Treatment and Outcome. Treatment was detailed in 53 of the 58 patients (Table VI). Twenty-five patients, including 21 in whom the diagnosis was established after death, received no therapy, and all 25 died. In two of these patients, histoplasmosis was localized to the lungs. Ten patients, all of whom had disseminated infection, were treated with 1 g or less of amphotericin B, including six who received less than 100 mg. All 10 patients died, and the nine who underwent necropsy examination had evidence of active histoplasmosis. Fifteen patients, 12 of whom had disseminated disease, received more than 1 g or 16 mg/kg amphotericin B. One patient with disseminated histoplasmosis died, and one child with acute lymphocytic leukemia and disseminated infection had a relapse twice after two separate short courses of amphotericin B therapy [ 171. Although two to three weeks of amphotericin B therapy is often effective in children with disseminated histoplasmosis, the failure to cure this child emphasizes that this type of therapy should not be given to immunosuppressed patients. Not one of the other 13 patients who received a full course of antifungal therapy had a relapse even though many later died of their underlying disease. If the diagnosis of histoplasmosis can be established early enough so that a full course of antifungal therapy can be given, our data suggest that mortality in immunosuppressed patients is quite low and relapse is not expected. This is in marked contrast to the reported mortality in immunosuppressed patients with infection due to Aspergillus [3,51] the phycomycetes [5] or C. immitis [6]. ADDENDUM Since preparation of this manuscript 11 additional cases of histoplasmosis in immunosuppressed patients have been reported [86-881.
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Histoplasmosis in lmmunosuppressed Patients
CAROL A. KAUFFMAN,
M.D.*
Cincinnati, Ohio KAREN S. ISRAEL, M.D.+ Indianapolis,
Indiana
JAMES W. SMITH, M.D. Indianapolis,
Indiana
ARTHUR C. WHITE, M.D. Indianapolis, Indiana JAN SCHWARZ,
M.D.
Cincinnati, Ohio GEORGE F. BROOKS, M.D.t Indianapolis,
Indiana
From the Division of Infectious Diseases, Cincinnati Veterans Administration Hospital and University of Cincinnati Medical Center; the Department of Pathology, Jewish Hospital and University of Cincinnati Medical Center, Cincinnati, Ohio: Division of Infectious Diseases, Indiana University Medical Center; and Department of Pathology, Indianapolis Veterans Administration Hospital and Indiana University Medical Center, Indianapolis, Indiana. Requests for reprints should be addressed to Dr. Carol A. Kauffman. Manuscript accepted November 11, 1977. Present address: Infectious Disease Service, Veterans Administration Hospital, Ann Arbor, Michigan 48105. + Present address: Lilly Research Laboratories, Indianapolis, Indiana 46202. t Present address: Infectious Disease Service, Veterans Administration Hospital, Martinez, California. l
Infection with Hi&plasma capsulatum in 58 patients whose immune responses were suppressed (Immunosuppressed patients) (18 from the present series and 42 described previously) was analyzed. The most common underlying diseases were Hodgkin’s dtsease (29 per cent), chronic lymphocytlc leukemia (19 per cent) and acute lymphocytic leukemia (17 per cent). Sixty-three per cent of the pattents had received cytotoxlc drugs, and 57 per cent had taken corticosteroids. Widely disseminated Infection occurred In 88 per cent of the patients, with predominant involvement of lungs and organs of the retlculoendothelial system. Localized pulmonary infection was present in the remaining patients. The most useful diagnostic method was bone marrow biopsy with microscopic examination for the intracellular yeast form of H. capsulatum. Biopsy of oral lesions, lung, liver and lymph noUe also proved diagnostically helpful. Growth of H. capsulatum In culture was frequently too stow to be beneftcial in dtagnoskq htstopl&mosts in ill patients. Serologic methods were of ltttle dlagnostlc help In this population of immunosuppressed patients. The response to amphoterlcln B therapy was excellent (8.7 per cent mortality rate) In those patients in whom the dlagnosts was established early and in whom a full course of antlfungal therapy could be given. In contrast, the mortality rate in patlents who recelved no antifungal therapy or less than 1 g of amphotericin B was 100 per cent. Fungal infections have become an increasingly severe problem in the immunologically compromised host [ 1,2]. The pathogenesis of infections due to opportunists such as Aspergillus [3], Candida [4] and the phycomycetes [5] has been extensively studied in many patients who are immunosuppressed. However, infections with usually pathogenic fungi have only recently been studied in the immunologically compromised patient [6]. The natural history of histoplasmosis in immunosuppressed patients is not well-documented; most reports are single case studies [7-361; the largest series consists of six children with acute leukemia [ 131. We report here our observations of active histoplasmosis in 16 immunologically compromised adult patients and review the English literature dealing with histoplasmosis in the immunologically compromised host. METHODS The medical records of 16 immunologically compromised adult patients with
histoplasmosis were reviewed. The patients were seen between September 1953 and December 1975 at the Indiana University Medical Center (12 pa-
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HISTOPLASMOSIS
IN IMMUNOSUPPRESSED PATIENTS-KAUFFMAN
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tients) and the University of Cincinnati Medical Center (four patients). Eight of the 16 cases occurred between 1970 and 1975. Immunologically compromised patients were those who met one or both of the following criteria: (1) patients with a hematologic malignancy, (2) patients treated with immunosuppressive drugs (corticosteroids and/or cytotoxic drugs) and/or radiation therapy for at least three months prior to the diagnosis of histoplasmosis. The diagnosis of histoplasmosis was made if patients had a clinical illness compatible with active disease and at least one of the following: (1) a positive culture from any site for H. capsulatum, (2) a biopsy specimen showing the characteristic intracellular yeast form of H. capsulatum. RESULTS
General
Characteristics
and Underlying
Diseases.
The 16 patients with histoplasmosis ranged in age from
23 to 76 years (Table I). Nine were men and seven women. Six patients had stage IV Hodgkin’s disease, and five had chronic lymphocytic leukemia. In nine of these 11 patients, the underlying disease was present from one to seven years (mean 4.3 years) prior to the recognition of histoplasmosis. In one patient (Case 5), chronic lymphocytic leukemia and histoplasmosis were diagnosed concomitantly just prior to death. Another patient (Case 14) had chronic cavitary pulmonary histoplasmosis at least nine months before the diagnosis of chronic lymphocytic leukemia was established. The other five patients had received immunosuppressive therapy for systemic lupus erythematosus (three patients), sarcoidosis (one patient) and following renal transplantation (one patient). These five patients had their underlying disease for 0.3 to seven years (mean 1.8 years) before the onset of histoplasmosis. Immunosuppressive Therapy. Fourteen of 15 patients had received immunosuppressive drugs and/or radiation therapy prior to the development of histoplasmosis. (Case 14 is excluded from this analysis because the initial episode of histoplasmosis occurred before chronic lymphocytic leukemia developed). Three patients (Cases 1,2 and 12) had not received any immunosuppressive therapy for five months to three years prior to the development of histoplasmosis.
TABLE I
Characteristics
of Hlstoplasmosls
Thirteen patients were treated with corticosteroids; most received moderately large doses (20 to 60 mg prednisone daily). Two patients (Cases 4 and 9) received only corticosteroids prior to the development of histoplasmosis. Although some patients received corticosteroids intermittently as part of intensive combined chemotherapy (MOPP, COPP) for lymphoma or leukemia, seven patients received continuous therapy for three to 24 months (mean eight months) prior to the diagnosis of histoplasmosis. Twelve patients received cytotoxic agents. The patients with Hodgkin’s disease generally received combination chemotherapy, such as MOPP or COPP. All but one of the patients with nonmalignant disease received azathioprine, vinblastine or 6-mercaptopurine in addition to corticosteroids. The renal allograft recipient also received antilymphocyte globulin. Radiation therapy was administered to five patients. One patient (Case 1) received high-dosage extended field radiation therapy four years before the development of histoplasmosis; four patients (Case 2, 3, 6 and 12) received only low-dosage local radiation therapy nine to 36 months preceding the onset of histoplasmosis. Dissemlnated Histoplasmosis. Eleven of the 16 patients had disseminated infection-seven of these had Hodgkin’s disease or chronic lymphocytic leukemia, three had systemic lupus erythematosus, and one had sarcoidosis (group I, Table I). Eight were receiving immunosuppressive drugs when the diagnosis of histoplasmosis was made. All 11 patients were febrile (from 1Ol’F to 104’F) and had weight loss, weakness and fatigue. Symptoms pointing to specific organ involvement included cough and/or dyspnea in eight and painful mouth ulcerations or sore throat in three. One patient with central nervous system involvement had seizures and another with central nervous system histoplasmosis presented with headache and confusion. Splenomegaly and lymphadenopathy were described in five and six patients, respectively, and three patients had hepatomegaly. Rales were detected in three patients. The extent of dissemination of H. capsulatum was
in lmmunosuppressed
Patients lnitlal
Ca=
W (yr)
No.
and Sex
Undsrlying Disease
lmmunosuppresslve Therapy
Prsssntlng Symptoms
Organ Involvement
Method of Dlagnorls
Treatment
Outcome
Group I: Dlaeemlnrtod 1
28, F
Hodgkln’s disease
Extended field radlatlon, MOPP
2
54, M
Hodgkin’s disease
Local radlatlon
Hletoplaatnosls Fever, malaise, Bone marrow, cough, dyspnea liver Fever, welght Spleen, lungs, loss, confuslon, adrenals, braln, headache menlnges l
Continued 924
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Bone marrow blopsy Necropsy
Amphotericln B (1.8 9) None
Survived
Died
HISTDPLA8MOSIS IN IMMUNOSUPPREGSEDPATIENTS-KAUFFMAN ET AL.
TABLE I (Cont’d.)
Case No.
AC (Y) and Sex
Chsracteristlcs of HistoplasmoslsIn ImmunosuppressedPatlents
Werfykrg Wssass
ImmunorupprOSSiVO
Prsssfltlng
TM+rspy
8rmptsms
Local radiation, MOPP, cyclophosphamide, vinblastine
Fever, dyspnea, cough, weakness
3
23, M
Hodgkin’s disease
4
51, F
5
66, M
Hodgkin’s Corticosteroids disease dose) Chronic lym- None phocytic leukemia
6
56. M
Organ Involvsrnsnl Bone marrow, liver, lungs, nodes, kidneys, adrenals, pancreas Spleen, nodes heart* Bone marrow, spleen, liver, lungs, adrenals, kidneys, brain, meninges’ Lungs, pharynx
lnftlal Mstflsd of DlsglOsfS
Tnstmsel
&lfcsms
Necropsy
None
Died
Necropsy
None
Died
Bone marrow culture
None
Died
l
7
50, F
8
65, M
9
23, F
10
35, M
11
41, F
Chronic lymphocytic leukemia Chronic lymphocytic leukemia Systemic lupus erythernatosus Systemic lupus erythematosus Systemic lupus erythematosus Sarcoidosis
(low
Local radiation, COPP, corticosteroids (low dose) COP, chlorambucil, corticosteroids (high dose)
Fever, fatigue, dyspnea Fever, malaise, weight loss
Fever, cough, fatigue, sore throat
Pharyngeal mass biopsy
Amphotericin B
survived
(2.6 g)
Fever, weakness, Lungs, adrenals, cough, dyspnea bone marrow (probable)?
Blood culturet
6_mercaptopurine, corticosteroids (high dose)
Fever, fatigue, dyspnea
Bone marrow, spleen, liver, lungs, kidneys’
Bone marrow biopsy
Corticosteroids (high dose)
Fever, malaise, weight loss
Bone marrow, liver, lungs
Liver biopsy
None
Amphotericin B
Died
Died
(39 mg) Amphotericin B
Survived
(1.5 9) 6-mercaptopurine, corticosteroids (high dose)
Fever, malaise, weight loss, dyspnea
Azathioprine, vincristine, vinblastine, corticosteroids (low dose)
Fever, fatigue, Lung, liver, bone dyspnea, mouth marrow ulcers
Lungs, kidneys, brain*
l
Necropsy
None
Lung biopsy, bone Amphomarrow biopsy tericin B
Died
Died
(440 mg)
GroupII: Pulmonary Histoplasmosls 12
48, M
Hodgkin’s disease
13
24, F
Hodgkin’s disease Chronic Chlorambucil lymphocytic leukemia Chronic Chlorambucil, lymphocytic corticosteroids leukemia (low dose) Renal Azathioprine, transplant corticosteroids (high dose), antilymphocyte globulin
14
46, M
15
76, M
16
54, F
Local radiation, nitrogen mustard, corticosteroids (low dose) MOPP, vinblastine
None
Fever, weakness, dyspnea
Lungs-diffuse*
Necropsy
Cough, weight loss Cough
Lungs-LUL
Lung biopsy
Amphotericin
Survived
Sputum culture
B (1.7 g) Amphotericin
Survived
Lungs-RUL
cavitary
Died
B (1.9 g) Fever, cough
Mediastinal nodes, lungs’
Necropsy
Fever, cough, dyspnea
Lungs-diffuse
Lung biopsy, transtracheal aspirate
None
Amphotericin
Died
Survived
B(t.4g)
NOTE: MOPP = nitrogen mustard, oncovin, prednisone, procarbazine; COPP = cytoxan. oncovin, prednlsone, procarbarine; COP = cytoxan, oncovin, prednisone. *Confirmed at necropsy. 7 No necropsy performed to conflrm adrenal and bone marrow involvement. t Positive culture reported after patient had died.
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ET AL.
demonstrated in the seven patients in whom necropsies were performed-extensive multiplication of organisms in the bone marrow, spleen, liver and lungs was found in almost all patients. Additionally, four patients had renal involvement, three had adrenal involvement, three had H. capsulatum demonstrated in the brain and/or meninges, and one each had organisms in the pancreas and myocardium. Pulmonary Histoplasmosis. In five patients-two each with Hodgkin’s disease and chronic lymphocytic leukemia and one who had received a renal allografthistoplasmosis was clinically confined to the respiratory tract (group II, Table I). Four of these five patients had received immunosuppressive therapy before the onset of histoplasmosis. One patient (Case 14) differed in that he had a previous history of treated chronic cavitary pulmonary histoplasmosis and the relapse of histoplasmosis occurred after the onset of chronic lymphocytic leukemia. The symptoms manifested by these patients were predominantly fever, cough and dyspnea. Pulmonary symptoms in three patients (Case 12, 13 and 14) led to their hospitalization but were never considered severe. One patient (Case 16) had acute respiratory distress secondary to diffuse pulmonary histoplasmosis. The initial clinical diagnosis in this patient was Pneumocystis carinii pneumonitis. One patient (Case 15) died of Pseudomonas pneumonia and septicemia, and pulmonary histoplasmosis was discovered at necropsy. It is unclear which, if any, symptoms were due to histoplasmosis in this patient. Objective findings of lung disease in these patients were not prominent. Rales were present in three patients, and signs of consolidation were not apparent in any case. Clubbing and cyanosis did not occur. Laboratory Findings. Chest roentgenograms were abnormal in 13 of the 16 patients. The most common roentgenographic manifestation of histoplasmosis was the occurrence of diffuse interstitial infiltrates in eight patients. Nodular lesions of varying sizes and patchy infiltrates were found in another five patients; in two patients cavities developed within the infiltrate. Significant anemia was common (12 patients), but it was present before the development of infection in at least seven patients. Three patients had granulocytopenia (< 1,500 neutrophils/mm3): two with chronic lymphocytic leukemia and one with systemic lupus erythematosus. One of the three patients with granulocytopenia had localized pulmonary histoplasmosis, whereas the other two had disseminated disease. Lymphocytopenia ( 16 mg/
kg. t One patient who survived received saramycetin in addition to sulfonamides.
ture are often necessary for initial diagnosis in very ill patients. Direct pathologic examination of infected tissue is the most useful procedure. Several investigators have emphasized the value of bone marrow aspiration in patients with disseminated histoplasmosis [ 12,17,32]. This proved to be the most useful test in the 34 patients in whom histoplasmosis was found antemortem (Table V). In 12 patients, the presence of typical intracellular yeast forms of H. capsulatum in bone marrow specimens stained with Giemsa or methenamine silver stains led to the diagnosis of histoplasmosis. Cultures of bone marrow were positive in six additional patients in whom morphologic examination failed to reveal H. capsulatum. Biopsy of other tissues (lung, liver, lymph nodes, skin, oral tissues and blood smears) yielded the diagnosis in another 11 patients. Serologic methods, using either the standard complement fixation test or precipitin tests have been very helpful in the diagnosis of histoplasmosis in the normal host. However, in immunosuppressed patients, serologic studies proved to be of little value. Only 11 of 26 (42 per cent) patients in whom serum complement fixation tests were performed had titers 11:16. This contrasts with the data of Deresinski and Stevens [6] who found that serology was usually positive in immunosuppressed patients with coccidioidomycosis. Histoplasmin skin testing, although a useful epide-
miologic tool, is of limited value in the diagnosis of individual cases of histoplasmosis in an endemic area. In immunosuppressed patients with histoplasmosis, skin testing appears to be of even less value. Only three of 22 patients, all of whom had disseminated disease, showed a positive reaction. Treatment and Outcome. Treatment was detailed in 53 of the 58 patients (Table VI). Twenty-five patients, including 21 in whom the diagnosis was established after death, received no therapy, and all 25 died. In two of these patients, histoplasmosis was localized to the lungs. Ten patients, all of whom had disseminated infection, were treated with 1 g or less of amphotericin B, including six who received less than 100 mg. All 10 patients died, and the nine who underwent necropsy examination had evidence of active histoplasmosis. Fifteen patients, 12 of whom had disseminated disease, received more than 1 g or 16 mg/kg amphotericin B. One patient with disseminated histoplasmosis died, and one child with acute lymphocytic leukemia and disseminated infection had a relapse twice after two separate short courses of amphotericin B therapy [ 171. Although two to three weeks of amphotericin B therapy is often effective in children with disseminated histoplasmosis, the failure to cure this child emphasizes that this type of therapy should not be given to immunosuppressed patients. Not one of the other 13 patients who received a full course of antifungal therapy had a relapse even though many later died of their underlying disease. If the diagnosis of histoplasmosis can be established early enough so that a full course of antifungal therapy can be given, our data suggest that mortality in immunosuppressed patients is quite low and relapse is not expected. This is in marked contrast to the reported mortality in immunosuppressed patients with infection due to Aspergillus [3,51] the phycomycetes [5] or C. immitis [6]. ADDENDUM Since preparation of this manuscript 11 additional cases of histoplasmosis in immunosuppressed patients have been reported [86-881.
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