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Acute disseminated histoplasmosis complicated with hypercalcaemia
i
CASE REPORTS
Acute Disseminated Histoplasmosis Hypercalcaemia
Complicated with
J. W. Liu*‘, T. C. Huang’, Y. C. Lu*, H. T. Lid, C. C. Li3, J. J. Wu6, J. W. Lin4 and W. J. Chen4 ‘Divisions of Infectious Diseasesand 2Endocrinology and Metabolism, Department of Internal Medicine, and ‘Division of Microbiology, 4Department of Pathology, and jDepartment of Dermatology, Chang Gung Memorial Hospital-l
Introduction Histoplasrnacapsulatumis a dimorphic fungus that grows in its mycelial form in soil at ambient temperatures and in a yeast form at the body temperature of mammals.’ Histoplasmosis is an inhalation-acquired Histoplasma infection. In view that disseminated histoplasmosis (DH) is an acquired immunodeficiency syndrome (AIDS)-defining disease in human immunodeficiency virus (HIV)-infected patients,> it is important to acquire a complete understanding of the whole spectrum of clinical manifestations of histoplasmosis in the AIDS era. We describe an unusual case of acute progressive DH complicated with hypercalcaemia and review the literature. though only non-HIV-infected patients have been involved in cases reported thus far.
Case Report A 46-year-old male sailor, native of Taiwan, previously in good health before suffering from a progressive diarrhoea for 2 months. For the previous 2 years, he had lived in Indonesia and spent most of his time working in sea waters there. He returned to his hometown because of prolonged diarrhoea and episodic fever was noted. He was, therefore. admitted to a local hospital. During hospitalization, diarrhoea was relieved: however, blood culture yielded Salmonella group B. As a result, chloramphenicol plus ampicillin was administered. Despite antimicrobial therapy, fever persisted and generalized erythematous papules developed, some of which evolved into crusted ulcers. Although he was advised to seek further management from a referral medical center, the patient opted to take herbal drugs at home.
Address correspondence to: J. W. Liu, Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial HospitalKaohsiung, 123 Ta Pei Road, Niao Sung Hsiang, Kaohsiung Hsien, Taiwan, Accepted
Republic of China. for publication 2 5 March
01~3.4453/99/0400X7
1999.
+ 10 $12.00/O
Unfortunately, progressively disturbed consciousness, shortness of breath and a yellowish skin discoloration developed. He was, therefore, brought to our hospital seeking medical help and was admitted via our Emergency Service. The patient was cache&c and lethargic upon hospitalization. Fever, respiratory distress, tachycardia, conjunctival paleness, jaundice, dry mucosa. and poor skin turgor were found. Auscultation revealed a bilateral diminished breathing sound. Though liver and spleen were not large enough to be palpable from the tense abdominal wall, abdominal echogram showed slight enlargement of both organs and some ascites. Generalized cutaneous crusted ulcers with erythematous margins of variable sizes, ranging from 0.3 to 3 cm were noted (Fig. 1). Chest roentgenography showed no active lung lesions but bilateral massive pleural effusion. Haemogram showed a peripheral white cell count of 13.0~10’11 with 94% polymorphonuclear cells, haemoglobin of 6.8 g/d1 and platelets of 6.0x10y/1. Blood biochemistry was as follows: serum albumin was 18 g/l (normal, 35-50); blood urea nitrogen, creatinine and aminotransferases were within normal limits: alkaline phosphatase was 182 IT/l (normal, 28-94). and total bilirubin was 306.10 pmol/l (normal, 3.42-23.94) with the direct bilirubin component of 158.86 pmol/l: serum sodium was 152 mmol/l (normal, 135-145). and total serum calcium, remarkably, was 3.30 mmol/l (normal, 1.97-2.47). Hydration with normal saline and bolus injection with furosemide were administered for correction of metabolic disorder in general, and hypercalcaemia in particular. Gram-staining of the exudative discharge of the unroofed crusted cutaneous lesion did not disclose any micro-organism. Empirical administration of ceftriaxone was initiated after sampling blood for culture. The subsequent assay disclosed that the serum level of intact parathyroid hormone was cl.0 pg/ml (normal range, lo-65), and serology study for HIV antibody was negative. Though the blood culture yielded Salmonellagroup CL which was susceptible to the prescribed antibiotic, the patient’s clinical condition deteriorated, and hypercalcaemia and thrombocytopenia persisted. Therefore, amphotericin-B and anti-tuberculosis 0 199Y The British
Infection
Society
Case Reports
agents were empirically added. Skin section stained with hematoxylin and eosin (H&E) as well as Grocott silver methenamine showed epidermal necrosis and the dermis infiltrated with poly morphonuclear cells and macrophages with and without intracellular yeast-form microorganisms, accompanied by prominent leukocytoclasis. Unfortunately. the patient eventually died of overwhelming sepsis with multiorgan failure on day 10 of hospitalization. Subsequently. the blood. skin, and pleural effusion cultures on brain-heart infusion (BHI) agar with sheep blood at 3(X all yielded brownish mycelial colonies. The isolates microscopically showed round to pyriform smooth-surfaced microconidia and tuberculated macroconidia. Transferring of the mycelial-form pathogen on the other BHI agar for culture at 37°C for a further 2 weeks showed a conversion to a yeast-form pathogen. The cultured microorganism was sent to the AKUP Laboratories (Salt Lake City, Utah, 1J.S.A) for further confirmation, where it gave a positive hybridization test for H. crrpslllaturtl (AccuProbe: Gen-Probe Inc.. San Diego, CA. I1.S.A). The pathogen was thus unequivocally identified.
Discussion Though H. crr/&atlrrrl is widely distributed. histoplasmosis is most frequently encountered on American continent, and is endemic to midwestern and south central portions of the United States in particular,’ Cases of indigenous histoplasmosis have been reported in South-East Asian countries of Indonesia. Malaysia. Thailand. Vietnam, i the Philippines. and Singapore.’ The standard diagnostic tests for histoplasmosis are not always available in these regions and this may lead to underdiagnosis. The published reports suggest that histoplasmosis is endemic to certain areas of South-East Asia and that there may be a large number of undiagnosed and subclinical cases4 We speculate that our patient contracted histoplasmosis in Indonesia, because the histoplasmin skin test study conducted in 19 5 3 suggested no indigenous histoptasmosis in Taiwan at that time, and all patients with histoplasmosis in the reports from Taiwan had a history of travel outside Taiwan. i The spectrum of clinical mailifestations al histoplasmosis has been well described. Ilnfortunately, acute progressive DH. which requires urgent
89
diagnosis for initiating a timely antifungal therapy, often clinically overlaps with sepsis of other aetiologies. Cutaneous lesions, the marked sign drawing physician’s attention and offering an easily accessible biopsy, occurs in around 5% of the patients 01 acute 1)H with an underlying AIDS.” From the section of H&Ii stained biopsied specimen of the infected tissue. yeast-form fungi are relatively easily visualized.’ The yeast form of If. c’rrl~~rlntt~l should be differentiated from the extracellular cyst forms of I+7~urnocystis cc~inii’,~ and of Pmidliun~ mnr~j~~~:f,~ the intracellular amastigotes of Msltmmi~ spp.’ and the intracellular trophozoites of Torm~~lc~.s~~c~ gordii.‘~7 None of the latter two pathogens take up fungal silver stains. The cyst-form Prlcllrtloc:l/sti,s carirlii does not bud and is extracellular. PcGcilZitlrll rflnrrlc~.j?i. an increasingly reported pathogen in HIVinfected patients in South-East Asia, proliferates bv fission instead of budding: the cyst form of l’micillim mrmcfr’~i is. typically, sept ate and elongated.; An earlier report indicated that, before the AIDS epidemic, risk factors for disseminated or fatal histoplasmosis included elderly (> 54 years), haematologic malignancy, and treatment with corticosteroids or immunosuppressive agents.” A later report indicated that HIV infection is an important predisposing factor and DH occurred in about 5% of AIDS patients residing in histoplasmosis-endemic areas of the United States.’ We postulate that the prolonged severe diarrhoea rendered our patient malnourished. and in turn immunocompromixcd. As a result. the latent histoplasmosis reactivated. An earlier report”’ suggests that diffuse pat-asitization of reticuloendothelial system by tfi,stoplrr,srw~ organisms may cause reticuloendothelial blockade. which then predisposes to systemic salmonellosis. It is uncertain whether or not systemic salmonetlosis concurrently rendered mortality in the present case. Histoplasmosis is histopathologically a granulomatous disease.” Because of the familv’s disapproval. neither autopsy 01 biopsy of our patient’s deeplseated tissue was obtained for further proof. Kegardless of the aetiology of granuloma. the mechanism of the induced hypercalcaemia involved the extrarenat overproduction of serum calcitriol. which in turn augments calcium absorption from the gut and bone reabsorption.“,’ ’ It stands to reason that histoplasmosis can cause hypercalcaemia such as that seen in patients suffering from other granulomatous disease. Three additional cases of hypercalcaemia complicating DH were found in the literature (Table Il.” I” All three patients lvere immunocompromized. The host of one case ~‘as an infant having immature immunit!, who suffered from I)H with the manifestation of failure to thrive.‘” The two remaining patients were adults: one was previously splenectomized” while the other had diabetes mellitus. Ii and both had renal insufficiency. These t\vo adults died of severe sepsis shortlv after hospitalization. Remarkably, both of them had confound& factors to which hypercalcaemia could be ascribed. One had the undertying sarcoidosis and hot h had renal dysfunction. Patients in the previously reported cases and ours as well were non-AIDS sufferers. However, in view that hypercalcaemia complication has been noted in patients with advanced AIDS suffering from other granulomatous diseases, ‘: it is logical to assume that this complication possibly occurs in severely immunocompromized AIDS patients when they develop DH. because granulomatous diseases have similar pathophysiology.’ ’ In the ATIX era, any clue that is potentially suggestive ol opportunistic infections and the predisposing underlying AlUS should be highly \,alued. Since DH is an AIDS-defining disease in lll\~-infected patients. the reported cases imply that physicians should have a high index of suspicion for l>H and underl!?ng
Case Reports
90 Table
1. Summary of reported clinical features of disseminated histoplasmosis complicated with hypercalcaemia
Source
Walker rt of.I4
Murray et nl. Ii
Steele et al.“‘
Liu rt nl.
Sex
M 5 6 years
M 62 years
Previous splenectomy Renal insufficiency No
Diabetes mellitus Renal insufficiency No
M 10 months Immature immunity
M 46 years Malnourished (prolonged diarrhea)
No
Yes
Died
Died
Survived
Died
Age
Immunity condition Cutaneous lesions Outcome
AIDS upon facing patients with hypercalcaemia until it is proven otherwise. This implication is particularly important in South-East Asia where an increasingly high prevalence of AIDS exists, because histoplasmosis is endemic to this region and the effective diagnostic tools are not always readily available.
Acknowledgment The authors thank Dr Bill Safranek for his technical assistance
References
10
11
1 Bullock WE. Histoplasma
12
2
13
3 4
5
6
capsulatum. In: Mandell CL. Bennett JE. Dolin R, eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. 4th edn. New York: Churchill Livingstone. 199 5: 2340-2353. Centers for Disease Control and Prevention. Revision of the CDC surveillance case definition for the acquired immunodeficiency syndrome. MMWR 1987: 36(Suppl. 1): S3-S9. Randhawa HS. Occurrence of histoplasmosis in Asia. 1Mgcopath Mgcol Appll970; 41: 75-89. Wang TL, Cheah JS. Holmberg I<. Case report and review of disseminated histoplasmosis in South-East Asia: clinical and epidemiological implications. Pop Med Int Health 1996: 1: 35-42. Kao TW, Hung CC. Hsueh PR. Lin TY, et al. Microbiologic and histologic diagnosis of histoplasmosis in Taiwan. 1 Formosan A4rd Assoc lYY7: 96: 374-37X. Sarosi CA, Johnson PC. Disseminated histoplasmosis in patients infected with human immunodeficiency virus. Clin Infect Dis 1992: 14(Suppl. 1): S60-S67.
14
15 16 17
Kennedy MJ. Sigler L. Asprrgilltts, Fuswium, and other opportunistic monilianceous fungi. In: Murray PR. Baron EJ, Pfaller MA, Tenover FC. Yolken RH, eds. Manual of Clinical Microbiology. 6th edn. Washington DC: American Society for Microbiology. 1995: 765-790. Wheat LJ, Slama TG. Norton JA. et al. Risk factors for disseminated or fatal histoplasmosis: analysis of a large urban outbreak. Ann Intern MedlY82:96: 159-163. Johnson PC, Khardori N, Najjar AE Butt F, Mansell PWA, Sarosi GA. Progressive disseminated histoplasmosis in patients with acquired immunodeficiency syndrome. Am JMed 1988: 85: 152-l 58. Wheat LJ, Rubin RH, Harris NIL rt al. Systemic salmonellosis in patients with disseminated histoplasmosis. Arch lntrrn Med 1987: 147: 561-564. Zumla A, James DG. Granulomatous infections: aetiology and classification. Clin Infect Dis 1996: 23: 146-158. Barbour GL. Coburn JW. Slatopolsky E. Norman AW. Horst RL. Hypercalcaemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1, 25dihydroxyvitamin D. N Engl 1 Mrd 1981; 305: 440-443. Kozeny GA. Barbato AL. Bansal VK, Vertuno LL, Hano JE. Hypercalcaemia associated with silicon-induced granulomas. NEngl JMed 1984: 311: 1103-I 105. Walker JV, Baran D. Yakub YN. Freeman RB. Histoplasmosis with hypercalcaemia. renal failure, and papillary necrosis. JAMA 19 77: 237: 1350-1352. Murray JL. Heim CR. Hypercalcaemia in disseminated histoplasmosis. AmJMed 1985: 78: 881-X84. Steele CJ. Kleiman MB. Disseminated histoplasmosis. hypercalcaemia and failure to thrive. Pediatr Inject Dis J 1994: 13: 421-422. Spindel SJ, Hamill RJ. Georghiou PR. Lacke CE. Green LK, Mallette LE. Vitamin D-mediated hypercalcaemia in fungal infections. Am J MedSci 1995: 310: 71-76.
CASE REPORTS
Acute Disseminated Histoplasmosis Hypercalcaemia
Complicated with
J. W. Liu*‘, T. C. Huang’, Y. C. Lu*, H. T. Lid, C. C. Li3, J. J. Wu6, J. W. Lin4 and W. J. Chen4 ‘Divisions of Infectious Diseasesand 2Endocrinology and Metabolism, Department of Internal Medicine, and ‘Division of Microbiology, 4Department of Pathology, and jDepartment of Dermatology, Chang Gung Memorial Hospital-l
Introduction Histoplasrnacapsulatumis a dimorphic fungus that grows in its mycelial form in soil at ambient temperatures and in a yeast form at the body temperature of mammals.’ Histoplasmosis is an inhalation-acquired Histoplasma infection. In view that disseminated histoplasmosis (DH) is an acquired immunodeficiency syndrome (AIDS)-defining disease in human immunodeficiency virus (HIV)-infected patients,> it is important to acquire a complete understanding of the whole spectrum of clinical manifestations of histoplasmosis in the AIDS era. We describe an unusual case of acute progressive DH complicated with hypercalcaemia and review the literature. though only non-HIV-infected patients have been involved in cases reported thus far.
Case Report A 46-year-old male sailor, native of Taiwan, previously in good health before suffering from a progressive diarrhoea for 2 months. For the previous 2 years, he had lived in Indonesia and spent most of his time working in sea waters there. He returned to his hometown because of prolonged diarrhoea and episodic fever was noted. He was, therefore. admitted to a local hospital. During hospitalization, diarrhoea was relieved: however, blood culture yielded Salmonella group B. As a result, chloramphenicol plus ampicillin was administered. Despite antimicrobial therapy, fever persisted and generalized erythematous papules developed, some of which evolved into crusted ulcers. Although he was advised to seek further management from a referral medical center, the patient opted to take herbal drugs at home.
Address correspondence to: J. W. Liu, Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial HospitalKaohsiung, 123 Ta Pei Road, Niao Sung Hsiang, Kaohsiung Hsien, Taiwan, Accepted
Republic of China. for publication 2 5 March
01~3.4453/99/0400X7
1999.
+ 10 $12.00/O
Unfortunately, progressively disturbed consciousness, shortness of breath and a yellowish skin discoloration developed. He was, therefore, brought to our hospital seeking medical help and was admitted via our Emergency Service. The patient was cache&c and lethargic upon hospitalization. Fever, respiratory distress, tachycardia, conjunctival paleness, jaundice, dry mucosa. and poor skin turgor were found. Auscultation revealed a bilateral diminished breathing sound. Though liver and spleen were not large enough to be palpable from the tense abdominal wall, abdominal echogram showed slight enlargement of both organs and some ascites. Generalized cutaneous crusted ulcers with erythematous margins of variable sizes, ranging from 0.3 to 3 cm were noted (Fig. 1). Chest roentgenography showed no active lung lesions but bilateral massive pleural effusion. Haemogram showed a peripheral white cell count of 13.0~10’11 with 94% polymorphonuclear cells, haemoglobin of 6.8 g/d1 and platelets of 6.0x10y/1. Blood biochemistry was as follows: serum albumin was 18 g/l (normal, 35-50); blood urea nitrogen, creatinine and aminotransferases were within normal limits: alkaline phosphatase was 182 IT/l (normal, 28-94). and total bilirubin was 306.10 pmol/l (normal, 3.42-23.94) with the direct bilirubin component of 158.86 pmol/l: serum sodium was 152 mmol/l (normal, 135-145). and total serum calcium, remarkably, was 3.30 mmol/l (normal, 1.97-2.47). Hydration with normal saline and bolus injection with furosemide were administered for correction of metabolic disorder in general, and hypercalcaemia in particular. Gram-staining of the exudative discharge of the unroofed crusted cutaneous lesion did not disclose any micro-organism. Empirical administration of ceftriaxone was initiated after sampling blood for culture. The subsequent assay disclosed that the serum level of intact parathyroid hormone was cl.0 pg/ml (normal range, lo-65), and serology study for HIV antibody was negative. Though the blood culture yielded Salmonellagroup CL which was susceptible to the prescribed antibiotic, the patient’s clinical condition deteriorated, and hypercalcaemia and thrombocytopenia persisted. Therefore, amphotericin-B and anti-tuberculosis 0 199Y The British
Infection
Society
Case Reports
agents were empirically added. Skin section stained with hematoxylin and eosin (H&E) as well as Grocott silver methenamine showed epidermal necrosis and the dermis infiltrated with poly morphonuclear cells and macrophages with and without intracellular yeast-form microorganisms, accompanied by prominent leukocytoclasis. Unfortunately. the patient eventually died of overwhelming sepsis with multiorgan failure on day 10 of hospitalization. Subsequently. the blood. skin, and pleural effusion cultures on brain-heart infusion (BHI) agar with sheep blood at 3(X all yielded brownish mycelial colonies. The isolates microscopically showed round to pyriform smooth-surfaced microconidia and tuberculated macroconidia. Transferring of the mycelial-form pathogen on the other BHI agar for culture at 37°C for a further 2 weeks showed a conversion to a yeast-form pathogen. The cultured microorganism was sent to the AKUP Laboratories (Salt Lake City, Utah, 1J.S.A) for further confirmation, where it gave a positive hybridization test for H. crrpslllaturtl (AccuProbe: Gen-Probe Inc.. San Diego, CA. I1.S.A). The pathogen was thus unequivocally identified.
Discussion Though H. crr/&atlrrrl is widely distributed. histoplasmosis is most frequently encountered on American continent, and is endemic to midwestern and south central portions of the United States in particular,’ Cases of indigenous histoplasmosis have been reported in South-East Asian countries of Indonesia. Malaysia. Thailand. Vietnam, i the Philippines. and Singapore.’ The standard diagnostic tests for histoplasmosis are not always available in these regions and this may lead to underdiagnosis. The published reports suggest that histoplasmosis is endemic to certain areas of South-East Asia and that there may be a large number of undiagnosed and subclinical cases4 We speculate that our patient contracted histoplasmosis in Indonesia, because the histoplasmin skin test study conducted in 19 5 3 suggested no indigenous histoptasmosis in Taiwan at that time, and all patients with histoplasmosis in the reports from Taiwan had a history of travel outside Taiwan. i The spectrum of clinical mailifestations al histoplasmosis has been well described. Ilnfortunately, acute progressive DH. which requires urgent
89
diagnosis for initiating a timely antifungal therapy, often clinically overlaps with sepsis of other aetiologies. Cutaneous lesions, the marked sign drawing physician’s attention and offering an easily accessible biopsy, occurs in around 5% of the patients 01 acute 1)H with an underlying AIDS.” From the section of H&Ii stained biopsied specimen of the infected tissue. yeast-form fungi are relatively easily visualized.’ The yeast form of If. c’rrl~~rlntt~l should be differentiated from the extracellular cyst forms of I+7~urnocystis cc~inii’,~ and of Pmidliun~ mnr~j~~~:f,~ the intracellular amastigotes of Msltmmi~ spp.’ and the intracellular trophozoites of Torm~~lc~.s~~c~ gordii.‘~7 None of the latter two pathogens take up fungal silver stains. The cyst-form Prlcllrtloc:l/sti,s carirlii does not bud and is extracellular. PcGcilZitlrll rflnrrlc~.j?i. an increasingly reported pathogen in HIVinfected patients in South-East Asia, proliferates bv fission instead of budding: the cyst form of l’micillim mrmcfr’~i is. typically, sept ate and elongated.; An earlier report indicated that, before the AIDS epidemic, risk factors for disseminated or fatal histoplasmosis included elderly (> 54 years), haematologic malignancy, and treatment with corticosteroids or immunosuppressive agents.” A later report indicated that HIV infection is an important predisposing factor and DH occurred in about 5% of AIDS patients residing in histoplasmosis-endemic areas of the United States.’ We postulate that the prolonged severe diarrhoea rendered our patient malnourished. and in turn immunocompromixcd. As a result. the latent histoplasmosis reactivated. An earlier report”’ suggests that diffuse pat-asitization of reticuloendothelial system by tfi,stoplrr,srw~ organisms may cause reticuloendothelial blockade. which then predisposes to systemic salmonellosis. It is uncertain whether or not systemic salmonetlosis concurrently rendered mortality in the present case. Histoplasmosis is histopathologically a granulomatous disease.” Because of the familv’s disapproval. neither autopsy 01 biopsy of our patient’s deeplseated tissue was obtained for further proof. Kegardless of the aetiology of granuloma. the mechanism of the induced hypercalcaemia involved the extrarenat overproduction of serum calcitriol. which in turn augments calcium absorption from the gut and bone reabsorption.“,’ ’ It stands to reason that histoplasmosis can cause hypercalcaemia such as that seen in patients suffering from other granulomatous disease. Three additional cases of hypercalcaemia complicating DH were found in the literature (Table Il.” I” All three patients lvere immunocompromized. The host of one case ~‘as an infant having immature immunit!, who suffered from I)H with the manifestation of failure to thrive.‘” The two remaining patients were adults: one was previously splenectomized” while the other had diabetes mellitus. Ii and both had renal insufficiency. These t\vo adults died of severe sepsis shortlv after hospitalization. Remarkably, both of them had confound& factors to which hypercalcaemia could be ascribed. One had the undertying sarcoidosis and hot h had renal dysfunction. Patients in the previously reported cases and ours as well were non-AIDS sufferers. However, in view that hypercalcaemia complication has been noted in patients with advanced AIDS suffering from other granulomatous diseases, ‘: it is logical to assume that this complication possibly occurs in severely immunocompromized AIDS patients when they develop DH. because granulomatous diseases have similar pathophysiology.’ ’ In the ATIX era, any clue that is potentially suggestive ol opportunistic infections and the predisposing underlying AlUS should be highly \,alued. Since DH is an AIDS-defining disease in lll\~-infected patients. the reported cases imply that physicians should have a high index of suspicion for l>H and underl!?ng
Case Reports
90 Table
1. Summary of reported clinical features of disseminated histoplasmosis complicated with hypercalcaemia
Source
Walker rt of.I4
Murray et nl. Ii
Steele et al.“‘
Liu rt nl.
Sex
M 5 6 years
M 62 years
Previous splenectomy Renal insufficiency No
Diabetes mellitus Renal insufficiency No
M 10 months Immature immunity
M 46 years Malnourished (prolonged diarrhea)
No
Yes
Died
Died
Survived
Died
Age
Immunity condition Cutaneous lesions Outcome
AIDS upon facing patients with hypercalcaemia until it is proven otherwise. This implication is particularly important in South-East Asia where an increasingly high prevalence of AIDS exists, because histoplasmosis is endemic to this region and the effective diagnostic tools are not always readily available.
Acknowledgment The authors thank Dr Bill Safranek for his technical assistance
References
10
11
1 Bullock WE. Histoplasma
12
2
13
3 4
5
6
capsulatum. In: Mandell CL. Bennett JE. Dolin R, eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. 4th edn. New York: Churchill Livingstone. 199 5: 2340-2353. Centers for Disease Control and Prevention. Revision of the CDC surveillance case definition for the acquired immunodeficiency syndrome. MMWR 1987: 36(Suppl. 1): S3-S9. Randhawa HS. Occurrence of histoplasmosis in Asia. 1Mgcopath Mgcol Appll970; 41: 75-89. Wang TL, Cheah JS. Holmberg I<. Case report and review of disseminated histoplasmosis in South-East Asia: clinical and epidemiological implications. Pop Med Int Health 1996: 1: 35-42. Kao TW, Hung CC. Hsueh PR. Lin TY, et al. Microbiologic and histologic diagnosis of histoplasmosis in Taiwan. 1 Formosan A4rd Assoc lYY7: 96: 374-37X. Sarosi CA, Johnson PC. Disseminated histoplasmosis in patients infected with human immunodeficiency virus. Clin Infect Dis 1992: 14(Suppl. 1): S60-S67.
14
15 16 17
Kennedy MJ. Sigler L. Asprrgilltts, Fuswium, and other opportunistic monilianceous fungi. In: Murray PR. Baron EJ, Pfaller MA, Tenover FC. Yolken RH, eds. Manual of Clinical Microbiology. 6th edn. Washington DC: American Society for Microbiology. 1995: 765-790. Wheat LJ, Slama TG. Norton JA. et al. Risk factors for disseminated or fatal histoplasmosis: analysis of a large urban outbreak. Ann Intern MedlY82:96: 159-163. Johnson PC, Khardori N, Najjar AE Butt F, Mansell PWA, Sarosi GA. Progressive disseminated histoplasmosis in patients with acquired immunodeficiency syndrome. Am JMed 1988: 85: 152-l 58. Wheat LJ, Rubin RH, Harris NIL rt al. Systemic salmonellosis in patients with disseminated histoplasmosis. Arch lntrrn Med 1987: 147: 561-564. Zumla A, James DG. Granulomatous infections: aetiology and classification. Clin Infect Dis 1996: 23: 146-158. Barbour GL. Coburn JW. Slatopolsky E. Norman AW. Horst RL. Hypercalcaemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1, 25dihydroxyvitamin D. N Engl 1 Mrd 1981; 305: 440-443. Kozeny GA. Barbato AL. Bansal VK, Vertuno LL, Hano JE. Hypercalcaemia associated with silicon-induced granulomas. NEngl JMed 1984: 311: 1103-I 105. Walker JV, Baran D. Yakub YN. Freeman RB. Histoplasmosis with hypercalcaemia. renal failure, and papillary necrosis. JAMA 19 77: 237: 1350-1352. Murray JL. Heim CR. Hypercalcaemia in disseminated histoplasmosis. AmJMed 1985: 78: 881-X84. Steele CJ. Kleiman MB. Disseminated histoplasmosis. hypercalcaemia and failure to thrive. Pediatr Inject Dis J 1994: 13: 421-422. Spindel SJ, Hamill RJ. Georghiou PR. Lacke CE. Green LK, Mallette LE. Vitamin D-mediated hypercalcaemia in fungal infections. Am J MedSci 1995: 310: 71-76.