Journal oJ Injection (1991) 22, 179-182
CASE REPORT
Histoplasma capsulatum
infection associated with continuous ambulatory peritoneal dialysis
W i l i n a Lim,*~ S. P. Chau,* P. C. K. C h a n t a n d I. K. P. C h e n g t
*Institute of Pathology, Sai Ying Pun Jockey Club Polyclinic, Hong Kong and t Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong Accepted for publication 25 July I99O Summary Fungal infection has become increasingly more important in patients undergoing continuous ambulatory peritoneal dialysis. We report here a case of Histoplasma capsulamm infection in such a Hong Kong Chinese patient who presented with fever and peritonitis. Histoplasma capsulatum was isolated from the dialysis fluid and histoplasma antibody was detected in the serum. The patient responded to the combined treatment of fluconazole, 5-flurocytosinc and amphotericin B. This is the first reported case of histoplasmosis in Hong Kong.
Introduction Although bacterial peritonitis is a well-known risk in patients undergoing chronic ambulatory peritoneal dialysis (CAPD), fungal infection has become increasingly more important. 1 We describe here a case of Histoplasma capsulatum infection in a local Chinese CAPD patient. Histoplasmosis has been reported from over 40 countries but never before from Hong Kongfl Since the clinical manifestations of histoplasmosis may be highly varied and non-specific, its diagnosis requires a high index of suspicion and an understanding of cultural and serological procedures.
Case report A 46-year-old Chinese man first presented with end stage renal failure of unknown aetiology in November 1987. A Tenckhoff catheter was inserted in the same month and he was maintained on CAPD. Apart from a granuloma at the exit site, the patient had no other complaint until February I989 when he developed low-grade fever and turbid dialysis fluid. Microscopy of the fluid revealed 254 × IO6/1 white cells which rose to 6o5 x Io6/1 after i week. Culture gave no growth. A chest X-ray showed increased basal markings but no other abnormality. Treatment with rifampicin 45o mg and ofloxacin 2oo mg daily was started empirically. T h e symptoms improved and the peritoneal dialysis fluid transiently cleared. By May I989, however, the patient complained of Address correspondence to: Dr Wilina Lira, Government Virus Unit, Queen Mary Hospital, Hong Kong. oi63-4453/9I/o2oi79 + o 4 $o3.o0/0
© I99I The British Society for the Study of Infection
I80
W. L I M E T A L .
persisting low-grade fever and increasing abdominal pain. T h e peritoneal dialysis fluid was turbid with 37o × IO6/1 white cells. In view of the high prevalence (7"6%) of tuberculosis in our CAPD patients, 3 tuberculous peritonitis was suspected despite negative cultural results. Antituberculous treatment ( I N A H 3oo mg, rifampicin 45o mg, pyrazinamide I g and ofloxacin 2oo mg daily) therefore began. In June 1989, several samples of the dialysis fluid, submitted for fungal culture, grew a saprophytic fungus. Serum, however, tested for fungal antibodies, was positive for histoplasma antibody. T h e dialysis fluid was cultured again and the patient was given oral fluconazole, 2oo mg as a loading dose and then IOO mg daily, while 5-fluorocytosine (5o mg/1) was added to the dialysis fluid for 4 weeks. When a fungus, identified as H. capsulatum, was subsequently isolated from the dialysis fluid, 3o mg amphotericin B were administered IV for IO days with a good response. Repeated cultures of the dialysis fluid remained negative 3 months after antifungal therapy stopped. Detailed questioning confirmed that the patient had neither left Hong Kong since undergoing CAPD treatment nor did he keep birds as pets at home.
Microbiology Dialysis fluid for fungal culture was centrifuged at 3000 rpm for 15 min. T h e deposit was examined microscopically and inoculated on plain Sabouraud dextrose agar (SDA), SDA supplemented with cycloheximide plus chloramphenicol and SDA supplemented with penicillin plus streptomycin. Fungal elements were not seen on microscopical examination. Fungal colonies, however, which were fluffy and buff brown, were detected on all inoculated plates of SDA after 4 weeks' incubation at 3o °C. Microscopy of the fungal colonies showed both macroconidia, 8-14 # m in diameter, and microconidia, 2-4 # m in diameter. T h e macroconidia had the characteristic tuberculated appearance. Histoplasma sp. was suspected, although the saprophytic fungus Sepedonium sp. could not be excluded. Attempts to convert the mycelial phase to the yeast phase by culture on brain-heart infusion agar supplemented with horse blood and by mouse inoculation were not successful. T h e fungus was at first regarded as a saprophyte. When, however, it was known that a test of the patient's serum was positive for histoplasma antibodies, identification of the mycelial form of the fungus in cultures was attempted by means of the exoantigen test described by Standard and Kaufman. 4 T h e result was positive for H. capsulatum. A sample of the fungus isolated was sent to the Division of Mycotic Diseases, Centers for Disease Control, Atlanta, U.S.A. where it was confirmed as being H. capsulatum. Fungal antibodies in the patient's were detected by counterimmunoelectrophoresis. 5 Reagents for this were obtained from Meridian Diagnostics, Inc. T h e M precipitin band, which is present in 75-85 % patients with histoplasmosis, was repeatedly detected in the patient's serum, while H precipitin band, which is present in the serum of only I5-2o % patients with histoplasmosis, was not detected on repeated testing.
Histoplasma capsulatum infection
I8I
Discussion
T h e aetiological agent ofhistoplasmosis, H. capsulatum, was described in 19o5 by Darling as protozoan. Later, the infectious agent was proved to be a diphasic fungus with a pathogenic yeast form and a saprophytic mycelial form. T h e growth o f H . capsulatum in soils enriched with birds' or bats' faeces is the main source of h u m a n and animal infection. T h e source of infection in our patient, however, is unknown. Since he never left Hong Kong after starting treatment with CAPD, he must have acquired the infection locally. Although peritonitis secondary to desseminated histoplasmosis in a patient on CAPD has been reported, Gwe believe that the infection in our patient was confined to the peritoneum. As far as we know, this is the first such description in a CAPD patient. In the presence of a Tenckhoff catheter, direct inoculation of the infective agent through the catheter, so causing primary peritonitis, is a distinct possibility. In Hong Kong, where tuberculosis is hyperendemic, manifestations of histoplasmosis may mimic tuberculosis. Isolation and identification of the fungus is thus mandatory so that appropriate treatment can be instituted in good time. Since histoplasmosis has never before been reported in Hong Kong, experience in detection and identification of the causative organism is lacking. Although the macroconidia have a characteristic tuberculated appearance, these structures are not absolutely diagnostic because the saprophytic fungus Sepedonium sp. also produces macroconidia of similar morphology. Differentiation of Histoplasma sp. from morphologically similar saprophytes requires conversion from the mycelial to the yeast form. Unfortunately, as in our case, such conversion cannot always be achieved. T h e exoantigen test, which is an accurate and rapid immunological method, is thus a valuable asset in the diagnostic laboratory. Serological tests for antibody to Histoplasma capsulatum are useful in the diagnosis of histoplasmosis. Antibodies develop 4-6 weeks following acute exposure. T h e tests most commonly used are the complement fixation (CF), immunodiffusion (ID) and counterimmuno-electrophoresis (CIE) tests. T h e ID and CIE tests are less sensitive than the CF test but are more specific. 5 T h e r e is > 90 % agreement between results obtained with the ID and CIE tests. Cross-reactivity may be seen in patients with blastomycosis, coccidioidomycosis, paracoccidioidomycosis, aspergillosis, candidiasis, cryptococcosis and tuberculosis. 7 In Hong Kong, where tuberculosis is common and histoplasmosis is rare, the result of a serological test must be interpreted with caution. Specific diagnosis should be based on cultural methods. Both the old and new azole antifungal agents are active in vitro against H. capsulatum and appear to be an effective treatment in non-life-threatening forms of histoplasmosis. 8 Since itraconazole penetrates the peritoneum poorly and fluconazole taken by mouth has been reported to result in an adequate concentration in peritoneal dialysis fluids 9 the use of fluconazole in a dosage suitable for a patient on CAPD in order to treat fungal infection seems justified. Although its penetration into the peritoneal fluid is unpredictable, amphotericin B is indicated in most immunosuppressed patients with 8
J I N 22
I82
W. L I M E T A L .
h i s t o p l a s m o s i s b e c a u s e o f t h e i r s u s c e p t i b i l i t y to d i s s e m i n a t e d i n f e c t i o n . 1° T h e c o m b i n e d u s e o f 5 - f l u o r o c y t o s i n e , f l u c o n a z o l e a n d a m p h o t e r i c i n B in o u r case a p p e a r s to h a v e e r a d i c a t e d t h e i n f e c t i o n w i t h o u t n e c e s s i t a t i n g r e m o v a l o f t h e Tenckhoff catheter. (We thank D r L. Ajello, Director, Division of Mycotic Diseases, Centers for Disease Control, Atlanta, U.S.A. for confirming the identity of our isolate as Histoplasma capsulatum.) References
r. Cheng IJP, Fang GX, Chan T M , Chan PCK, Chart MK. Fungal peritonitis complicating peritoneal dialysis: report of 27 cases and review of treatment. Q J Med I989; 265: 407-416. 2. Larsh HW, Hall NK. Histoplasma capsulatum. In : Braude AI, Ed. Medical microbiology and infectious diseases. 2nd ed. New York: W. B. Saunders, 1986; 580-584. 3. Chan PCK, Yeung CK, Chan MK. Tuberculosis in peritoneal dialysis patients. Sing M e d J I988 ; zg: IO3-IO4. 4. Standard PG, Kaufman L. Specified immunological test for the rapid identification of members of the genus Histoplasma. J Clin Microbiol I976; 3: I9I-I99. 5. Kaufman L, Reiss E. Serodiagnosis of fungal diseases. In: Lennette EH, Ed. Manual of clinical microbiology. 4th ed. Washington, D.C. : American Society for Microbiology, I985; 937--938. 6. Ma KW. Disseminated histoplasmosis in dialysis patients. Clin Nephrol I985; 24: I55--I57. 7" Wheat J, FrenchMLV, Kamel S, Tewari RP. Evaluation of cross-reaction in Histoplasma capsulatum serological tests. J Clin Microbiol I986; z3: 493-499. 8. Dismukes WE. Azole antifungal drugs: old and new. Ann Intern Med I988 ; IO9: I77-I79. 9. Ahlmen J, Edebo L, Eriksson C, Carlsson L, Torgersen AK. Fluconazole therapy for fungal peritonitis in continuous ambulatory peritoneal dialysis (CAPD): a case report. Periton Dialysis Inter 1989; 9: 79-80. IO. Sathapatayavongs B, Batteiger BE, Wheat J, Slama TG, Wass JL. Clinical and laboratory features of disseminated histoplasmosis during two large urban outbreaks. Medicine I983 ; 62 : 263-270.
CASE REPORT
Histoplasma capsulatum
infection associated with continuous ambulatory peritoneal dialysis
W i l i n a Lim,*~ S. P. Chau,* P. C. K. C h a n t a n d I. K. P. C h e n g t
*Institute of Pathology, Sai Ying Pun Jockey Club Polyclinic, Hong Kong and t Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong Accepted for publication 25 July I99O Summary Fungal infection has become increasingly more important in patients undergoing continuous ambulatory peritoneal dialysis. We report here a case of Histoplasma capsulamm infection in such a Hong Kong Chinese patient who presented with fever and peritonitis. Histoplasma capsulatum was isolated from the dialysis fluid and histoplasma antibody was detected in the serum. The patient responded to the combined treatment of fluconazole, 5-flurocytosinc and amphotericin B. This is the first reported case of histoplasmosis in Hong Kong.
Introduction Although bacterial peritonitis is a well-known risk in patients undergoing chronic ambulatory peritoneal dialysis (CAPD), fungal infection has become increasingly more important. 1 We describe here a case of Histoplasma capsulatum infection in a local Chinese CAPD patient. Histoplasmosis has been reported from over 40 countries but never before from Hong Kongfl Since the clinical manifestations of histoplasmosis may be highly varied and non-specific, its diagnosis requires a high index of suspicion and an understanding of cultural and serological procedures.
Case report A 46-year-old Chinese man first presented with end stage renal failure of unknown aetiology in November 1987. A Tenckhoff catheter was inserted in the same month and he was maintained on CAPD. Apart from a granuloma at the exit site, the patient had no other complaint until February I989 when he developed low-grade fever and turbid dialysis fluid. Microscopy of the fluid revealed 254 × IO6/1 white cells which rose to 6o5 x Io6/1 after i week. Culture gave no growth. A chest X-ray showed increased basal markings but no other abnormality. Treatment with rifampicin 45o mg and ofloxacin 2oo mg daily was started empirically. T h e symptoms improved and the peritoneal dialysis fluid transiently cleared. By May I989, however, the patient complained of Address correspondence to: Dr Wilina Lira, Government Virus Unit, Queen Mary Hospital, Hong Kong. oi63-4453/9I/o2oi79 + o 4 $o3.o0/0
© I99I The British Society for the Study of Infection
I80
W. L I M E T A L .
persisting low-grade fever and increasing abdominal pain. T h e peritoneal dialysis fluid was turbid with 37o × IO6/1 white cells. In view of the high prevalence (7"6%) of tuberculosis in our CAPD patients, 3 tuberculous peritonitis was suspected despite negative cultural results. Antituberculous treatment ( I N A H 3oo mg, rifampicin 45o mg, pyrazinamide I g and ofloxacin 2oo mg daily) therefore began. In June 1989, several samples of the dialysis fluid, submitted for fungal culture, grew a saprophytic fungus. Serum, however, tested for fungal antibodies, was positive for histoplasma antibody. T h e dialysis fluid was cultured again and the patient was given oral fluconazole, 2oo mg as a loading dose and then IOO mg daily, while 5-fluorocytosine (5o mg/1) was added to the dialysis fluid for 4 weeks. When a fungus, identified as H. capsulatum, was subsequently isolated from the dialysis fluid, 3o mg amphotericin B were administered IV for IO days with a good response. Repeated cultures of the dialysis fluid remained negative 3 months after antifungal therapy stopped. Detailed questioning confirmed that the patient had neither left Hong Kong since undergoing CAPD treatment nor did he keep birds as pets at home.
Microbiology Dialysis fluid for fungal culture was centrifuged at 3000 rpm for 15 min. T h e deposit was examined microscopically and inoculated on plain Sabouraud dextrose agar (SDA), SDA supplemented with cycloheximide plus chloramphenicol and SDA supplemented with penicillin plus streptomycin. Fungal elements were not seen on microscopical examination. Fungal colonies, however, which were fluffy and buff brown, were detected on all inoculated plates of SDA after 4 weeks' incubation at 3o °C. Microscopy of the fungal colonies showed both macroconidia, 8-14 # m in diameter, and microconidia, 2-4 # m in diameter. T h e macroconidia had the characteristic tuberculated appearance. Histoplasma sp. was suspected, although the saprophytic fungus Sepedonium sp. could not be excluded. Attempts to convert the mycelial phase to the yeast phase by culture on brain-heart infusion agar supplemented with horse blood and by mouse inoculation were not successful. T h e fungus was at first regarded as a saprophyte. When, however, it was known that a test of the patient's serum was positive for histoplasma antibodies, identification of the mycelial form of the fungus in cultures was attempted by means of the exoantigen test described by Standard and Kaufman. 4 T h e result was positive for H. capsulatum. A sample of the fungus isolated was sent to the Division of Mycotic Diseases, Centers for Disease Control, Atlanta, U.S.A. where it was confirmed as being H. capsulatum. Fungal antibodies in the patient's were detected by counterimmunoelectrophoresis. 5 Reagents for this were obtained from Meridian Diagnostics, Inc. T h e M precipitin band, which is present in 75-85 % patients with histoplasmosis, was repeatedly detected in the patient's serum, while H precipitin band, which is present in the serum of only I5-2o % patients with histoplasmosis, was not detected on repeated testing.
Histoplasma capsulatum infection
I8I
Discussion
T h e aetiological agent ofhistoplasmosis, H. capsulatum, was described in 19o5 by Darling as protozoan. Later, the infectious agent was proved to be a diphasic fungus with a pathogenic yeast form and a saprophytic mycelial form. T h e growth o f H . capsulatum in soils enriched with birds' or bats' faeces is the main source of h u m a n and animal infection. T h e source of infection in our patient, however, is unknown. Since he never left Hong Kong after starting treatment with CAPD, he must have acquired the infection locally. Although peritonitis secondary to desseminated histoplasmosis in a patient on CAPD has been reported, Gwe believe that the infection in our patient was confined to the peritoneum. As far as we know, this is the first such description in a CAPD patient. In the presence of a Tenckhoff catheter, direct inoculation of the infective agent through the catheter, so causing primary peritonitis, is a distinct possibility. In Hong Kong, where tuberculosis is hyperendemic, manifestations of histoplasmosis may mimic tuberculosis. Isolation and identification of the fungus is thus mandatory so that appropriate treatment can be instituted in good time. Since histoplasmosis has never before been reported in Hong Kong, experience in detection and identification of the causative organism is lacking. Although the macroconidia have a characteristic tuberculated appearance, these structures are not absolutely diagnostic because the saprophytic fungus Sepedonium sp. also produces macroconidia of similar morphology. Differentiation of Histoplasma sp. from morphologically similar saprophytes requires conversion from the mycelial to the yeast form. Unfortunately, as in our case, such conversion cannot always be achieved. T h e exoantigen test, which is an accurate and rapid immunological method, is thus a valuable asset in the diagnostic laboratory. Serological tests for antibody to Histoplasma capsulatum are useful in the diagnosis of histoplasmosis. Antibodies develop 4-6 weeks following acute exposure. T h e tests most commonly used are the complement fixation (CF), immunodiffusion (ID) and counterimmuno-electrophoresis (CIE) tests. T h e ID and CIE tests are less sensitive than the CF test but are more specific. 5 T h e r e is > 90 % agreement between results obtained with the ID and CIE tests. Cross-reactivity may be seen in patients with blastomycosis, coccidioidomycosis, paracoccidioidomycosis, aspergillosis, candidiasis, cryptococcosis and tuberculosis. 7 In Hong Kong, where tuberculosis is common and histoplasmosis is rare, the result of a serological test must be interpreted with caution. Specific diagnosis should be based on cultural methods. Both the old and new azole antifungal agents are active in vitro against H. capsulatum and appear to be an effective treatment in non-life-threatening forms of histoplasmosis. 8 Since itraconazole penetrates the peritoneum poorly and fluconazole taken by mouth has been reported to result in an adequate concentration in peritoneal dialysis fluids 9 the use of fluconazole in a dosage suitable for a patient on CAPD in order to treat fungal infection seems justified. Although its penetration into the peritoneal fluid is unpredictable, amphotericin B is indicated in most immunosuppressed patients with 8
J I N 22
I82
W. L I M E T A L .
h i s t o p l a s m o s i s b e c a u s e o f t h e i r s u s c e p t i b i l i t y to d i s s e m i n a t e d i n f e c t i o n . 1° T h e c o m b i n e d u s e o f 5 - f l u o r o c y t o s i n e , f l u c o n a z o l e a n d a m p h o t e r i c i n B in o u r case a p p e a r s to h a v e e r a d i c a t e d t h e i n f e c t i o n w i t h o u t n e c e s s i t a t i n g r e m o v a l o f t h e Tenckhoff catheter. (We thank D r L. Ajello, Director, Division of Mycotic Diseases, Centers for Disease Control, Atlanta, U.S.A. for confirming the identity of our isolate as Histoplasma capsulatum.) References
r. Cheng IJP, Fang GX, Chan T M , Chan PCK, Chart MK. Fungal peritonitis complicating peritoneal dialysis: report of 27 cases and review of treatment. Q J Med I989; 265: 407-416. 2. Larsh HW, Hall NK. Histoplasma capsulatum. In : Braude AI, Ed. Medical microbiology and infectious diseases. 2nd ed. New York: W. B. Saunders, 1986; 580-584. 3. Chan PCK, Yeung CK, Chan MK. Tuberculosis in peritoneal dialysis patients. Sing M e d J I988 ; zg: IO3-IO4. 4. Standard PG, Kaufman L. Specified immunological test for the rapid identification of members of the genus Histoplasma. J Clin Microbiol I976; 3: I9I-I99. 5. Kaufman L, Reiss E. Serodiagnosis of fungal diseases. In: Lennette EH, Ed. Manual of clinical microbiology. 4th ed. Washington, D.C. : American Society for Microbiology, I985; 937--938. 6. Ma KW. Disseminated histoplasmosis in dialysis patients. Clin Nephrol I985; 24: I55--I57. 7" Wheat J, FrenchMLV, Kamel S, Tewari RP. Evaluation of cross-reaction in Histoplasma capsulatum serological tests. J Clin Microbiol I986; z3: 493-499. 8. Dismukes WE. Azole antifungal drugs: old and new. Ann Intern Med I988 ; IO9: I77-I79. 9. Ahlmen J, Edebo L, Eriksson C, Carlsson L, Torgersen AK. Fluconazole therapy for fungal peritonitis in continuous ambulatory peritoneal dialysis (CAPD): a case report. Periton Dialysis Inter 1989; 9: 79-80. IO. Sathapatayavongs B, Batteiger BE, Wheat J, Slama TG, Wass JL. Clinical and laboratory features of disseminated histoplasmosis during two large urban outbreaks. Medicine I983 ; 62 : 263-270.
