A probable case of histoplasmosis presenting as portal hypertension and bone lesion in a case of common variable immunodeficiency syndrome.

A 17-year-old boy developed right shoulder pain and swelling, which was diagnosed as tuberculosis based on magnetic resonance imaging (MRI), He was then started on anti-tuberculosis treatment (ATT) with no improvement over a 3 month period. He developed right abdominal pain, anorexia, low-grade fever, and weight loss. His past history was one of Bacillus Calmette–Guérin (BCG) vaccine granuloma in the left axilla at the age of nine months, and histopathologically confirmed tuberculosis at the age of 13 years. At that age, he had completed 9 months of ATT with an excellent response.

When he came to us for non response to ATT, he had a right shoulder lump, a body mass index (BMI) of 15 kg/m2, and hepatosplenomegaly. There was ascites and persistent low-grade fever. Liver biochemistry was normal except for low albumin (2.1 gm / dL). The serum ascites albumin gradient (SAAG) was 1.8. Review of an MRI of the shoulder showed altered marrow signal of the terminal clavicle and acromian process, with cortical disruption and large soft tissue collection [Figure 1]. Computed tomography (CT) of the abdomen revealed multiple hypodense, necrotic, rim-enhancing abdominal lymph nodes, the largest being 3 cm. His human immunodeficiency virus (HIV) serology test was negative. Upper gastrointestinal (UGI) endoscopy showed gastric varices with portal hypertensive gastropathy (PHG). Fine needle aspiration (FNA) from the right shoulder lump showed the presence of lymphocytes and plasma cells, epithelioid cell granuloma, and many scattered macrophages. The macrophages contained multiple intracellular yeast forms, which were suggestive of Histoplasma capsulatum, and were seen as round-to-ovoid (1-4 μm) structures with a thin, clear zone around them [Figure 2]. Culture for Mycobacteria was negative. His fundoscopy was normal. The nitro blue tetrazolium test was normal and immunoglobulin electrophoresis showed low immunoglobulin A and G, with elevated immunoglobulin E and M. Flow cytometry analysis indicated a low CD3 positive count [Table 1].

Figure 1

MRI of the shoulder joint showing altered marrow signal of the terminal clavicle and acromian process with cortical disruption and large soft tissue collection

Figure 2

FNAC from the shoulder lesion showing macrophages having multiple intracellular yeast forms with single eccentric nuclei and a surrounding ‘halo’ suggestive of Histoplasma capsulatum (Giemsa stain, ×1000)

Table 1

Flow cytometry of the peripheral blood

Lymphocyte subpopulation	Result % lymphocyte	Absolute lymphocyte count/mm3	Normal absolute count/mm3
Lymphocytes	10	750	1400-3300
B lymphocytes CD19+	33	248	110-570
T lymphocytes CD3+	53	398	1000-2000
Th lymphocytes CD3+CD4+	18	135	530-1300
Tc lymphocytes CD3+CD8+	30	225	330-920
NK cells CD3-CD16+CD56+	12	90	70-480

Evaluation for other causes of liver disease, such as, chronic viral hepatitis (hepatitis B and hepatitis C), autoimmune liver disease (antinuclear antibody negative, anti-smooth muscle antibody, anti-liver–kidney microsomal antibody), Wilsons disease (S. ceruloplasmin, 24-hour urinary copper), celiac disease (Immunoglobulin A anti-tissue transglutaminase antibody), Budd–Chiari syndrome (color Doppler), and alpha 1 antitrypsin levels, were all negative. A liver biopsy revealed portal fibrosis with a presence of moderate portal tract inflammation — predominantly mononuclear cells. A diagnosis of probable histoplasmosis with common variable immunodeficiency (CVID), with portal hypertension was made, and the patient was initially treated with intravenous amphotericin B for 28 days, followed by oral maintenance therapy with itraconazole, with liver function test monitoring during follow-up. At 12 months of follow-up, he is asymptomatic and all bone and abdominal lesions have disappeared. However, a repeat upper endoscopy still shows varices and portal hypertensive gastropathy.

Disseminated histoplasmosis is usually seen in immunocompromised patients.[1] CVID predisposes to opportunistic and recurrent infections and is associated with histoplasmosis.[2] Histoplasmosis is an under-recognized disease in India, very rarely diagnosed in our hospital, and rarely reported from western India. Our patient had portal hypertension and portal hepatitis. Portal hepatitis due to disseminated histoplasmosis has been reported, but we are not aware of any report of portal hypertension due to histoplasmosis.[3] Our patient had also received ATT comprising of isoniazid, which is known to cause fibrosis. Our patient had a lump in the acromion process and clavicle. In a disseminated infection, due to histoplasmosis, it is usually found in the bone marrow or may be associated with hemophagocytosis.[4] Histoplasmosis and tuberculosis have similar clinical manifestations and predisposing factors, and have been reported to be coexistent.[5] Diagnosis of histoplasmosis cannot be made on imaging only and patients may be wrongly treated with ATT, as had occurred in our patient, and also reported from a previous study from India.[6] In our patient, we were unable to perform a culture or molecular diagnosis of the fungus which is a limitation. Thus, Histoplasmosis should be considered in the differential diagnosis of patients with prolonged fever, hepatosplenomegaly, and granulomatous disease on histopathology. When tissue biopsy specimens show granuloma(s), fungal stains should be routinely performed for diagnosis.