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Disseminated histoplasmosis presenting as an acute tenosynovitis
251
DLAGN MICROBIALINFECT DIS 1985;3:251-255
CASE REPORTS
Disseminated Histoplasmosis Presenting as an Acute Tenosynovitis Michael A. Pfaller, Michael Kyriakos, Paul M. Weeks, and George S. Kobayashi
Disseminated histoplasmosis is usually a mtdtifocal process with a wide variety of clinical presentations. Despite frequent bone marrow involvement, overt bone and joint disease is uncommon and isolated synovial involvement is extremely rare. We describe in this report an unusual case of disseminated histoplasmosis presenting as acute tenosynovitis. To our knowledge, this is only the second reported case of synovial involvement by H. capsulatum without a concomitant osseous lesion.
The protean clinical manifestations of histoplasmosis have been the subject of numerous case reports and review articles (Goodwin et al., 1980; Goodwin et al., 1981; Silverman et al., 1955}. In contrast to the other systemic mycoses, sporotrichosis blastomycosis and coccidioidomycosis, disseminated histoplasmosis rarely presents with overt bone or joint disease despite ~ e frequent involvement of the bone marrow (Goodwin et el., 1980; Jones and Goodwin, 1981; Perlman et al., 1972}. In addition, there has been only one previous report of gynovial involvement by Histoplosma capsulatum without a concomitant osseous lesion (Perlman et el., 1972}. We describe in this report an immunosuppressed patient who presented with an acute tenosynovitis due to involvement of the digital synovium by H. capsulatum. Case Report. A 48-year-old female resident' of Missouri was admitted to Barnes Hospital with a chief complaint of progressive swelling and stiffness of her left hand. Several years previously, the patient had been diagnosed as having systemic lupus erythematosus (SLE) and was started on methylprednisolone (16 mg/day) and azathioprine (150 mg/day), with a g o o d clinical response. Six months prior to admission, the patient noted a tender swelling on the lateral aspect of her left third finger. There was no history of trauma preceding the development of the lesion. During the next 4 months, progressive pain, stiffness, swelling, and erythema developed over the palmar aspect of her left hand. In addition, she noted that her left ankle had become swollen and tender. Azathioprine was continued and the methylprednisolone was increased to 40 mg/day, without relief of her symptoms. The patient began to complain of generalized malaise, fatigue, and arthralgias; From the Division of Laboratory Medicine, Departments of Medicine and Pathology, (M.A.P.,
M.K., G.S.K.), and Division of Plastic Surgery, Department of Surgery {P.M.W.), Washington University School of Medicine, St. Louis, Missouri. Address ~print requests to: Michael A. Pfaller, M.D., Department of Pathology, University of Iowa Hospitals & Clinics, Iowa City, IA 52242. Received June 12, 1984; revised and accepted August 8, 1984. © 1985 Elsevier Science Publishing Co., Inc. 52 Vanderbilt Avenue, New York, NY 10017
0732-8893/85/$03.30
252
M.A. Pfaller et al.
she was a d m i t t e d to the hospital w h e n she was noted to have temperatures to 101°C with a c c o m p a n y i n g chills. On admission, the left h a n d was warm, with induration and erythema over the m i d d l e and distal palm; there was marked tenderness over the flexor t e n d o n of the third finger. A 2.0 x 3.0-cm mass was palpable at the base of the volar aspect of the third finger. A 1.0-cm fluctuant, n o n t e n d e r n o d u l e was present over the lateral aspect of the distal p h a l a n x of the third finger (Figure 1). No ulceration was present. Active and passive m o t i o n of the fingers was limited because of pain and swelling. The dorsal aspect of the left foot was also swollen, tender, and erythematous. A chest roentgenogram was normal, and radiologic studies of the left h a n d and foot s h o w e d soft tissue swelling. It was felt that the patient had tenosynovitis and that an exploration of the p a l m a r space should be performed. At operation, the p a l m a r fascia was found to be m a r k e d l y attenuated by a redgray mass in the palm. The mass c o m p l e t e l y encircled the flexor tendons of the third finger. Dissection to the level of the flexor t e n d o n showed the mass to be attached to the s u b l i m u s tendon. The mass was c o m p l e t e l y excised, sparing the tendons. The n o d u l e on the distal aspect of the third finger was incised, and a small a m o u n t of yellow-gray fluid was drained and sent for culture. Microscopic e x a m i n a t i o n of the palmar mass showed skeletal muscle and some nonspecific necrotic soft tissue. Throughout the muscle, there was an inflammatory infiltrate c o m p o s e d of histiocytes, p o l y m o r p h o n u c l e a r leukocytes, and lymphocytes. No granulomas were seen. The most striking feature was that the c y t o p l a s m of vir-
FIGURE 1. Preoperative appearance of the involved hand showing swelling of the long finger with extension over the palmar aspect of the hand. The fluctuant nodule is also evident over the distal phalanx of the third finger.
Disseminated Histoplasmosis
253
tually every histiocyte was filled by numerous small, basophilic, uniformly shaped organisms, each of which was surrounded by a clear zone (Figure 2}. These were easily seen on hematoxylin and eosin sections, and they stained with Gomori's methenamine-silver stain. Their morphology was consistent with H. capsulatum. Cultures of the palmar mass and the fluid from the distal phalangeal nodule and a needle aspirate of fluid from the swelling over the left foot grew H. capsulatum. A bone marrow biopsy and aspirate was performed on the day before surgery; although microscopic examination of the biopsy was negative, a culture grew H. capsulatum. Multiple blood cultures were performed, using a vented bottle containing broth {tryptic soy broth); all were negative after prolonged (30-day} incubation. Sera obtained on admission revealed a compliment fixation titer to H. capsulatum yeast phase antigen {CFY) of less than 1 : 8. On the basis of the microscopic findings, amphotericin B therapy was begun immediately, with an inital dose of I mg/day increasing over 4 days to 20 mg/day (0.35 mg/kg). The patient received a total of 336 mg of amphotericin B over the next 4 weeks and responded slowly, with persistent erythema and swelling of her hand. The left foot continued to be swollen, tender, and erythematous, and was considered to be a site of active H. capsulatum infection in spite of amphotericin B therapy. The patient was considered to have active SLE, as well as disseminated histoplasmosis, with increasingly severe lupus nephritis. Corticosteroids were required throughout her hospital course in an attempt to limit her progressive renal failure. Despite these measures, the renal function continued to deteriorate while she was on amphotericin B, necessitating discontinuation of the drug after a total of 336 mg
FIGURE 2. Histiocytic cells Whose cytoplasm is filled by small, uniformly shaped organisms are seen (hematoxylin and eosin, × 600}. (Insert) Higher magnification view shows that each organism is surrounded by an artifactual clear zone (hematoxylin and eosin, x 1500).
254
M.A. Pfaller et al.
had been administered. Serologic studies at that time showed an increase in CFY titer to 1 : 64. Repeat cultures of the left foot and of the bone marrow were negative for H. capsulatum. Because of the patient's renal status and her slow clinical response to amphotericin B, the decision was made to treat her with miconazole nitrate (15 mg/kg twice daily). During the course of the miconazole therapy, there appeared to be some resolution of the erythema and swelling in the hand and foot. Repeat bone marrow cultures were consistently negative. Serologic studies showed a further increase in CFY titer to 1 : 256 and then a subsequent decrease to 1 : 8 over a 1-month period. Unfortunately, the patient expired due to multiple severe complications of her SLE. An autopsy showed marked interstitial pneumonitis composed predominantly of histiocytes and mononuclear cells; however, no organisms or granulomas were found. Neither were organisms or granulomata seen in sections of the liver, spleen, or kidneys. All postmortem cultures were negative for H. capsulatum. DISCUSSION Infection with H. capsulatum is usually a benign localized pulmonary process and virtually all residents in highly endemic areas have been infected at one time or another (Goodwin et al., 1981; Silverman et al., 1955; Wheat et al., 1981). Rarely, H. capsulatum may cause disseminated disease, which may be fatal if inadequately treated (Goodwin et al., 1980). Dissemination of histoplasmosis is usually hematogenous and results in multifocal organ involvement (Goodwin et al., 1980; Silverman et al., 1955). Focal lesions occurring in bone or synovium are extremely rare despite the high incidence of bone marrow involvement (Bayer et al., 1980; Jones and Goodwin, 1981). We found only one reported case of isolated synovial involvement unassociated with bone involvement (Perlman et al., 1972). The patient was a 24-year-old man who presented with carpal tunnel syndrome caused by involvement with H. capsulatum. This patient differed from ours in that he had no underlying disease and no other evidence of disseminated histoplasmosis. The clinical presentation was typical of carpal tunnel syndrome and quite different from the acute tenosynovitis present in our patient. Successful management was obtained by synovectomy and administration of amphotericin B therapy. Of major concern in our patient was her compromised immunologic state. Although H. capsulatum is generally considered a primary pathogen capable of causing disseminated disease in patients without known predisposing conditions, there is mounting evidence that progressive disseminated infection may result from abnormalities in the host (Davies et al., 1978; Kauffman et al., 1978). Several authors have noted the association of disseminated histoplasmosis with the administration of glucocorticoids or other immunosuppressive drugs (Davies et al., 1978; Kauffman et al., 1978; Sieving et al., 1975; Watson et al., 1968). Kauffman et al, (1978) stress that although there is no conclusive evidence for an increased prevalence of this disease in immunosuppressed patients, it appears that there is a propensity for more severe infection to occur in these hosts. Our patient is an example of an unusual presentation of disseminated histoplasmosis. As discussed above, synovial involvement with H. capsulatum is extremely rare. The combination of this rare presentation and the clinical setting of systemic lupus erythematosus and immunosuppressive therapy presented a confusing picture and masked the signs and symptoms of histoplasmosis, thus delaying the diagnosis until the organism was demonstrated histologically. The patient's demise was due to multiple complications of her severe SLE and probably not due to disseminated
Disseminated Histoplasmosis
255
histoplasmosis. The falling serologic titers and conversion of bone marrow cultures from positive to negative suggests that she had received adequate antifungal t h e r a p y although a d m i n i s t r a t i o n of a m p h o t e r i c i n B therapy was c o m p r o m i s e d by her progressive renal failure. We feel that the consideration of d i s s e m i n a t e d histoplasmosis s h o u l d be entertained in i m m u n o s u p p r e s s e d patients w i t h focal inflammatory lesions u n r e s p o n s i v e to usual therapeutic measures, especially if they have been in an endemic area. This work was supported in part by training grant 1-T32-AI 07172 from the National Institute of Allergy and Infectious Diseases. REFERENCES Bayer AS, Choi C, Tillman DB, Guze LB (1980) Fungal arthritis. V. Cryptococcal and histoplasmal arthritis. Semin Arthritis Rheum 9:218. Davies SF, Khan M, Sarosi GA (1978) Disseminated histoplasmosis in immunologically suppressed patients. Occurrence in a nonendemic area. Am J Med 64:94. Goodwin RA Jr, Shapiro JL, Thurman GH, Thurman SS, Des Prez RM (1980) Disseminated histoplasmosis: Clinical and pathological correlations. Medicine (Baltimore) 59:1. Goodwin RA, Loyd JE, Des Prez RM (1981) Histoplasmosis in normal hosts. Medicine (Baltimore) 60:231. Jones RC, Goodwin RA Jr (1981) Histoplasmosis of bone. Am J Med 70:864. Kauffman CA, Israel KS, Smith JW, White AC, Schwarz J, Brooks GF (1978) Histoplasmosis in immunosuppressed patients. Am J Med 64:923. Perlman R, Jubelirer RA, Schwarz J (1972) Histoplasmosis of the common palmar tendon sheath. J Bone Joint Surg 54-A(3):676. Sieving RR, Kauffman CA, Watanakunakorn C (1975) Deep fungal infection in systemic lupus erythematosus. J Rheumatol 2:61. Silverman FN, Schwarz J, Lahey ME, Carson RP (1955) Histoplasmosis. Am J Med 19:410. Watson JI, Mandl MAJ, Rose B (1968) Disseminated histoplasmosis occurring in association with systemic lupus erythematosus. Can Med Assac J 99:958. Wheat LJ, Slama TG, Eitzen HE, Kohler RB, French MLV, Biesecker JL (1981) A large urban outbreak of histoplasmosis: Clinical features. Ann Intern Med 94:331.
DLAGN MICROBIALINFECT DIS 1985;3:251-255
CASE REPORTS
Disseminated Histoplasmosis Presenting as an Acute Tenosynovitis Michael A. Pfaller, Michael Kyriakos, Paul M. Weeks, and George S. Kobayashi
Disseminated histoplasmosis is usually a mtdtifocal process with a wide variety of clinical presentations. Despite frequent bone marrow involvement, overt bone and joint disease is uncommon and isolated synovial involvement is extremely rare. We describe in this report an unusual case of disseminated histoplasmosis presenting as acute tenosynovitis. To our knowledge, this is only the second reported case of synovial involvement by H. capsulatum without a concomitant osseous lesion.
The protean clinical manifestations of histoplasmosis have been the subject of numerous case reports and review articles (Goodwin et al., 1980; Goodwin et al., 1981; Silverman et al., 1955}. In contrast to the other systemic mycoses, sporotrichosis blastomycosis and coccidioidomycosis, disseminated histoplasmosis rarely presents with overt bone or joint disease despite ~ e frequent involvement of the bone marrow (Goodwin et el., 1980; Jones and Goodwin, 1981; Perlman et al., 1972}. In addition, there has been only one previous report of gynovial involvement by Histoplosma capsulatum without a concomitant osseous lesion (Perlman et el., 1972}. We describe in this report an immunosuppressed patient who presented with an acute tenosynovitis due to involvement of the digital synovium by H. capsulatum. Case Report. A 48-year-old female resident' of Missouri was admitted to Barnes Hospital with a chief complaint of progressive swelling and stiffness of her left hand. Several years previously, the patient had been diagnosed as having systemic lupus erythematosus (SLE) and was started on methylprednisolone (16 mg/day) and azathioprine (150 mg/day), with a g o o d clinical response. Six months prior to admission, the patient noted a tender swelling on the lateral aspect of her left third finger. There was no history of trauma preceding the development of the lesion. During the next 4 months, progressive pain, stiffness, swelling, and erythema developed over the palmar aspect of her left hand. In addition, she noted that her left ankle had become swollen and tender. Azathioprine was continued and the methylprednisolone was increased to 40 mg/day, without relief of her symptoms. The patient began to complain of generalized malaise, fatigue, and arthralgias; From the Division of Laboratory Medicine, Departments of Medicine and Pathology, (M.A.P.,
M.K., G.S.K.), and Division of Plastic Surgery, Department of Surgery {P.M.W.), Washington University School of Medicine, St. Louis, Missouri. Address ~print requests to: Michael A. Pfaller, M.D., Department of Pathology, University of Iowa Hospitals & Clinics, Iowa City, IA 52242. Received June 12, 1984; revised and accepted August 8, 1984. © 1985 Elsevier Science Publishing Co., Inc. 52 Vanderbilt Avenue, New York, NY 10017
0732-8893/85/$03.30
252
M.A. Pfaller et al.
she was a d m i t t e d to the hospital w h e n she was noted to have temperatures to 101°C with a c c o m p a n y i n g chills. On admission, the left h a n d was warm, with induration and erythema over the m i d d l e and distal palm; there was marked tenderness over the flexor t e n d o n of the third finger. A 2.0 x 3.0-cm mass was palpable at the base of the volar aspect of the third finger. A 1.0-cm fluctuant, n o n t e n d e r n o d u l e was present over the lateral aspect of the distal p h a l a n x of the third finger (Figure 1). No ulceration was present. Active and passive m o t i o n of the fingers was limited because of pain and swelling. The dorsal aspect of the left foot was also swollen, tender, and erythematous. A chest roentgenogram was normal, and radiologic studies of the left h a n d and foot s h o w e d soft tissue swelling. It was felt that the patient had tenosynovitis and that an exploration of the p a l m a r space should be performed. At operation, the p a l m a r fascia was found to be m a r k e d l y attenuated by a redgray mass in the palm. The mass c o m p l e t e l y encircled the flexor tendons of the third finger. Dissection to the level of the flexor t e n d o n showed the mass to be attached to the s u b l i m u s tendon. The mass was c o m p l e t e l y excised, sparing the tendons. The n o d u l e on the distal aspect of the third finger was incised, and a small a m o u n t of yellow-gray fluid was drained and sent for culture. Microscopic e x a m i n a t i o n of the palmar mass showed skeletal muscle and some nonspecific necrotic soft tissue. Throughout the muscle, there was an inflammatory infiltrate c o m p o s e d of histiocytes, p o l y m o r p h o n u c l e a r leukocytes, and lymphocytes. No granulomas were seen. The most striking feature was that the c y t o p l a s m of vir-
FIGURE 1. Preoperative appearance of the involved hand showing swelling of the long finger with extension over the palmar aspect of the hand. The fluctuant nodule is also evident over the distal phalanx of the third finger.
Disseminated Histoplasmosis
253
tually every histiocyte was filled by numerous small, basophilic, uniformly shaped organisms, each of which was surrounded by a clear zone (Figure 2}. These were easily seen on hematoxylin and eosin sections, and they stained with Gomori's methenamine-silver stain. Their morphology was consistent with H. capsulatum. Cultures of the palmar mass and the fluid from the distal phalangeal nodule and a needle aspirate of fluid from the swelling over the left foot grew H. capsulatum. A bone marrow biopsy and aspirate was performed on the day before surgery; although microscopic examination of the biopsy was negative, a culture grew H. capsulatum. Multiple blood cultures were performed, using a vented bottle containing broth {tryptic soy broth); all were negative after prolonged (30-day} incubation. Sera obtained on admission revealed a compliment fixation titer to H. capsulatum yeast phase antigen {CFY) of less than 1 : 8. On the basis of the microscopic findings, amphotericin B therapy was begun immediately, with an inital dose of I mg/day increasing over 4 days to 20 mg/day (0.35 mg/kg). The patient received a total of 336 mg of amphotericin B over the next 4 weeks and responded slowly, with persistent erythema and swelling of her hand. The left foot continued to be swollen, tender, and erythematous, and was considered to be a site of active H. capsulatum infection in spite of amphotericin B therapy. The patient was considered to have active SLE, as well as disseminated histoplasmosis, with increasingly severe lupus nephritis. Corticosteroids were required throughout her hospital course in an attempt to limit her progressive renal failure. Despite these measures, the renal function continued to deteriorate while she was on amphotericin B, necessitating discontinuation of the drug after a total of 336 mg
FIGURE 2. Histiocytic cells Whose cytoplasm is filled by small, uniformly shaped organisms are seen (hematoxylin and eosin, × 600}. (Insert) Higher magnification view shows that each organism is surrounded by an artifactual clear zone (hematoxylin and eosin, x 1500).
254
M.A. Pfaller et al.
had been administered. Serologic studies at that time showed an increase in CFY titer to 1 : 64. Repeat cultures of the left foot and of the bone marrow were negative for H. capsulatum. Because of the patient's renal status and her slow clinical response to amphotericin B, the decision was made to treat her with miconazole nitrate (15 mg/kg twice daily). During the course of the miconazole therapy, there appeared to be some resolution of the erythema and swelling in the hand and foot. Repeat bone marrow cultures were consistently negative. Serologic studies showed a further increase in CFY titer to 1 : 256 and then a subsequent decrease to 1 : 8 over a 1-month period. Unfortunately, the patient expired due to multiple severe complications of her SLE. An autopsy showed marked interstitial pneumonitis composed predominantly of histiocytes and mononuclear cells; however, no organisms or granulomas were found. Neither were organisms or granulomata seen in sections of the liver, spleen, or kidneys. All postmortem cultures were negative for H. capsulatum. DISCUSSION Infection with H. capsulatum is usually a benign localized pulmonary process and virtually all residents in highly endemic areas have been infected at one time or another (Goodwin et al., 1981; Silverman et al., 1955; Wheat et al., 1981). Rarely, H. capsulatum may cause disseminated disease, which may be fatal if inadequately treated (Goodwin et al., 1980). Dissemination of histoplasmosis is usually hematogenous and results in multifocal organ involvement (Goodwin et al., 1980; Silverman et al., 1955). Focal lesions occurring in bone or synovium are extremely rare despite the high incidence of bone marrow involvement (Bayer et al., 1980; Jones and Goodwin, 1981). We found only one reported case of isolated synovial involvement unassociated with bone involvement (Perlman et al., 1972). The patient was a 24-year-old man who presented with carpal tunnel syndrome caused by involvement with H. capsulatum. This patient differed from ours in that he had no underlying disease and no other evidence of disseminated histoplasmosis. The clinical presentation was typical of carpal tunnel syndrome and quite different from the acute tenosynovitis present in our patient. Successful management was obtained by synovectomy and administration of amphotericin B therapy. Of major concern in our patient was her compromised immunologic state. Although H. capsulatum is generally considered a primary pathogen capable of causing disseminated disease in patients without known predisposing conditions, there is mounting evidence that progressive disseminated infection may result from abnormalities in the host (Davies et al., 1978; Kauffman et al., 1978). Several authors have noted the association of disseminated histoplasmosis with the administration of glucocorticoids or other immunosuppressive drugs (Davies et al., 1978; Kauffman et al., 1978; Sieving et al., 1975; Watson et al., 1968). Kauffman et al, (1978) stress that although there is no conclusive evidence for an increased prevalence of this disease in immunosuppressed patients, it appears that there is a propensity for more severe infection to occur in these hosts. Our patient is an example of an unusual presentation of disseminated histoplasmosis. As discussed above, synovial involvement with H. capsulatum is extremely rare. The combination of this rare presentation and the clinical setting of systemic lupus erythematosus and immunosuppressive therapy presented a confusing picture and masked the signs and symptoms of histoplasmosis, thus delaying the diagnosis until the organism was demonstrated histologically. The patient's demise was due to multiple complications of her severe SLE and probably not due to disseminated
Disseminated Histoplasmosis
255
histoplasmosis. The falling serologic titers and conversion of bone marrow cultures from positive to negative suggests that she had received adequate antifungal t h e r a p y although a d m i n i s t r a t i o n of a m p h o t e r i c i n B therapy was c o m p r o m i s e d by her progressive renal failure. We feel that the consideration of d i s s e m i n a t e d histoplasmosis s h o u l d be entertained in i m m u n o s u p p r e s s e d patients w i t h focal inflammatory lesions u n r e s p o n s i v e to usual therapeutic measures, especially if they have been in an endemic area. This work was supported in part by training grant 1-T32-AI 07172 from the National Institute of Allergy and Infectious Diseases. REFERENCES Bayer AS, Choi C, Tillman DB, Guze LB (1980) Fungal arthritis. V. Cryptococcal and histoplasmal arthritis. Semin Arthritis Rheum 9:218. Davies SF, Khan M, Sarosi GA (1978) Disseminated histoplasmosis in immunologically suppressed patients. Occurrence in a nonendemic area. Am J Med 64:94. Goodwin RA Jr, Shapiro JL, Thurman GH, Thurman SS, Des Prez RM (1980) Disseminated histoplasmosis: Clinical and pathological correlations. Medicine (Baltimore) 59:1. Goodwin RA, Loyd JE, Des Prez RM (1981) Histoplasmosis in normal hosts. Medicine (Baltimore) 60:231. Jones RC, Goodwin RA Jr (1981) Histoplasmosis of bone. Am J Med 70:864. Kauffman CA, Israel KS, Smith JW, White AC, Schwarz J, Brooks GF (1978) Histoplasmosis in immunosuppressed patients. Am J Med 64:923. Perlman R, Jubelirer RA, Schwarz J (1972) Histoplasmosis of the common palmar tendon sheath. J Bone Joint Surg 54-A(3):676. Sieving RR, Kauffman CA, Watanakunakorn C (1975) Deep fungal infection in systemic lupus erythematosus. J Rheumatol 2:61. Silverman FN, Schwarz J, Lahey ME, Carson RP (1955) Histoplasmosis. Am J Med 19:410. Watson JI, Mandl MAJ, Rose B (1968) Disseminated histoplasmosis occurring in association with systemic lupus erythematosus. Can Med Assac J 99:958. Wheat LJ, Slama TG, Eitzen HE, Kohler RB, French MLV, Biesecker JL (1981) A large urban outbreak of histoplasmosis: Clinical features. Ann Intern Med 94:331.