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  Table of Contents  
Year : 2020  |  Volume : 38  |  Issue : 3  |  Page : 485-488

Adrenal histoplasmosis in immunocompetent individuals a case series from the North-Western part of India, Rajasthan province: An emerging endemic focus

1 Department of Endocrinology, SMS Medical College, Jaipur, Rajasthan, India
2 Department of Medicine, SP Medical College, Bikaner, Rajasthan, India
3 Department of Endocrinology, BLDE Medical College, Vijayapur, Karnataka, India
4 Department of Pathology, SMS Medical College, Jaipur, Rajasthan, India

Date of Submission21-Jun-2020
Date of Decision10-Aug-2020
Date of Acceptance24-Aug-2020
Date of Web Publication4-Nov-2020

Correspondence Address:
Dr. Balram Sharma
N-17, Navya Path, Gandhi Nagar, Jaipur - 302 015, Rajasthan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijmm.IJMM_20_280

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 ~ Abstract 

Histoplasmosis is a fungal infection caused by Histoplasma capsulatum and very few cases reported from North-West India. Adrenal histoplasmosis is an even more uncommon mycotic disease. We describe five immunocompetent men with adrenal histoplasmosis presenting with constitutional symptoms. Four patients had bilateral adrenal involvement, whereas one had unilateral adrenal mass. Three patients had adrenal insufficiency at presentation and the other two developed adrenal insufficiencies during follow-up. All the patients received amphotericin B and itraconazole treatment which led to symptomatic improvement but adrenal insufficiency persisted in all patients at the end of the follow-up.

Keywords: Adrenal histoplasma, immunocompetent, Rajasthan

How to cite this article:
Sharma B, Nehara HR, Bhavi VK, Maan P, Saran S. Adrenal histoplasmosis in immunocompetent individuals a case series from the North-Western part of India, Rajasthan province: An emerging endemic focus. Indian J Med Microbiol 2020;38:485-8

How to cite this URL:
Sharma B, Nehara HR, Bhavi VK, Maan P, Saran S. Adrenal histoplasmosis in immunocompetent individuals a case series from the North-Western part of India, Rajasthan province: An emerging endemic focus. Indian J Med Microbiol [serial online] 2020 [cited 2021 Jan 21];38:485-8. Available from:

 ~ Introduction Top

Histoplasmosis is a systemic mycosis caused by Histoplasma capsulatum. The majority of the infections are asymptomatic or self-limiting; less commonly it can result in progressive disseminated histoplasmosis (PDH) with the involvement of many organs, including the adrenal glands, and must be followed carefully as it can lead to the development of adrenal insufficiency. PDH is more common in immunocompromised individuals, though it can rarely occur in immunocompetent.[1] Histoplasmosis is known to be endemic in the Northeast part of India, though occasional cases were reported from nearly every region of the country since the AIDS epidemic.[2] Very few cases are reported from the Northwest part of India, particularly Rajasthan province.[3] We retrospectively analysed five cases of adrenal histoplasmosis presenting to the Endocrinology outpatient department, in a tertiary care institute of Northwest India, from the year 2016 to 2019.

 ~ Case Reports Top

Case 1

A 68-year-old male, presented with fever, weight loss multiple skin lesions and dry cough over the past 3 months [Table 1]. On examination, he had body mass index (BMI) of 20.8 kg/m2, blood pressure of 112/66 mm Hg with postural fall, mucocutaneous hyperpigmentation and skin-coloured to reddish, painless papular skin lesions all over the body and an oval ulcer over the hard palate, no lymphadenopathy or hepatosplenomegaly [Figure 1]. On evaluation, the contrast-enhanced computed tomography (CECT) of the abdomen revealed enlarged bilateral adrenals with heterogeneous enhancement, irregular margins and central attenuation and normal chest X-ray. He had anaemia (haemoglobin [Hb] 9.2 g/dl), hyperkalemia (5.8 mEq/l), low 0800 h serum cortisol (5.5 μg/dl) and subnormal response (11.8 μg/dl) on adrenocorticotropic hormone (ACTH) stimulation and negative HIV serology. Punch biopsy of the skin and ultrasound-guided adrenal biopsy revealed histoplasmosis. He was started on oral prednisolone, fludrocortisone and parenteral amphotericin-B deoxycholate for 2 weeks, followed by oral itraconazole for 1 year. His condition steadily improved and doing well at 2 years follow-up, although the adrenal insufficiency persisted [Table 2].
Table 1: Demographics and clinical characteristics of the patients with adrenal histoplasmosis

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Figure 1: Skin-coloured to reddish, papular skin lesions all over the body, an oval ulcer over the hard palate with irregular margins and buccal mucosal pigmentation

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Table 2: Clinical profile, treatment and follow-up of the patients with adrenal histoplasmosis

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Case 2

A 55-year-old male, chronic smoker and alcoholic presented with fever, weight loss and flank pain for the past 2 months [Table 1]. On examination, he had no hyperpigmentation or postural drop in blood pressure and any other abnormalities. On investigation, haemogram, biochemistry and HIV serology were normal. Serum cortisol at 0800 h was 18.6 μg/dl and was suppressible after overnight dexamethasone suppression test (<0.5 μg/dl). X-ray chest was normal and the CECT of the abdomen revealed bilateral large (45 × 30 mm and 50 × 28 mm) suprarenal heterogenous enhancing mass with smooth margins [Figure 2]. The 24 h urinary fractionated metanephrine and normetanephrine were normal. Fine-needle aspiration cytology (FNAC) revealed only necrotic material. Bilateral adrenalectomy was done under steroid cover and excised masses revealed extensive necrosis and histopathology was consistent with histoplasmosis. Oral hydrocortisone and fludrocortisone were continued and subsequently given amphotericin B deoxycholate, followed by itraconazole. The patient is under regular follow-up and doing well [Table 2].
Figure 2: Bilateral adrenals enlargement (right adrenal 45 × 30 mm, left 50 × 28 mm) with heterogeneous density and smooth margins

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Case 3

A 40-year-old male, smoker, presented with complaints of low-grade fever, decreased appetite and weight loss for 3 months and coughs and pain abdomen for the past 1 month [Table 1]. On clinical examination, he was thin built (BMI - 17.6 kg/m2), had no hyperpigmentation or postural fall in blood pressure and systemic examination revealed tenderness in the right hypochondrium. On investigation, he had anaemia (Hb 9.2 g/dl), normal biochemistry and HIV serology was negative. Serum cortisol at 0080 h was 20.7 μg/dl and was suppressible after an overnight dexamethasone suppression test (1.2 μg/dl). Chest X-ray showed bilateral hilar opacities and computed tomography (CT) imaging of the abdomen revealed right heterogeneous mass (4.6 cm × 5.2 cm) with irregular margin and central necrosis. FNAC of the mass showed only necrotic material. Histopathology of excised mass (adrenalectomy of the right side) was consistent with histoplasmosis [Figure 3]. The post-operative course was uneventful and he was started on parenteral amphotericin B deoxycholate followed by oral itraconazole. At 1 month follow-up, he presented with adrenal insufficiency (0080 h cortisol 2.8 μg/dl) and was started on prednisolone and fludrocortisone. Currently, he is doing well and is under regular follow-up [Table 2].
Figure 3: H and E stain (×10) showing lymphohistiocytic infiltrate with variable numbers of primarily intracellular organism with perinuclear halos within histiocytes consistent with histoplasmosis

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Case 4

A 52-years-old male, diabetic for the past 3 years, presented with decreased appetite, weight loss, easy fatigue and intermittent low-grade fever and recurrent hypoglycemia for the past 2 months [Table 1]. On examination, he had a BMI of 19.2 kg/m2, mucocutaneous hyperpigmentation, significant postural drop in blood pressure, no lymphadenopathy and hepatosplenomegaly. Chest X-ray was unremarkable and the CECT of the abdomen revealed enlarged bilateral adrenals with heterogeneous enhancement, central attenuation and irregular margins. His blood investigation revealed anaemia (Hb 10.4 g/dl), hyperkalemia, low 0080 h serum cortisol levels (3 μg/dl), paired with high serum adrenocorticotropic hormone (129 pg/ml) and consistent with primary adrenal insufficiency. Ultrasound-guided biopsy of the enlarged adrenals confirmed the diagnosis of histoplasmosis. He was started on parenteral amphotericin B deoxycholate followed by oral itraconazole along with oral hydrocortisone and fludrocortisone replacement, which led to symptomatic improvement [Table 2].

Case 5

A 56-year-male, a chronic smoker, presented with nausea, decreased appetite, lethargy, weight loss (8 kg) and low-grade fever of 3 months duration [Table 1]. On examination, he was thin built (BMI; 17.2 kg/m2), had mucocutaneous pigmentation and significant postural hypotension with the unremarkable systemic examination. On investigation, he had anaemia (Hb: 9.6 g/dl), high normal serum potassium (5.4 mEq/l), negative HIV serology, low 0080 h serum cortisol (5.5 μg/dl) and subnormal cortisol response (11.4 μg/dl) after the ACTH stimulation. CT of the abdomen revealed bilaterally enlarged adrenals with smooth margins, central necrosis and absence of calcification. CT guided FNAB from the adrenals was suggestive of histoplasmosis. He was started on liposomal amphotericin-B for 2 weeks, followed by itraconazole 200 mg twice daily for a total of 12 months along with prednisolone and fludrocortisone. He was doing well and was under regular follow-up [Table 2].

 ~ Discussion Top

We retrospectively analysed five cases of adrenal histoplasmosis with adrenal insufficiency. All the patients reported with severe constitutional symptoms, one had associated cutaneous involvement (case 1) and one had associated hilar lymphadenopathy (case 3), whereas three had isolated adrenal involvement. The patients were diagnosed with a combination of biochemical, radiological and histopathological tests, and following confirmation of the diagnosis all patients were treated with steroids and antifungals which led to significant clinical improvement.

The first case of histoplasmosis from India was reported in 1954 by Panja and Sen from Kolkata.[4] The majority of the cases of histoplasmosis in India were reported from North-East India[2]. According to a recent review, 426 patients of histoplasmosis were reported from India.[3] Very few cases of adrenal histoplasmosis were reported from Northwest India and out of which only five cases were from Rajasthan.[5],[6] This fungal infection is largely under-reported from the north-west part of India, possibly due to asymptomatic or self-limiting course of the mild disease, lack of awareness by the clinician, tuberculosis masquerading as histoplasmosis and lack of proper antigenic and serologic diagnostic test.[5]

Although histoplasmosis has been traditionally thought to be a disease of immunocompromised individuals, the occurrence of the disease in immunocompetent hosts has also been reported.[5] Histoplasmosis in India is largely seen in the middle-aged male population with a history of soil exposure.[2] All our patients were immunocompetent, middle-aged males (except case 1, aged 68 years), and all were involved in occupation with exposure to soil except one (case 5). The clinical manifestations of the disease vary from asymptomatic or mild self-limiting disease to progressive disseminated disease involving various organs and usually present with fever, weight loss and constitutional symptoms. Primary adrenal insufficiency occurs in 26%–70% of adrenal histoplasmosis cases and is the commonest cause of death.[1] Tuberculosis, histoplasmosis, lymphoma and adrenocortical carcinoma should always be kept in the differential diagnosis when an individual presents with fever, weight loss and adrenal mass.[7] Three of our patients presented with adrenal insufficiency (cases 1, 4 and 5) and two developed later on (cases 2 and 3). One of our patients had unilateral adrenal mass (case 3) and undergone unilateral adrenalectomy and he developed adrenal insufficiency during follow-up. This may be explained by contralateral adrenal involvement at a later stage or the other possibility that he had subclinical contralateral adrenal involvement in the initial stages which may not be detected on imaging.[5]

The typical CT findings of adrenal histoplasmosis are bilateral symmetrical adrenal enlargement with low-density areas of necrosis and haemorrhage.[7] In our series 4 (cases 1, 2, 4 and 5) out of 5 cases, had bilateral adrenal involvement at presentation. Although all our patients had peripheral enhancement with central hypodensity, two had smooth margins (cases 2 and 5) of adrenals and three had irregular margins (cases 1, 3 and 4) which suggest more advanced disease with significant tissue destruction. Demonstration of the yeast on pathological stains and isolation of the mold in culture constitutes the gold standard tests for the diagnosis of histoplasmosis. The characteristic histopathological findings include lymphohistiocytic infiltrate with numerous small spherical or oval yeast forms surrounded by a clear ring of space resembling a capsule inside the cytoplasm of the histiocytes, as observed in our cases.[8] Diagnosis of histoplasmosis was established based on the histopathology, radiological features and response to antifungal drugs, and none of the biopsy/FNAC or tissue was submitted to culture.

The recommended treatment for moderately severe to severe disease is liposomal amphotericin B (3.0 mg/kg daily) or amphotericin B deoxycholate (0.7–1.0 mg/kg daily) for 2 weeks, followed by oral itraconazole 200 mg twice daily for 1 year.[9] All our patients received amphotericin B followed by oral itraconazole and showed a very good response, however, adrenal functions not improved in any patient. Bhansali et al. also reported that adrenal insufficiency persisted in all five patients with adrenal histoplasmosis after 6-18 months of therapy.[5] Measurement of serum or urine antigen levels can be used as an aid to early diagnosis, to monitor response to therapy, and detect failure or relapse, but this test is not widely available in India.[9] The functional scan like 18-fluorodeoxyglucose-positron emission tomography (18FDG-PET) is useful in determining the activity, the extent of the disease and to detect relapse of disease, as the trace uptake denotes ongoing infection and inflammation.[10] Unfortunately, the facility of 18FDG-PET is not available in our institute.

 ~ Conclusion Top

Adrenal histoplasmosis does occur in immunocompetent patients from non-endemic areas and should be considered in the differential diagnosis of patients presenting with constitutional symptoms and unilateral or bilateral mass with or without adrenal insufficiency. Treatment with parenteral and oral antifungals for the prolonged duration is rewarding, and amphotericin B deoxycholate is an alternate for the patient not affording liposomal amphotericin B. Systematic and comprehensive studies in this field, and rapid diagnostic test like histoplasma antigen in serum/urine is required to know the exact burden of histoplasmosis in India.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) have their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

 ~ References Top

Wheat LJ, Azar MM, Bahr NC, Spec A, Relich RF, Hage C. Histoplasmosis. Infect Dis Clin North Am 2016;30:207-27.  Back to cited text no. 1
Gupta A, Ghosh A, Singh G, Xess I. A twenty- first-century perspective of disseminated histoplasmosis in India: Literature review and retrospective analysis of published and unpublished cases at a Tertiary Care Hospital in North India. Mycopathologia 2017;182:1077-93.  Back to cited text no. 2
Randhawa HS, Gugnani HC. Occurrence of histoplasmosis in the Indian sub-continent: An Overview and Update. J Med Res Prac 2018; 7:71-83.  Back to cited text no. 3
Panja G, Sen S. A unique case of histoplasmosis. J Indian Med Assoc 1954;23:257-8.  Back to cited text no. 4
Bhansali A, Das S, Dutta P, Walia R, Nahar U, Singh SK, et al. Adrenal histoplasmosis: Unusual presentations. J Assoc Physicians India 2012;60:54-8.  Back to cited text no. 5
Patel AK, Patel KK, Toshniwal H, Gohel S, Chakrabarti A. Histoplasmosis in non-endemic North-Western part of India. Indian J Med Microbiol 2018;36:61-4.  Back to cited text no. 6
[PUBMED]  [Full text]  
Mukherjee JJ, Villa ML, Tan L, Lee KO. Bilateral adrenal masses due to histoplasmosis. J Clin Endocrinol Metab 2005;90:6725-6.  Back to cited text no. 7
Azar MM, Hage CA. Laboratory diagnostics for histoplasmosis. J Clin Microbiol 2017;55:1612-20.  Back to cited text no. 8
Wheat LJ, Freifeld AG, Kleiman MB, Baddley JW, McKinsey DS, Loyd JE, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007;45:807-25.  Back to cited text no. 9
Umeoka S, Koyama T, Saga T, Higashi T, Ito N, Kamoto T, et al. High 18F-fluorodeoxyglocose uptake in adrenal histoplasmosis; a case report. Eur Radiol 2005;15:2483-6.  Back to cited text no. 10


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]


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