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Home , Histoplasma capsulatum, Histoplasmosis

REVIEW ARTICLE

Occurrence of in the Indian Sub-Continent: An Overview and Update https://doi.org/10.20936/jmrp/07/03/02

Harbans S Randhawa* and Harish C Gugnani** ISSN : 2162-6391 (Print) 2162-6375 (Online)

ABSTRACT The occurrence of histoplasmosis and its environmental sources of infection are reviewed. It covers the regional distribution of 388 cases of histoplasmosis reported since 1995 to till date. The highest number of cases occurred in West Bengal, followed by Uttar Pradesh, Delhi Union territory (UT), Rajasthan, Maharashtra, Haryana, and Bihar. A sharp rising trend in reporting cases observed in recent years is particularly noteworthy. Also, discussed are the variable clinico-pathological manifestations of 388 cases from India, 20 from Bangladesh, five from Nepal, four from Pakistan, and three from Sri Lanka. Being a primary pathogen, the etiological agent capsulatum can infect immunocompetent as well as the immunocompromised patients. The disease is fatal unless diagnosed early and treated with specific drugs. It has a predilection for reticuloendothelial system, leading to , a prominent feature of disseminated histoplasmosis. It poses an ever-increasing threat to public health due to burgeoning population of immunocompromised patients resulting from the spread of AIDS and immunosuppressive therapy in patients undergoing organs transplantation. Non-recognition of the true burden of histoplasmosis in the Indian sub-continent is attributed to possible misdiagnosis as , malignancy or other diseases, and to lack of awareness and inadequate mycological diagnostic facilities. The need for exploring the natural foci of H. capsulatum infections, using molecular techniques, and delineating the endemic zones of histoplasmosis is strongly emphasized. Core tip Nomenclature of Histoplasma, its ecology, pathogenesis, clinical spectrum and laboratory diagnosis, and regional distribution of histoplasmosis in India are described. The highest number of cases of the disease occurred in West Bengal. The varying clinical manifestations of 388 cases from India, 20 from Bangladesh, five from Nepal, four from Pakistan, and three from Sri Lanka are described. The decade-wise occurrence of histoplasmosis in India showed a rising trend of reporting 200 cases being recorded during the period 2004–2013, and 161 cases from 2014 to till date. In view of the available evidence, histoplas- mosis is endemic in the subcontinent. However, supportive scientific evidence like demonstration of natural reservoirs of the pathogen and its occurrence in the local animal populations remains largely unexplored. KEYWORDS histoplasmosis, var. capsulatum, Indian, subcontinent, update

INTRODUCTION histoplasmosis. The organism may also enter the body Histoplasmosis is a non-contagious systemic fungal through the mouth, and from there can cause infec- infection of worldwide distribution, caused by a ther- tion in the intestines1,2. Histoplasmosis in humans has mally dimorphic , Histoplasma capsulatum which two clinical entities: Histoplasmosis capsulati caused by thrives in a warm and humid environment such as soils H. capsulatum var. capsulatum (Darling’s disease, enriched with nitrogenous compounds and phosphates American histoplasmosis, classical histoplasmosis, small derived from avian excreta and . The microco- form histoplasmosis), and Histoplasmosis duboisii caused nidia and short hyphal fragments of Histoplasma when by H. capsulatum var. duboisii, commonly called African inhaled by mammalian hosts reach the alveoli, followed histoplasmosis (large form histoplasmosis). Investigators by the rapid conversion to its form that can per- linked to the division of medical mycology, VPCI, have sist in host tissues and may disseminate through the been interested since 1960 in clinical and epidemiologi- bloodstream and lymphatics to other organs, causing cal aspects of histoplasmosis3. The first case of histoplas- mosis from India was reported in 1954 by Panja and Sen4 *I /4"&NFSJUVT4DJFOUJTUFY%JSFDUPS from Kolkata. A survey on skin testing with histoplasmin ** 3FUE1SPGFTTPS)FBE %JWJTJPOPG.FEJDBM.ZDPMPHZ %FQBSUNFOUPG.JDSPCJPMPHZ on small segments of population residing in rural, urban 7BMMBCICIBJ1BUFM$IFTU*OTUJUVUF 71$* 6OJWFSTJUZPG%FMIJ %FMIJ *OEJB and riverine area was performed by Viswanathan et al.5 Corresponding author: 1SPG 3FUE Harish C Gugnani during the period 1957–1959. The prevalence of 12.3% J 3/45, Rajouri Garden, New Delhi 110027, India. histoplasmin sensitivity found in the riverine area was Email: [email protected] the highest reported from any part of India. However, Conflicts of interest: None. no case of histoplasmosis was detected among the pos- Source of funding: None. itive reactors. Data on histoplasmin sensitivity in other Author contribution: Both authors contributed equally. parts of India have been reviewed by Randhawa and

J Med Res Prac | Volume 07 | Issue 03 | 71–83 Received: 01 March 2018 Accepted: 21 may 2018 Published Online: 06 June 2018 72 Harbans S Randhawa and Harish C Gugnani

Khan6. Since then, the disease has been the subject of a temperature of 22–29°C and relative humidity of 67–97% large number of case reports7–9, and several reviews10–12. for optimum growth. Activities such as cleaning of chicken A rare case of epididymal histoplasmosis masquerad- coops, visiting bat-infested caves or other such sites, exca- ing as tuberculosis diagnosed by culture of semen was vation, demolition and remodeling of old buildings, and reported by Randhawa et al.13 This paper reviews the cutting of dead trees lead to disruption of soil containing clinico-pathological and epidemiological features of the organism, and aerosolization of microconidia2. the 388 cases of histoplasmosis, reported in India since 1995, and also those reported from Bangladesh, Nepal, Clinical spectrum and laboratory diagnosis Pakistan, and Sri Lanka. Histoplasmosis caused by H. capsulatum var. capsulatum METHODS is a disease of reticuloendothelial system. A majority (50–90%) of the infections result in clinically insignifi- All publications on histoplasmosis in the Indian sub- cant or mild -like illness. continent were scanned by thorough search of the litera- Some infections may cause pulmonary histoplas- ture, using PubMed, MEDLINE, Biomed Lib, Med Facts, mosis, manifested by non-productive cough, dyspnea, and different sets of keywords, viz. India, Bangladesh, hoarseness, chest pain, cyanosis associated with fever, Pakistan, Nepal, Sri Lanka, Bhutan, histoplasmosis, sys- , muscle/joint pain, weight loss, malaise, and temic/deep mycoses, etc. Besides, cross-references in the fatigue. Acute pulmonary histoplasmosis may be con- papers collected were accessed. All of the papers were fused with tuberculosis/miliary tuberculosis2, although critically reviewed to extract relevant clinico- pathological involvement of upper lobes and pleural effusion is more features and demographic data of each case. Cases diag- common in the latter1,2. Chest X-ray findings in most nosed solely on clinical suspicion without histopatholog- patients with asymptomatic pulmonary histoplasmo- ical evidence or positive cultures were excluded. sis are normal. A single pulmonary nodule is, however, frequently seen. Most patients recover within 2 weeks OBSERVATIONS of onset of symptoms, although fatigue may persist longer. Progressive disseminated histoplasmosis occurs Nomenclature of Histoplasma and its ecology in approximately 10% of the patients with hepatospleno- Histoplasmosis has three clinical entities with separate megaly, fever, anemia, leukopenia, weight loss, and gen- etiologic agents (Table 1). Based on phenotypic char- eralized , pulmonary symptoms being acters, Histoplasma is divided into three varieties, viz. less prominent2. Males are more frequently affected than H. capsulatum var. capsulatum, H. capsulatum var. duboi- females by 4:1 ratio. Patients with AIDS are at high risk sii and H. capsulatum var. farciminosum. The commonest for disseminated histoplasmosis; prevalence rates range environmental sources of H. capsulatum var. capsulatum is 2–27% in United States and 29% in India1,6. are soil around chicken houses, under roosting gregarious Laboratory diagnosis of histoplasmosis is based on birds such as , blackbirds, and soil of bat- infested histopathology/cytopathology, recovery of Histoplasma caves or old buildings (CFU can exceed 105/g of soil/bat in culture from clinical samples, serological tests for guano)1,2. Birds cannot be infected by the fungus and do , and detection. Cultures are 58–85% not transmit the disease. However, avian excreta contam- positive in cases of disseminated and chronic forms of inate the soil, thereby providing an enriched medium for histoplasmosis; usually, up to 4 weeks is required to iso- growth of the fungus. On the other hand, can get late the organism in culture2. Several culture media have infected and transmit H. capsulatum to new sites through been used for recovery of H. capsulatum var. capsulatum their droppings1,2. The fungus is found in the upper 15 cm from clinical specimens. In our experience, brain-heart of soil, never deeper than 22.5 cm, and requires a mean infusion (BHI) biphasic medium appears to be the best

TABLE 1 Nomenclature of Histoplasma, natural habitats and geographic distribution. Geographic Etiological agent* Clinical entity Yeast form morphology Natural habitat distribution H. capsulatum var. capsulatum Histoplasmosis (histoplasmosis Globose or ovoid 2–4 μm, thin- Soil enriched with Worldwide with variable (Teliomorph Ajellomyces capsualtus) capsualti, classical histoplasmosis) walled cells with a narrow base avian or bat excreta endemicity H. capsulatum var. duboisii Histoplasmosis duboisii (African Ovoid 6–15 μm thick-walled Rarely isolated Central and West Africa, (Teliomorph Ajellomyces capsualtus) histoplasmosis, large form histoplasmosis) cells with a broad base from soil and Madagascar H. capsutatum var. farcinimosum Histoplasmosis farciminosi Ovoid 2–3 μm, thin-walled Unknown Africa, Asia and Europe (Teliomorph Ajellomyces capsualtus) (epizootic lymphagitis) cells with a narrow base *Studies of isolates of H. capsulatum from Europe, Australasia, Asia, Netherlands, North America and by Kasuga et al.14 and Teixeira et al.15 have detected several phylogenetic clades, suggesting that the existing varieties are taxonomically invalid.

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TABLE 2 Regional distribution of histoplasmosis reported from India (1995-to-date). State/Union Territory No. of cases References West Bengal 56 9, 16–39 Uttar Pradesh 37 9, 12, 13, 40–61 Delhi 26 62–83 Rajasthan 24 60, 84–93 Maharashtra 20 94–109 Haryana 19 60, 110–119 Bihar 18 9, 12, 60, 120–123 Chandigarh 17 124–129 Tamil Nadu 15 9, 21, 130–134 Assam 13 9, 21, 135–137 Kerala 11 9, 138–143 Karnataka 10 144–152 Andhra Pradesh 8 9, 153–156 Gujarat 8 93, 157 Madhya Pradesh 5 158–162 Manipur 5 163–166 Odisha 5 9, 167–170 Himachal Pradesh 4 171–174 Punjab 4 175–178 Uttarakhand 4 179–182 Telangana, Meghalaya, Tripura, Chhattisgarh, Jammu & 10 21, 183–189 Kashmir, Jharkhand Cases of unknown origin 69 12, 190–199 Total 388 for rapid recovery of maximum growth of H. capsula- tum. Yeast phosphate and BHI agar are nearly as good as these media also recover multiple colonies of the fungus. Galactomannan antigen detection in body fluids offers a rapid means of diagnosis. The antigen is detectable in 80–95% of cases of progressive disseminated and sub- acute histoplasmosis2.

Magnitude of problem in India

The data on the occurrence of histoplasmosis in India reported since 1995 is presented in Table 2 and depicted in Fig. 1. West Bengal accounted for the high- est number of 56 cases, followed by Uttar Pradesh, Delhi (UT), Rajasthan, Maharashtra, Haryana, and Bihar. The diagnosis of a majority of the cases was based on histological/cytopathological demonstration of the char- acteristic yeast form of H. capsulatum. Confirmation by culture was done in about 20% of the cases. Additional Fig. 1 3FHJPOBMEJTUSJCVUJPOPGDBTFTPGIJTUPQMBTNPTJTSFQPSUFEGSPN*OEJB tests, viz. serology, PCR, and sequencing were done only UPEBUF  in a few cases. The literature search did not reveal the

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occurrence of any case from the States of Arunachal , and renal transplant. It is notewor- Pradesh, Goa, Mizoram, Nagaland, and Sikkim, and the thy that adrenal histoplasmosis was frequently observed Union Territories of Daman and Diu, Dadra and Nagar in transplant recipients. Adrenal involvement also seems Haveli and Pondicherry, and Andaman and Nicobar, and to be common in immunocompetent patients with dis- Lakshadweep islands. Histoplasmosis possibly occurs in seminated histoplasmosis. Sometimes cutaneous lesions these areas but has not been detected due to lack of aware- were the only sign of serious systemic histoplasmosis in ness among the physicians and paucity of laboratory post-transplant patients. A number of cases occurred diagnostic facilities. It is noteworthy that a large number in association with hemophagocytic lymphocyto- of cases of oral and adrenal histoplasmosis (mostly in sis29,43,62,169,178,180; other unusual comorbidities included renal transplant recipients) have been documented hairy cell leukemia with ascites28, juvenile SLE38, lym- during the period under review. The decade-wise occur- phoidal co-infection with cryptococcosis55, CMV infec- rence of histoplasmosis is shown in Table 3 and depicted tion58, aplastic anaemia74, Coomb’s positive hemolytic in Fig. 2. Notably, the number of cases reported during anaemia90, myelodysplastic syndrome/myeloproliferative the period 1954–1993 was 37, followed by a sharp rising neoplasm (MDS/MPN)128, mixed phenotype leukemia129 trend of reporting. Thus, 200 cases were recorded during and BK virus nephropathy194. Another unusual case of the period 2004–2013, and 161 during the period from comorbidity was the occurrence of rectal histoplasmosis 2014 to till date. This significant change can be attributed in a patient with Job’s syndrome51. A few cases of oral his- to increased awareness among clinicians, pathologists toplasmosis simulated carcinoma111,122,149, whereas some and microbiologists, and their collaboration. The avail- laryngeal/pulmonary/disseminated cases mimicked ability of enhanced laboratory facilities in many medi- and laryngeal carcinoma79,95,110,143,159,181. Likewise, one cal colleges and hospitals in some parts of the country is each case simulated lepromatous leprosy82, non-Hodgkin another contributing factor for increased reporting from lymphoma83, idiopathic thrombocytopenic purpura89, those areas. abdominal tuberculosis98,187, Langerhans cell histiocyto- The predominant clinical features and the involve- sis134, and two cases of eyelid involvement simulated basal ment of different organs in the cases reviewed were cell carcinoma109,152. Some other unusual presentations of essentially the same as described previously2.6,7,11,12. The histoplasmosis were parenchymal diseases with ascites24, commonest comorbidities were HIV infection, diabetes, colonic pseudotumors67, portal hypertension with bone involvement105, pancreatic head mass with gastric outlet TABLE 3 Data on decade-wise occurrence of histoplasmosis in India, obstruction114, and and prostatitis148. The showing a sharp rising trend in its reporting during the decade 2004–2013, frequent involvement of gastrointestinal tract in several and thereafter during the period of 2014-to-date. cases as observed in the current review points out the Period No. of cases need for considering gastrointestinal histoplasmosis in the differential diagnosis of malignancy, inflammatory 1954–1963 4 bowel disease, and intestinal tuberculosis. Oral lesions 1964–1973 14 were common in the series of cases in our review, involv- 1974–1983 12 ing several sites, viz. buccal mucosa, tongue, gingivae, 1984–1993 7 and palate; in many of the cases there was no indication 1994–2003 28 of pulmonary lesions. However, the prior occurrence of self-resolving pulmonary histoplasmosis cannot be ruled 2004–2013 200 out. In tuberculosis-endemic regions as in the Indian 2014-to-date 161 sub-continent, disseminated histoplasmosis can easily Total 426 be mistaken for tuberculosis owing to its similar clini- cal presentation. Presence of military shadows in chest X-ray is frequently attributed to tuberculosis without further etiological investigation1,2. In patients with pro- longed fever, hepatosplenomegaly, and lymphadenopa- thy, histoplasmosis must be considered in the differential diagnosis, particularly, if there is no response to empir- ical anti-tubercular therapy (ATT). Further, in patients of pulmonary histoplasmosis with pre-existing lung dis- ease, hilar, and peripheral lymphadenopathy, radiologi- cal signs suggestive of histoplasmosis may not be present. Also, several cases of histoplasmosis in the subcontinent may present as non-healing oral ulcers mimicking muco- cutaneous leishmaniasis. It needs to be emphasized that Fig. 2 %BUBPOEFDBEFXJTFPDDVSSFODFPGIJTUPQMBTNPTJTJO*OEJB TIPXJOH histoplasmosis should be considered in the differen- BTIBSQSJTJOHUSFOEJOJUTSFQPSUJOHEVSJOHUIFEFDBEF BOE tial diagnosis of patients with mucocutaneous lesions, UIFSFBGUFS UPEBUF . J Med Res Prac | Volume 07 | Issue 03 | 71–83 Histoplasmosis in the Indian subcontinent 75

hepatosplenomegaly, adrenal insufficiency, malignancy, reported. The clinico- epidemiological features of 20 pub- inflammatory bowel disease, and in patients clinically lished cases are provided in Table 4. All of the patients diagnosed as oral and abdominal tuberculosis. were adult males of aged 30–75 years. As is evident, most of the cases were disseminated with varying clini- CASES IN BANGLADESH, NEPAL, PAKISTAN, AND SRI LANKA co-pathological manifestations, viz. hepatosplenomeg- aly, generalized lymphadenopathy with oropharyngeal A brief account of the histoplasmosis cases reported and laryngeal ulcers, bilateral adrenomegaly, and skin from Bangladesh, Nepal, Pakistan, and Sri Lanka is given lesions in the form of a generalized maculopapular in Table 4 along with references. or hyperpigmented skin nodules. Four of the patients had AIDS, one of them with concurrent esophageal candidi- Bangladesh asis; in addition to the five patients gave a history of TB with ATT. One of the patients had Crohn’s colitis. It is In a histoplasmin skin sensitivity survey in Bangladesh worth mentioning that eight of the patients were farm- (when it was called East Pakistan) in 1962200, 2,729 persons, ers, and one each was a building maintenance and brick- including patients in the hospital, students and nurses, field worker. One of the patients, immigrant in workers in a jute mill, a paper mill, and staff and students (Sr. no 5) had made several visits to Bangladesh, the last of an agricultural farm area were tested. There was no sig- one 6 months prior to his illness. Diagnosis of all the nificant difference in the number of positive reactors to cases was based on histopathology, barring one culture histoplasmin in the first four groups (12.58–13.75%), but positive for H. capsulatum. the number of positive reactors in the agricultural farm was nearly double (23.18%) of that of any other group. Nepal Subsequently in 1971201, 461 of 2,522 (17.92%) patients in institutions of tuberculosis and other chest diseases were Four autochthonous cases have been reported. found to be positive reactors. These surveys indicated Additionally, one case has occurred in a Nepalese endemicity of histoplasmosis in Bangladesh. Recently, migrant to United Sates with evidence of infection an increasing number of histoplasmosis cases have been being acquired in Nepal (Table 4). Four of these cases

TABLE 4 Histoplasmosis in Bangladesh, Nepal, Pakistan, and Sri Lanka. Sr. no Age/sex Place of reporting Clinico-pathological manifestations References Bangladesh 1 60 M Dhaka Oral hepato-, odynophagia Islam et al. Bangladesh Med Res Counc Bull. 1982;8:21–22. 2 40 M Qatar h/o frequent Splenomegaly, bilateral adrenomegaly fever, night sweating Al Ani MA et al. Qatar Med J. 2002;11:57–59. visits to Bangladesh 3 41 M Chittagong Hepato-splenomagaly, , high fever, weight Rahman MM et al. J Bangladesh Coll Phys Surg. loss with AIDS & esophageal 2005;23:43–45. 4 Adult Vellore, Disseminated histoplasmosis. Details of organ involvement not Subramanian et al. JAPI. 2005;53:185–189. Tamil Nadu, India known. Weight loss and fever 5 60 M New York Hyperpigmented nodules on left cheek and right fore-arm. Rappo U et al. Transpl Infect Dis. 2010;12: Had a renal transplant 155–160. 6 57 M Dhaka Generalized lymphadenopathy, hepatomegaly, backache, fever, Parvin et al. J Med. 2010;11:170–175. spastic paraplegia, paravertebral soft tissue mimicking TB 7 45 M Not given Generalized lymphadenopathy, oral ulcers, odynophagia, Parvin et al. J Med. 2010;11:170–175 fever, abdominal pain and jaundice, history of ATT

8 45 M Dhaka Generalized lymphadenopathy, oral ulcers, odynophagia Shamin Ahmad Md et al. BSMMU J. 2010;3: fever, ascites, weight loss 44–46 9 56 M Dhaka Respiratory distress, fever disorientation, cough Mehbub Md S et al. J Med. 2010;11:70–73 10 32 M Not given Supraclavicular lymphadenitis, multiple ulcers in nasopharynx, fever, Parvez Md M et al. Health Popul Nutr. weight loss, anorexia 2010;28:305–307. 11 75 Gopalganj Bilateral adrenomegaly, partial adrenal insufficiency, anorexia, Sarwar-e-Alam AMB et al. J Bangladesh Coll Phys evening fever with chills, weight loss Surg. 2011;235–240. 12 60 M Dhaka Oral ulcers, bilateral sub-mandibular lymphadenopathy, odynophagia Sadat SMA et al. J Bangladesh Coll Phys Surg. 2012;30:229–233.

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TABLE 4 Histoplasmosis in Bangladesh, Nepal Pakistan, and Sri Lanka—(Continued). Sr. no Age/sex Place of reporting Clinico-pathological manifestations References 13 65 M Dhaka Oral ulcers, bilateral sub-mandibular lymphadenopathy, odynophagia Sadat SMA et al. J Bangladesh Coll Phys Surg. 2012;30:229–233. 14 30 M Northern Bangladesh Cough, fever, weight loss, anorexia, hyper-pigmented papular Bhuyian MNZ et al. JAFMC Bangladesh. (Place unspecified) eruptions on several parts of the body, bleeding from ear, nose, gums 2012;8(2);81–86. and rectum, severe anemia with AIDS 15 45 M Dhaka Oral and genital ulcers, hepatomegaly, generalized maculo-papular Yasmin R et al. Bangladesh J Med. 2013;24:78– rash 81. 16 62 M Dhaka Generalized lymphadenopathy, mild hepatomegaly, spastic Singha CK et al. J Med. 2013;4:201–203. para-plague, fever, back pain 17 65 M Dhaka Hepato-splenomegaly, oral ulcers. History of pulmonary TB with Sadat SMA et al. Med Today. 2013;5:99–102. irregular ATT, Heavy smoker 18 32 M Parbotinogar, Dhaka Bilateral adrenomegaly, hepato-splenomegaly, fever, weight loss, Parvin R, Rafique Udin AKM. J Gen Pract. anorexia, history of ATT for presumed TB 2013;1:103. doi:10.4172/2329-9126.1000103 19 60 M Mymensingh Ulcerative growth in the left vocal cord, cough, hoarseness. History of Maasud MK et al. Mymensingh Med J. ATT for presumed TB 2014;23(3):566–567. 20 34 M New York, USA Crohn’s colitis with persistent bloody diarrhea, high grade fever and Marion-Anna P et al. Inflamm Bowel Dis. 2014;20 joint pains. Colonoscopy revealed shallow rectosigmoid ulcers. (Suppl 1):S27–S28. doi:10.1097/01. MIB.0000456773.37078.b6 Nepal 1 59 M Not given Hepato-splenomegaly, bilateral adrenomegaly, thrombovytopenia Sookpraneet et al. J Infect Dis Antimicrob Agents. chronic fever, diabetic 1993;10(1):35–38. 2 40 M Dhahran Multiple, painless, non-healing, discharging lesions on the anterior Koirala et al. Health Renaissance Case Rep. chest wall for the last 6 years. 2010;7(1):61–63. 3 52 M Kathmandu Bilateral adrenomegaly, fever, fatigue, weight loss Subedi et al. JSSN. 2014;17(1):42–43. 4 65 F New York Painless ulcer on the dorsum of tongue, fever, productive cough, chest Gandhi V et al. Chest Imaging and Pathology for pain. Chest X-ray showed dense opacity in the right lung. h/o of ATT Clinicians. 2015;147(4):e140–e147. in Nepal 5 14 M Rural Nepal (District Persistent multiple skin lesions on face, dry cough, hepato- Thapa S et al. Am J Trop Med Hyg. not specified) splenomegaly, complicated by severe mitral stenosis. Chronic 2016;94(2):249–250. exposure to chickens. h/o rheumatic heart disease Pakistan 1 45 M Karachi Bilateral basal infiltrates in the . Paratracheal, crainal, anterior Zia SA et al. JPMA. 2002. August issue. aortic and hilar lymphadenopathy, hepatosplenomegaly, bilateral adrenal gland enlargement, fever, weight loss, Jaundice, and history of ATT 2 Adult M Karachi Endocarditis Bhatti S et al. J Infect. 2005;51(1):2–9. (age?) 3 5 M Karachi Mediastinal, para-aortal and mesenteric lymphadenitis, h/o**, Qureshi A. JPMA. 2008;58(8):457–458. ATT*** 4 60 M Battagram Chest pain, weight loss, dry cough, pleural effusion with h/o of ATT Aziz R et al. Unpublished data from Ayub Teaching and left hydro-pneumothorax and long standing diabetes Hospital, Abbottabad. Sri Lanka 1 Not Not given Ulcers in the buccal cavity. Details of the case not known Jayaweera FRB et al. Ceylon Med J. known 1975;20(1):45–47. 2 30 M Kandy Oral ulcers and multiple, enlarged submandibular and submental Karunanayake L. et al. Abstract in the Bulletin lymph nodes. HIV-positive. Had non-Hodgkin lymphoma with of the Annual Academic Sessions of the Kandy extensive abdominal and pelvic lymphadenopathy Society of Medicine in February, 2009. 3 24 F Germany Disseminated histoplasmosis with hepatosplenomegaly, multiple Harten P et al. Clin Investig. 1994;72(11): lymphadenopathy, ascites, fever, thrombocytopenia and polyserositis 878–882. diagnosis based on histopathology

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were disseminated, involving the lung, liver and spleen, of Maharashtra. Investigation of 630 small wild animals or adrenal glands; the fifth had multiple discharging belonging to 11 species and 10 genera from different lesions on the anterior chest wall for the last 6 years. parts of India by Gugnani207 did not yield any isolation Four of the patients were males and one female. One of of this fungus. Epizootic lymphangitis caused by H. cap- the males, a 14-year-old boy was persistently exposed sulatum var. farciminosum has been reported in equines to chickens, and had a history of rheumatic heart dis- and camels from several countries15 including India208. ease, complicated by severe mitral stenosis. Two of the patients were farmers, one of whom (Sr. no 4) had SOIL AS NATURAL HABITAT OF H. CAPSULATUM VAR. recently migrated to New York, United States. CAPSULATUM H capsulatum Pakistan Information on the natural habitats of . var. capsulatum in the Indian subcontinent is restricted Altogether 575 subjects, comprising healthy men, to a single report of its isolation from a sample of soil women, and school children, as also pulmonary tubercu- admixed with bat guano. The sample was collected from losis and patients in Punjab province of Pakistan, a 300-year-old building infested with bats of the species were tested for skin sensitivity to histoplasmin202. All Scotophilus heathi in Serampur, near Kolkata, situated on of the subjects were non-reactors, excepting those who the river bank209. All of the 209 soil samples col- had traveled abroad to endemic areas indicting non- lected from other areas in and around Kolkata were nega- endemicity of histoplasmosis in Pakistan. Our literature tive for Histoplasma. Likewise, 523 soil samples collected search has now revealed four authentic indigenous cases from chicken pens, bat-infested sites, and rat burrows in of histoplasmosis (Table 4). Three of them had symp- India and Nepal were negative210,211. Besides, 236 samples toms of disseminated histoplasmosis with prior history of avian excreta examined from Delhi and other parts of of ATT; the fourth was an unusual case of Histoplasma India and 419 samples of bat guano/soil and avian excreta endocarditis. examined from Delhi were also negative212, Randhawa et al. (unpublished data). Considering that many of the Sri Lanka cases in our review gave history of exposure to bats in old buildings, the need for further environmental stud- A survey of histoplasmin sensitivity conducted in 1969 ies, using molecular techniques, can hardly be overem- comprised of 1,366 students and prisoners (524 males, 842 phasized. females). This included 133 tuberculosis patients diag- nosed by bacteriologic or histopathologic examination CONCLUDING REMARKS from different parts of the country. Notably, this group revealed 78 strongly positive reactors203. However, only Histoplasmosis poses a difficult diagnostic challenge three autochthonous cases of histoplasmosis have been because of its highly protean clinical manifestations. documented so far. One of them, a 24-year-old German Being a primary pathogen, the etiologic agent, H. cap- woman had possibly acquired infection in Sri Lanka or sulatum var capsulatum infects the immunocompetent Maldives, while on a 10 days holiday trip to this region. as well as immunocompromised patients. At room tem- Information on the occurrence of African histoplas- perature (25–30°C) in the laboratory, H. capsulatum var. mosis in the Indian subcontinent is lacking. The case capsulatum appears as a slow growing , requiring reported by Ravindran et al.204 in 2015 from Kerala state 3–6 weeks for its cultivation. Although culture has been of India lacks authentication. The photomicrograph pro- considered as the gold standard among the laboratory vided in Fig. 6 of this publication is entirely incompatible diagnostic tests, its value is limited by the fact that most with H. capsulatum var. duboisii. It depicts arthrocon- of the diagnostic microbiology laboratories in the hospi- dida like bodies suggestive of and not the tals discard their cultures after 48–72 hours. Moreover, large yeast form cells characteristic of H. capsulatum var. routinely used as a mycological medium duboisii. is unsuitable for this fastidious fungal pathogen. To add further to these difficulties, direct microscopy of wet HISTOPLASMOSIS IN ANIMALS mounts or stained tissue sections/smears of clinical spec- imens is lacking in sensitivity and requires expertise of Histoplasmosis has been reported in several species a cytopathologist/histopathologist for interpretation. of small mammals including wild rats and oposums205. The afore-mentioned difficulties have been overcome Demonstration of histoplasmosis in animals helps to with the development of PCR but this molecular tech- establish endemicity of the disease in a given area. There nology is not accessible to a vast majority of the diagnos- is no report of isolation of Histoplasma from small mam- tic centers in the Indian subcontinent. Further studies mals in India. Kalra and Wanchoo206 reported negative applying the latest molecular techniques are strongly findings in investigation of 325 rats, 65 bandicoots, nine indicated. Disseminated histoplasmosis is fatal unless shrews, and four house mice examined from Pune State diagnosed early and treated with specific antifungal

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agents. Histoplasma capsulatum var. capsulatum has a 10. Misra SK, Sandhu RS. Deep mycoses in India: a critical review. Mycopathol predilection for the reticuloendothelial system. Hence, Mycol Appl. 1972;48:339–365. hepatosplenomegaly is a prominent feature of dissemi- 11. Kathuria, S, Capoor MR, Yadav S, Singh A, Ramesh V. Disseminated histo- nated histoplasmosis. plasmosis in an apparently immunocompetent individual from north India: A sharp rising trend in the number of histoplasmosis a case report and review of literature. Med Mycol. 2013;51:774–778. cases reported in recent years is a notable observation. 12. Gupta A, Ghosh A, Singh G, Xess I. A twenty-first-century perspective of This is attributable to increased awareness apart from disseminated histoplasmosis in India: literature review and retrospective further development and expansion of mycological diag- analysis of published and unpublished cases at a tertiary care hospital in nostic facilities. Although its occurrence is widespread, North India. Mycopathologia. 2017. doi:10.1007/s11046-017-0191-z the burden of disease in the subcontinent remains unde- (published online). termined due to paucity of systematic and comprehensive 13. Randhawa HS, Chaturvedi S, Khan ZU, Chaturvedi VP, Jain SK, Jain RC, et al. studies, using recently introduced molecular techniques. Epididymal histoplqsmosis diagnosed by isolation of Histoplasma capsula- Considering that an overwhelming number of the cases tum from semen. Mycopathologia. 1995;131:173–177. had not traveled abroad to the endemic areas of the dis- 14. Kasuga T, White TJ, Koenig G, McEwen J, Restrepo A, Castaneda E, et al. ease in North America, the disease is endemic in the Phylogeography of the fungal pathogen Histoplasma capsulatum. Mol Ecol. subcontinent. However, supportive scientific evidence 2003;12:3383–3401. like the demonstration of natural reservoirs of the patho- 15. Teixeira Mde M, Patané JS, Taylor ML, Gómez BL, Theodoro RC, de Hoog S, gen and its occurrence in the local animal populations et al. Worldwide phylogenetic distributions and population dynamics of the remains largely unexplored. To sum up, our current genus Histoplasma. PLoS Negl Trop Dis. 2016;10:e0004732. doi:10.1371/ knowledge of the global geographic distribution of his- journal.pntd.0004732 toplasmosis and other systemic mycoses is far from ade- 16. Duraiswami R, Diwan RN, Kalghatgi, AT, Mukerjee B. Unusual pathogens quate. We strongly uphold the observation made in 1966 in HIV cases. A report of two cases. Med J Armed Forces India. 1998;54: by Ainsworth213 that the available literature reflects the 170–172. distribution of mycologists more accurately than it does 17. Goswami PB, Pramanik N, Banerjee D, Raza MM, Guha SK, Maiti PK. the distribution of mycoses and their relative importance Histoplasmosis in Eastern India: the tip of the iceberg? Trans Roy Soc Trop in a given area. 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107. Bhoweer A, Ranpise SG. Oral lesions leading to diagnosis of histoplasmosis. 128. Rastogi P, Sharma P, Kumar N, Rudramurthy SM, Verma N, Verma S. A case of IJSS Case Rep Rev. 2016;3:4–8. histoplasmosis in a patient with MDS/MPN. Blood Res. 2016;51:206–207. 108. Kriplani DM, Kante KA, Maniar JK, Khubchandani SR. Histoplasmosis 129. Sharma S, Singh P, Sahu KK, Rajwanshi A, Malhotra P, Naseem S. in an immunocompetent host: a rare case report. Int J Res Med Sci. Histoplasmosis in pleural effusion in a 23-year-old man with mixed- 2017;5:1148–1150. phenotype acute leukemia. Lab Med. 2017;48:249–252. 109. Gupta H, Tankhiwale SS. A case of bilateral eyelid histoplasmosis mistaken 130. Kumar N, Singh S, Govil S. Adrenal histoplasmosis: clinical presentation and as basal cell carcinoma. Can J Ophthalmol. 2017;52:e45–e46. imaging features in nine cases. Abdom Imaging. 2003;28:703–708. 110. Gulati SP, Gupta A, Wadhera A, Deep A, Kalra R. Histoplasmosis of larynx 131. 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148. Baig WW, Attur RP, Chawla A, Reddy S, Pillai L, Rao K, et al. Epididymal and 168. Mishra DP, Ramamurthy S, Behera SK. Histoplasmosis presenting as isolated prostatic histoplasmosis in a renal transplant recipient from southern India. cervical lymphadenopathy: a rare presentation. J Cytol. 2015;32:188–190. Transpl Infect Dis. 2011;13:489–491. doi:10.04.103/109871-68856 149. Mohammed S, Sinha M, Chavan P, Premalata CS, Rudhramurthy SM, 169. Mohanty P, Bhuyan P, Kar A, Behera PK, Mohapatra CS. SLE associated Jayshree RS, et al. Oral histoplasmosis masquerading as oral cancer in HIV- hemophagocytic lymphohistiocytosis with disseminated histoplasmosis infected patient: a case report. Med Mycol Case Rep. 2012;1:85–87. in a HIV seropositive patient. J Evid Based Med Health. 2016;3(80):4374– 150. Chawla A, Chawla K, Thomas G. Genitourinary histoplasmosis in post- 4376. doi:10.18410/jebmh/2016/930 renal transplant patient: diagnostic dilemma. Indian J Urol. 2012;28: 170. 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Histoplasmosis as a cause of Med J. 2008;40:221–224. nodular myositis in an AIDS Patient diagnosed on fine needle aspiration 165. Vasudevan B, Bahal A, Sagar A, Mohanty AP. Primary cutaneous histo- cytology. A case report. Acta Cytol. 2007;51:89–91. plasmosis in a HIV-positive individual. J Glob Infect Dis. 2010;2112–115. 184. Agarwal VK, Prusty BSK, Preira KR. An uncommon presentation of dissemi- doi:10.4103/0974-777X.62884 nated histoplasmosis. Ann Trop Med Public Health. 2016;9:279–282. 166. Devi S, Leifanbagam S, Singh NK, Doris E. Cytological study of cutaneous 185. Devana JV, Chakravarthi RM, Saleem M. A rare case of histoplasmosis in a lesions in HIV-infected patients. J Med Soc. 2013;27:212–215. renal allograft recipient. J Acad Clin Microbiol. 2016;18:124–126. 167. Panda JK, Mohanty CBK, Sahoo P, Devi A, Sahu H. Cutaneous histoplasmo- 186. Ete T, Mondal S, Sinha D, Beyong T, Warjri SB, Pal J, et al. Idiopathic CD4 sis: an unusual case presentation. 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