A Diagnosis in Flux: Initial Histoplasmosis Unraveling the Underlying Active Pulmonary Tuberculosis in an Apparently Immunocompetent Patient

Dear Editor, Histoplasmosis, caused by Histoplasma capsulatum, can range from asymptomatic infection to pulmonary, mucocutaneous, or progressive disseminated disease involving lungs, skin, reticuloendothelial, and central nervous system. We present a case of disseminated histoplasmosis in an immunocompetent patient, concurrently diagnosed with pulmonary tuberculosis (TB), which complicated the therapeutic response to antifungal treatment. A 55-year-old man presented with multiple red, raised, asymptomatic lesions that initially appeared around the nostrils and progressively spread to involve the cheeks, ears, neck, and palms over five months. The patient also reported loss of appetite, malaise, and significant weight loss over four months. Clinical examination revealed erythematous, umbilicated, nontender, firm papules and nodules located in the periorbital region, cheeks, anterior nares, angle of the mouth, tragus, neck, and left palm, with no associated lymphadenopathy. Our differential diagnoses included histoplasmosis, cryptococcosis, disseminated molluscum contagiosum, and histoid Hansen disease. Routine investigations, including hemogram, chest radiograph, and blood sugar levels, were normal. ELISA for HIV 1/2 antibodies, hepatitis B surface antigen, and hepatitis C antibody were negative. Histopathology of the papule revealed a well-circumscribed dermal granulomatous infiltrate with intra- and extracellular eosinophilic spores surrounded by a clear halo [Figure 1a and 1b]. Periodic acid- Schiff staining and Gomori methenamine silver (GMS) identified intracellular yeast cells with narrow-based budding, suggestive of histoplasmosis [Figure 1c and 1d]. Alcian blue staining was negative, ruling out cryptococcosis. Despite these findings, fungal cultures were negative. Based on the histopathological findings, a diagnosis of mucocutaneous histoplasmosis was made, and the patient was treated with itraconazole 200 mg capsule thrice daily for three days, followed by twice daily for a total duration of 12 months.Figure 1: (a) Well-circumscribed dermal nodular infiltrate, abutting the epidermis (Hematoxylin and eosin stain, 2x). (b) Round-to-oval yeast cells with narrow-based budding (Hematoxylin and eosin, 40x). (c) Periodic acid- Schiff stain showing magenta pink yeast cells (40x). (d) Gomori methenamine silver stain showing black round-to-oval yeast cells with narrow-based budding (40x). (e) Left-sided air fluid level suggests pleural effusion after 1.5 months of antifungal treatmentAfter 1.5 months of treatment, the patient showed no signs of clinical improvement. A repeat chest radiograph revealed left-sided pleural effusion [Figure 1e], bilateral lung fibrosis, and nodules. Sputum Gene-Xpert detected Mycobacterium tuberculosis, indicating active pulmonary TB. The evaluation of contacts for TB turned out to be negative. Immunological testing revealed a reduced CD4+ T-cell count (277 cells/μL). Contrast enhanced computed tomography of abdomen revealed bilateral enlarged adrenal glands with peripheral rim of enhancement. Adrenal endocrine profile revealed low serum basal cortisol and normal adrenocorticotropic hormone level, along with hyponatremia and hyperkalemia, suggestive of primary adrenal insufficiency. GMS staining of fine needle aspirate from the adrenal glands demonstrated yeast cells with narrow-based budding, consistent with histoplasmosis. Repeat testing for HIV 1/2 at six weekly intervals was repeated and it still came out to be negative. The patient was subsequently treated with category I antitubercular therapy (ATT) for six months along with itraconazole. To prevent adrenal crisis, fludrocortisone 0.1 mg and prednisolone 5 mg tablets were administered daily. There was significant regression of cutaneous lesions along with improvement of CD4+ T cell count (419 cells/μL) on follow-up visit after three months [Figure 2]. Repeat chest X-ray at ATT completion showed resolution of left-sided pleural effusion.Figure 2: (a-c) Erythematous to pink umbilicated papules and nodules on the nose, cheeks, and tragus before treatment; (d, e, f) Resolution of papules and nodules after initiation of antitubercular treatment alongside itraconazoleHistoplasmosis is increasingly being reported as an endemic infection in Asian countries, such as Thailand, Indonesia, and China, suggesting that endemicity in India is also a strong possibility.[1] In the Indian subcontinent, histoplasmosis most commonly presents as progressive disseminated histoplasmosis, characterized by cutaneous or pulmonary involvement, along with systemic features such as fever, weight loss, hepatosplenomegaly, and lymphadenopathy. The probable source of histoplasmosis in this patient could be the bats in the hilly region where he was residing in. Histoplasmosis and TB coinfection have important diagnostic and treatment implications as both these infections have similar pulmonary, nodal, and disseminated miliary involvement. In our case, the patient tested negative for HIV on serial investigations, had no history of immunosuppressive therapy, and reported no prior major illnesses or recurrent minor infections until the current episode. Pulmonary TB, even among immunocompetent individuals, may induce a state of transient immunosuppression, potentially predisposing the patient to opportunistic infections like histoplasmosis. Proposed hypothesis for the reduced CD4+ T-cell counts observed in patients with TB involves an atypical immune response with preferential homing of lymphocytes to infected tissues rather than remaining in circulation. This transient immunocompromised state may also explain the initial suboptimal response to antifungal therapy in our case. Another differential to consider in such cases is idiopathic CD4+ lymphocytopenia, characterized by opportunistic infections and a CD4+ T-cell count of less than 300 cells/mm3 in the absence of HIV infection, or immunosuppressive therapy.[2] Several mechanisms have been proposed to explain this condition, including selective impairment of CXCR4 expression in T cells, increased apoptotic deletion of T cells, defective thymic maturation, and impaired production of cytokines, such as TNF-α and IFN-γ. Another notable feature in our case was adrenal involvement by Histoplasma, a well-documented manifestation in immunocompetent individuals, particularly within the Asian population.[3,4] Our patient responded to oral itraconazole after initiation of anti-tuberculous therapy, which highlights that low CD4+ counts may result from underlying TB, impairing the treatment response to other opportunistic infections.[5] The overall long-term prognosis of the patient appears to be favorable, given the improvement in CD4 counts and clinical response to itraconazole post- ATT initiation. Authors’ contributions We confirm that all authors have read and approved the manuscript for submission. All authors meet authorship criteria, and the manuscript represents honest work. Declaration of patient consent The authors certify that they have obtained all appropriate parent consent forms. In the form the their consent for the patient’s images and other clinical information to be reported in the journal. The parent understand that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Use of artificial intelligence (AI) The preparation of this manuscript was carried out entirely by the authors without the use of artificial intelligence technologies.