598 Thorax 1994;49:598-601 Tropical respiratory medicine * 3

Series editor: A Bryceson Thorax: first published as 10.1136/thx.49.6.598 on 1 June 1994. Downloaded from and pulmonary involvement in the tropics

S Houston

History and microbiology found in 4-34% of several populations in Histoplasmosis was first described by Darling Thailand with somewhat lower rates in in 1905, in a postmortem specimen from the Burma, India, and Malaysia. Information tropical country of Panama, although the from is more limited, but rates based on greater part of subsequent published experi- small samples range from 0% to 31% in ence has been from the United States.' The , 9% to 49% in Ivory Coast, and 1% to name reflects his 20% in Liberia, Mali, Sudan, Rwanda, Zaire, hypothesis that the organism was an encapsu- and South Africa. Findings in West Africa lated protozoan. The organism was cultured may reflect the presence of H capsulatum var and shown to be a in 1934.2 duboisii. Histoplasma capsulatum infection is The mycelial form produces spores which are found in both temperate and tropical regions, readily airborne and able to reach the small although rarely in areas that are very dry or bronchi and alveoli. The organism takes the have no warm season. form at body temperature; in histological Reports of clinical disease due to H capsula- specimens it is found almost exclusively in tum parallel, to some degree, the reported macrophages. The "capsule" is an artefact of prevalence of skin test sensitivity. Outside the certain stains such as haematoxylin and eosin. USA histoplasmosis is best documented in Histoplasma capsulatum var duboisii, a var- Latin America and the Caribbean. The num- iant found only in Africa, was first reported in ber of reported cases remains relatively small. http://thorax.bmj.com/ 1952.34 It is characterised by yeast cells which Up to 1978 only 34 cases of progressive forms are of larger size and with thicker walls in of histoplasmosis had been reported in Brazil, tissue section than those of H capsulatum var of which only four had mainly pulmonary capsulatum.5 Throughout this article the term disease.8 Five epidemics of acute histoplasmo- H capsulatum will be used to include both sis (four involving caves) had also been de- variants unless otherwise specified. scribed at that time, as had infections in several animal species. A review of 162 cases of deep mycoses from 6152 postmortem examinations on October 5, 2021 by guest. Protected copyright. Epidemiology and 85 386 biopsies and surgical specimens in Histoplasma is found in soil in endemic areas Columbia revealed only a single case of histo- and shows a striking association with sites plasmosis.9 Small numbers of cases have which are heavily contaminated with bat or been reported from Mexico'° as have cave- avian faeces. Disturbance of such sites - for associated epidemics of acute histoplasmosis example, by construction - can generate large from Costa Rica, Belize, and Panama."1-'3 numbers of airborne spores. Clusters of cases Three cases of acute histoplasmosis and two of acute histoplasmosis have been associated of chronic disease were found in Trinidad with these activities6 and with visiting bat in a study which also included Barbados and caves. Birds are not infected, probably because Guyana. '4 of their high body temperature, but bats may Small numbers of scattered cases only have be infected and excrete the organism in their been reported from south east Asia and Ocea- faeces. Other mammals are readily infected, nia.15'8 In New Caledonia, for example, a total but it is not known what part they play in the of five cases have been described, all with epidemiology of Histoplasma infection in hu- pulmonary involvement. A 1970 review de- mans. scribed only 30 cases of human histoplasmosis Our understanding of the prevalence and from Asia."9 Among these lung disease was distribution of the infection worldwide is identified in only six, although seven others based mainly on skin test surveys. These in- were considered "disseminated". Division of Infectious dicate rates of infection Histoplasma capsulatum var capsulatum has Diseases, 2E4.11 widely varying Walter Mackenzie between and within countries. Infection is been reported from several countries in Centre, University of nearly universal in some areas of the east Africa including some which overlap with Alberta Hospitals, central United States. Central America and the geographical range of H capsulatum var Edmonton, Alberta, Canada T6G 2B7 northern South America appear to have the duboisii.228 Calcifications on chest radio- S Houston next highest documented prevalences with graphy were associated with histoplasmin rates over 40% in certain of in both tuberculin and nega- Reprint requests to of populations reactivity positive Dr S Houston. several countries.7 Skin test positivity was tive Kenyans.29 Cave-related acute pulmonary Histoplasmosis and pulmonary involvement in the tropics 599

histoplasmosis has been described in Tanza- subacute clinical presentation usually resolve nia, Zimbabwe, and South Africa.3"33 spontaneously but with scarring, some loss of Disease due to H capsulatum var duboisii has lung tissue, and a risk of recurrence. The been recognised only in Africa (if Madagascar development of cavities, particularly with is included) or in individuals who have lived in thick walls, is an indicator of progressive dis- Thorax: first published as 10.1136/thx.49.6.598 on 1 June 1994. Downloaded from Africa. A review in 1986 found 206 reported ease. In H capsulatum endemic areas of the cases.34 While reported primarily from West USA it is estimated that 2-3% of patients Africa35-38 it has been found in patients from as diagnosed as having tuberculosis actually have far apart as Sudan,39 Ethiopia,40 Malawi,4' histoplasmosis, a diagnostic problem of par- South Africa,42 and Madagascar.43 The - ticular concern in tropical and developing ism has been identified in a small number of countries where tuberculosis is common and African animals, but little is known of its often diagnosed without microbiological con- ecology or the source of human infection.44 firmation. Furthermore, tuberculosis and histoplasmosis occasionally coexist.45 A defini- tive diagnosis may not always be possible, even Clinical features where fungal culture facilities are available, as The clinical spectrum of infection with H the sensitivity of sputum culture is only about capsulatum has been well documented, par- 60% in chronic pulmonary histoplasmosis.645 ticularly in the USA. No recognisable illness Serological tests are positive in most patients occurs in approximately 99% of infections with chronic pulmonary histoplasmosis, and following low level exposure to the organism; may support a clinical and epidemiological it is presumed to have been contained by cell diagnosis, but cross reactions with other fungal mediated immunity. Late reactivation of dis- infections can cause false positives.46 The ease can occur if the individual becomes clinical course, particularly when thick immunosuppressed. Persisting calcification in walled cavities are present, is usually one of the lung, lymph nodes, or is common. slowly progressive destruction of pulmonary Most symptomatic histoplasmosis falls into parenchyma. Antifungal treatment is usually one ofthree categories: acute, chronic pulmon- indicated, but some patients with chronic pul- ary, or disseminated disease. monary histoplasmosis have a poor response to Acute pulmonary histoplasmosis is a self- chemotherapy. limited illness characterised by fever with Disseminated histoplasmosis in children is headache, cough, or both, sometimes with characteristically a fulminant illness which chest pain and occasionally accompanied by may or may not have clinically apparent pul- erythema nodosum or multiforme. Following monary involvement. Less rapidly progressive high level point source exposure, the incidence disseminated disease, often with localised or- http://thorax.bmj.com/ of symptomatic illness may be over 50%. The gan involvement - for example, the meninges, incubation period in non-immune hosts is ap- adrenal glands, gastrointestinal tract, peri- proximately two weeks. The chest radiograph liver, spleen, and occasionally the but may show pulmonary cardium, is usually normal, lungs - may be seen in adults who often have infiltrates or hilar adenopathy in more severe of underlying deficiency in cell cases. The diagnosis is usually made when a some degree epi- mediated immunity. cluster of cases occurs in the appropriate clinical syndrome has been associ- demiological setting - for example, after visit- A distinct but ated with H capsulatum var duboisii. The on October 5, 2021 by guest. Protected copyright. ing a bat cave. Cultures are rarely positive, fre- serological examination can confirm the diag- clinical picture is characterised by a high nosis. The illness almost always resolves with- quency of skin, bone, and lesions out treatment. with occasional mucous membrane and gas- Chronic pulmonary histoplasmosis is a rela- trointestinal involvement.3738 Several authors tively well defined clinical syndrome in histo- have commented on the relative rarity of pul- plasmosis endemic areas. Even in populations monary disease in H capsulatum var duboisii where H capsulatum infection is nearly univer- infection.3637 No clinical or radiological evid- sal, the incidence of chronic pulmonary histo- ence of pulmonary disease was found in one plasmosis is estimated to be only one per series of 56 cases.37 Clark and Greenwood, 100 000 per year.45 In a series of 118 patients however, reported 12 cases with some evidence with chronic pulmonary histoplasmosis almost of pulmonary involvement and a number of all were smokers and most had evidence of reports have described cases with either loca- chronic obstructive airway disease or emphy- lised pulmonary involvement, or involvement sema.45 It is thought that underlying lung as part of a disseminated process, or at post- disease is a usual, if not a necessary, precondi- mortem examination.2>384752 If pulmonary tion for the development of chronic pulmonary disease is indeed less frequent in infections histoplasmosis. The clinical presentation is with H capsulatum var duboisii than with similar in many ways to tuberculosis although H capsulatum var capsulatum, it is not clear chest pain was more common and night sweats whether this is because of differences between less frequent in the series reported by Good- the two organisms or because of a lower pre- win et al.45 Histoplasmosis shares with tuber- valence in Africa of the emphysematous culosis a predilection for apical and posterior changes which predispose to chronic pulmon- segments of the lung as well as for slowly ary histoplasmosis. Host characteristics could progressive fibrotic lesions and calcification on also play a part as chronic pulmonary histo- chest radiography. "Early" non-cavitating plasmosis occurs more frequently in white pulmonary lesions associated with an acute or than black subjects in the USA.45 600 Houston

Treatment itraconazole alone is often effective, even in Amphotericin B is the established treatment HIV-infected patients.5967 for patients who are seriously ill with histo- Relapse is very common unless suppressive plasmosis. Ketoconazole, usually for at least treatment with either intermittent amphoteri- Thorax: first published as 10.1136/thx.49.6.598 on 1 June 1994. Downloaded from six months, is effective in most of those with cinm or daily oral itraconazole is continued less acute forms of disease. The response of indefinitely. Ketoconazole appears not to be H capsulatum var duboisii to drug treatment adequate either for initial treatment or sup- appears to be similar to that of H capsulatum pression of relapse in HIV-infected patients. var capsulatum.5354 Early experience in H cap- Achlorhydria, which is common in patients sulatum var capsulatum infection with triazole with AIDS, significantly reduces absorption of drugs, particularly itraconazole, suggests that this drug. it is likely to be at least as effective as ketocon- azole and may be better tolerated.5 Conclusions Although histoplasmosis is not likely to be a Histoplasmosis and HIV infection common cause of lung disease anywhere in the Histoplasmosis was not added to the list of tropics, it is probably underdiagnosed because AIDS-defining conditions until 1987, yet in of the technical difficulties of microbiological histoplasmosis endemic areas of the USA it diagnosis and the likelihood of confusion may be the leading opportunistic infection in with tuberculosis. Histoplasma capsulatum var AIDS.56 Histoplasma capsulatum var capsula- duboisii is a pathogen unique to Africa; it is not tum associated with HIV infection has now yet clear whether this organism is truly less been reported from tropical co-endemic reg- likely to cause pulmonary involvement than is ions such as the Caribbean, Africa, and South H capsulatum var capsulatum in Africa. Histo- America.57-59 There are also a few reports of plasmosis as an opportunistic infection in disseminated H capsulatum var duboisii associ- HIV-infected patients is likely to be recog- ated with HIV infection."' nised increasingly in the tropics. These obser- Histoplasmosis was the AIDS-defining ill- vations may add to our understanding of the ness in just under half of the patients in two geographical distribution of histoplasmosis by series,6465 suggesting that it can occur earlier in demonstrating previously unrecognised ende- the course ofHIV-related immunosuppression mic areas. While histoplasmosis is a relatively than is the case with such opportunistic treatable complication of HIV infection, the infections as Mycobacterium avium. Fever and limited availability of sophisticated diagnostic weight loss are almost invariably present. Res- facilities and the present high cost of treatment piratory symptoms are present in more than are likely to limit the possible benefits of http://thorax.bmj.com/ half of the cases. A reticulonodular pattern is treatment for many affected patients in the seen on the chest radiograph in more than tropics. half,65 while mediastinal lymphadenopathy 1 Darling ST. A protozoan general infection producing was noted in only 2 8-45% of cases.64 Calcifi- pseudo tubercles in the lungs and focal necrosis in the cation in the lung or mediastinum was present liver, spleen and lymph nodes. JAMA 1906;46:1283-5. in only 2-5% of American patients. Hepato- 2 DeMonbreun WA. The cultivation and cultural character- istics of Darling's H capsulatum. Am J Trop Med megaly or splenomegaly are seen in a substan- 1934;14:93-125. 3 Dubois A, Janssens PG, Brutsaert P. Un cas d'histoplas- on October 5, 2021 by guest. Protected copyright. tial minority, and skin or gastrointestinal tract mose africaine, avec une note mycologique sur Histo- involvement in a few. A septic shock-like plasma duboisii n. sp. par R Van breuseghem. Ann Soc Beig Med Trop 1952;32:569-84. picture with coagulopathy has also been 4 Duncan JT. Tropical African histoplasmosis. Trans R Soc described. Trop Med Hyg 1958;52:468-74. 5 Kwon-Chung KJ. Perfect state (Emmonsiella capsulata) of In HIV-infected patients the diagnosis of the fungus causing large-form African histoplasmosis. histoplasmosis is usually made by isolation of Mycologia 1975;67:980-9. 6 Wheat LJ, Wass J, Norton J, Kohler RB, French MLV. the organism from blood or tissue. Wheat et al Cavitary histoplasmosis occurring during two large urban found the rate of positive cultures of both outbreaks. Medicine 1984;63:201-9. blood and bone marrow to be > 90% when a 7 Edwards PQ, Billings E. Worldwide pattern of skin sensiti- vity to histoplasmin. Am J Trop Med Hyg 1971;20:288- lysis centrifugation technique was used.64 Cul- 319. 8 Londero A, Ramos CD. The status of histoplasmosis in ture of respiratory secretions or lung biopsy, Brazil. Mycopathologia 1978;64:153-6. urine, lymph node tissue or biopsy of other 9 Pena CE. Deep mycotic infections in Colombia. Am J Clin Pathol 1967;47:505-20. clinically involved tissue may be diagnostic. 10 Ortega RA. Deep mycoses in Mexican children. It J An immediate diagnosis can sometimes be Dermatol 1974;13:287-92. 11 Centers for Disease Control. Cave-associated histoplasmo- made from microscopic examination of bone sis-Costa Rica. MMWR 1988;259:3535-6. marrow or even peripheral blood. Antigen 12 Larrabee WF, Ajello L. Kaufman. An epidemic of histo- plasmosis on the isthmus of Panama. AmJ Trop Med Hyg detection shows promise as a tool for diagnosis 1978;27:281-5. and following response to treatment.66 13 Quinones F, Koplan JP, Pike L, Staine F, Ajello L. Histo- plasmosis in Belize, Central America. Am J7 Trop Med Depending on the technique and the labora- Hyg 1978;27:558-61. tory, serological tests for histoplasmosis may 14 Hay RJ, White HS, Fields PE, Quamina DBE, Dan M, Jones TR. Histoplasmosis in the eastern Caribbean: a be positive in >70% of patients with HIV preliminary survey of the incidence of the infection. infection and histoplasmosis,64 but there is J Trop Med Hyg 1981;84:9-12. 15 Ajello L. The mycoses of Oceania. Mycopathol Mycol Appl little experience in relying on this as a primary 1972;46:87-95. diagnostic method in this patient population. 16 Huerre M, Ravisse P, Dubourdieu D, Morillon M, McCarthy S, Bobin P. Les mycoses profondes observees Amphotericin B is considered the standard en Nouvelle-Caledonie. Bull Soc Pathol Exot Filiales treatment for HIV-associated histoplasmosis 1991;84:247-56. 17 Apperloo AJ, Nelis GF. Asian form of disseminated histo- and has been associated with a response rate of plasmosis diagnosed by CT-guided biopsy of the adrenals at least 80%. Two recent reports suggest that treated with ketoconazole. Neth I Med 1988;33:225-31. Histoplasmosis and pulmonary involvement in the tropics 601

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