A Rare Case of Disseminated Histoplasmosis in an Immunocompetent Girl

Dear Editor,

Histoplasmosis is a deep fungal infection caused by H. capsulatum var capsulatum. In India, it is endemic in north-eastern states, mainly Assam. It manifests as three types: acute primary, chronic cavitary, and progressive disseminated histoplasmosis. Disseminated histoplasmosis (DH) is defined as a condition where the fungus is present in more than one location and is the rarest and mostly found in immuno-compromised individuals.[1]

In our case, a 23-year-old woman, residing in central India, presented with asymptomatic papules and nodules over the body since 5 years with a sudden increase in the last 3 months. On examination, non tender erythematous papules, nodules, and plaques were present over the trunk, bilateral upper limbs, lower limbs, and face, sparing the palms and soles [Figure 1a, c, e, g ]. A few papules and nodules showed ulceration. A few non-tender indurated plaques were present over the mucosal side of her upper lip since 3 years [Figure 1i]. She had intermittent swelling and pain in the proximal inter-phalangeal joint of the left hand since 2 years without the history of morning stiffness and photo-sensitivity. There was no history of fever, malaise, loss of sensation over lesions, tingling or numbness, glove and stocking anesthesia, slipping of chappals while walking, or sudden significant weight loss.

Figure 1.

(a, c, e and g) Pre-treatment photographs showing non-tender erythematous papules, nodules, and plaques present over the face, trunk, upper limbs and lower limbs (i) Pre-treatment photographs showing indurated whitish plaques present over the mucosal side of upper lip (b, d, f, h, j) Post-treatment photographs of the face, trunk, upper limbs, lower limbs, and mucosal side of upper lip showing significant reduction in lesions

The differential diagnoses considered were mucocutaneous leishmaniasis, sarcoidosis, lepromatous leprosy, connective tissue disease, deep fungal infection, and mycosis fungoides.

Biopsy from both cutaneous and mucosal lesions showed numerous basophilic bodies with peripheral halo within the macrophages and giant cells [Figure 2a and b], which were intensified on Periodic acid Schiff (PAS) [Figure 2c] stain, and these bodies stained black with Gomori methenamine silver (GMS) stain [Figure 2d].

Figure 2.

(a) Normal epidermis without a Grenz zone and with nodular granulomas composed of mainly lymphocytes depicted by the yellow star (H&E, 10x) (b) Macrophages and giant cells showing basophilic inclusion bodies with perinuclear halo depicted by a red arrow (H&E, 100x) (c) Perinuclear halo in macrophages seen better on Periodic acid Schiff staining (d) Black staining of the inclusion bodies on Gomori methenamine silver staining depicted by an orange arrow in 100x magnification (e) Potassium hydroxide (KOH) staining showing budding yeast depicted by a black arrow (f) Gram stain showing budding yeast cells along with tissue debris depicted by a yellow arrow (g) Growth of white cottony mold at 25 degrees Celsius in Sabouraud dextrose agar as depicted by a blue arrow (h) Characteristic large, spherical, tuberculate macroconidia bearing finger-like appendages seen on lactophenol cotton blue staining depicted by a green arrow (i) Numerous small round smooth-walled microconidia borne on short conidiophores with branching and septate hyphae depicted by a pink arrow

On potassium hydroxide (KOH) stain of the tissue, multiple budding yeast cells were seen [Figure 2e] which was further confirmed on Gram stain of the tissue [Figure 2f], and when this tissue was cultured in Sabauraud dextrose agar medium at 25°C, white cottony mould forms grew [Figure 2g], which on lactophenol cotton blue stain showed characteristic tuberculate macroconidia and numerous smooth-walled microconidia [Figure 2h and i].

Slit skin smear (SSS) for M. leprae and viral markers including hepatitis B, hepatitis C, and HIV-1, 2 were negative. Sensory, motor, and peripheral nerve examinations were normal. Baseline blood biochemistry including ACE levels, serum calcium, ANA, anti-dsDNA, and RA factor was within normal limits. However anti-CCP antibody was positive. Her chest X-ray, ultra-sonograph of abdomen pelvis, and HRCT chest were normal, and her PET scan was negative.

On the basis of clinical, histopathological, and culture findings, diagnosis of histoplasmosis was made. Since dimorphism of the organism was not proven, as there was no growth on tissue culture at 37°C, the sample was sent to a higher centre which confirmed histoplasmosis on polymerase chain reaction.

Bone marrow biopsy was done, and findings were consistent with histoplasmosis. CD4 percentage came out to be normal (43.2%), so our final diagnosis was DH in an immuno-competent individual with seronegative rheumatoid arthritis.

She was initially treated with conventional amphotericin B (0.5 mg/kg/day); however, after 12 days, she developed hypokalemia and hypomagnesemia; hence, it was switched to liposomal amphotericin B (3 mg/kg/day), which was given till day 21. The response after 21 days was remarkable with flattening of almost 80% of the lesions and reduction in erythema [Figure 1b, d, f, h, j]. Thereafter, she was started on oral itraconazole (8 mg/kg/day) for 6 months. She was followed up till 2 years after treatment, and only slight post-inflammatory hyperpigmentation was present at a few sites.

Histoplasmosis, also known as Darling’s or Cave’s disease, is caused by inhaling microconidia and mycelial fragments of the organism present in bat and bird feces, which are commonly present in damp humid places and caves.[2]

Histoplasma is identified as small intracellular yeast form, 2 to 4 μm in size, with a surrounding clear halo within giant cells and macrophages. DH is the rarest form mostly found in immuno-compromised individuals. Such dissemination in our patient remains unexplained, with her being immuno-competent.

Although histoplasmosis is a rheumatologic mimic and the patient can develop bone swelling during the course of disease, our case showed anti-CCP positivity, which is a specific marker for RA. Also, her proximal inter-phalangeal joint swelling did not decrease after intravenous amphotericin B but showed improvement with oral hydroxychloroquine given to her for rheumatoid arthritis.

There are a few reports of histoplasmosis occurring with connective tissue diseases in immuno-compromised patients under treatment with biologics.[3] However, our patient was not under treatment for RA and is immuno-competent. More research is needed regarding the same. Our case was unique in its presentation and association, and was treated laboriously following a stringent protocol for administration of amphotericin B. To conclude, immunocompetent persons may not be immune to this grave disease.[4]

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