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Histoplasmosis is an important systemic fungal infection caused by a dimorphic fungus, Histoplasma capsulatum. In India, the disease has been reported from several parts of the country - most cases being from eastern India, considered to be endemic for the disease. The causative fungus is present in the soil, acquired through inhalation, and has three types of manifestations - acute primary, chronic cavitary, and progressive disseminated histoplasmosis. Among the forms of histoplasmosis, Disseminated histoplasmosis (DH) is the rarest and generally found in immune-compromised individuals. It can manifest as varying symptoms because of the involvement of various organ systems. Here we present an immunocompetentpatient with disseminated histoplasmosis who presented withlowergastrointestinal(GI) bleeding.

A 48 year-old male from Delhi, without any previous co-morbidities, presented to us with a 15 day history of high-grade intermittent fever with loss of weight and appetite. He had no history of unprotected sexual exposure, diabetes mellitus, or tuberculosis. On physical examination, he  had a Body Mass Index of 17 kg/m2, pallor and had an ulcer over the hard palate. Investigations showed pancytopenia (Hb - 7.9 gm/dL, TLC - 2300 cells/mm3, Platelet count - 55,000/mm3). Serology for HIV- 1 and 2 was negative. Abdominal ultrasonographyand CECT of the abdomen revealed hepato-splenomegalywith minimal free fluid in the pelvis.

Bone marrow biopsy showed normal cellular marrow and phagocytes engulfing the yeast cells (Figure 1). Bone marrow culture in Saboraud’s Dextrose Agar and Brain Heart Infusion Agar grew colonies of Histoplasma capsulatum.

During his hospital stay, he developed bleeding per rectum containing dark blood with clots, for two days. UGI endoscopy was normal, and colonoscopy revealed caecal erosions, a biopsy of which showed features of histoplasmosis (Figure 2).

He was treated with intravenous Amphotericin B(AMB) 100 mg twice daily, and the dose was gradually escalated. After 3 days of starting treatment the fever episodes and per-rectal bleeding subsided. After seven days of anti-fungal course, he was discharged in a stable condition and advised home-based IV AMB, for a total dose of 3 gm. 

On follow up, his lab parameters improved substantially, and USG of the abdomen also revealed a decrease in the size of his spleen. However, after four weeks of discharge, he noticed cutaneous nodules (Figure 3) starting on the ventral aspect of his trunk that spread rapidly to involve the dorsum as well as the upper limbs. However, there were no associated symptoms except occasional malaise. Biopsy from the cutaneous nodules revealed cutaneous histoplasmosis (Figure 4). Finally, he was started on tablet Itraconazole 200 mg twice daily and is now on regular follow up with the resolution of the cutaneous nodules (Figure 5).

Inhalation of either fungal conidia or mycelial fragments is the primary mode of acquisition of histoplasmosis. Once inhaled, these fungal elements transform into yeast forms and may disseminate systemically. The clinical manifestations of histoplasmosis often appear after prolonged exposure to large inocula. The initial pulmonary infection may disseminate systemically with hematogenous spread and produce extra-pulmonary manifestations, and spread to the regional lymph nodes through the lymphatics. Primary pulmonary histoplasmosis is usually asymptomatic (approximately 90%) or presents with subclinical disease. Symptomatic hosts with primary pulmonary histoplasmosis often present with nonspecific symptoms of fever, chest pain, and cough, which are self-limited. Systemic spread usually occurs in patients with impaired cellular immunity, including patients with hemato-lymphoid malignancies, solid organ transplants, and those exposed to immuno suppressive agents. The development of progressive DH indicates impaired cell-mediated immune responses. Patients who are immunosuppressed and thus unable to develop effective cell-mediated immunity against the organism, are likely to manifest symptomatic  disease during the period of acute dissemination. It may lead to the involvement of the central nervous system, the reticuloendothelial system(RES), including the liver, spleen, lymph nodes, bone marrow, and rarely, the mucocutaneous tissues. Progressive disseminated histoplasmosis occurs in 1 per 2000 cases in adults who are immunocompetent¹. Histoplasmosis capsulatum is endemic to Ohio, Missouri, and Mississippi River valleys in the United States, as well as some river valleys in Central America². In India, histoplasmosis is found predominantly along the Gangetic plains, namely West Bengal and Uttar Pradesh².

Progressive disseminated histoplasmosis is rare in immunocompetent adult hosts. The size of the inoculum plays an important role such that immunocompetent adults exposed to a low quantity of inoculum are usually asymptomatic. However, the inhalation of a large inoculum can cause diffuse pulmonary symptoms and may have a protracted course. Chronic progressive DH is a slowly progressive infection due to Histoplasma capsulatum that occurs mostly in older adults who are not overtly immunosuppressed³. These patients have no obvious immunosuppression, but their macrophages cannot effectively kill H. capsulatum³. 

The symptoms of DH include fever, malaise, anorexia, and weight loss. Physical examination often shows hepatosplenomegaly, lymphadenopathy, pallor, and petechiae due to RES involvement. In some patients, mucous membrane ulcerations, skin ulcers, nodules, or molluscum-like papules may be present³. Among the forms of histoplasmosis reported from India, DH is the rarest. Numerous case series have published histoplasmosis from all over India, the most extensive series being from Delhi, a compilation of 37 patients from all over India⁴. Since clinical and laboratory features have considerable overlap, it is important to consider fungal infections while dealing with a disseminated granulomatous infection, even in immunocompetent hosts.

We present a case of disseminated histoplasmosis in an immunocompetent individual presenting with fever and a palatal ulcer who later developed lower GI bleeding and cutaneous nodules. Frequently, in cases of disseminated infection, oral lesions appear as the initial clinical manifestation. The palate, gingiva, and oropharynx are the most frequent sites of oral histoplasmosis. Oral lesions can vary from ulcers, erythematous or vegetative nodules, to wart-like growths. Many reports show the development of ulcerating, indurated, and painful ulcers.

Isolated intestinal histoplasmosis is uncommon. The majority of intestinal histoplasmosis cases occur with disseminated disease and hence are more likely to be encountered in immunodeficient patients. GI involvement occurs in 70%-90% of cases of DH5, manifesting as abdominal pain, diarrhea, anorexia, nausea, bilious vomiting, constipation, tenesmus, and abdominal tenderness⁵. There are also reports of GI complications such as bleeding, bowel obstruction, perforation, and even protein loss due to enteropathy. Healthcare providers may miss the diagnosis as GI endoscopic examinations are not offered sometimes due to a lack of related symptoms. Our case highlights the occurrence of disseminated histoplasmosis in an immunocompetent patient with caecal erosions found on colonoscopy and diagnosis confirmed by biopsy and fungal culture.

Progressive DH is treated beginning with lipid formulation amphotericin B (3-5 mg/ kg/d) or amphotericin B (0.7-1.0 mg/kg/d for 1-2 weeks), followed by Itraconazole (200 mg twice daily for 8-12 months) with a near complete resolution in most cases. However, failure to diagnose or treat at an appropriate time is uniformly fatal, especially in the disseminated form. 

Disseminated histoplasmosis is not uncommon in India with high prevalence areas along the Gangetic plains. Our case describes the occurrence of progressive disseminated histoplasmosis in an immunocompetent individual, from a non-endemic area, with predominant gastrointestinal involvement and pancytopenia. He initially responded to treatment with Amphotericin B, but later disease recurred with cutaneous nodules, which responded further to treatment with Itraconazole.