What is the most likely opportunistic infection causing granulomatous lymphadenitis, pleural effusion, tender hepatomegaly with cholestasis, in a patient with a CD4 (Cluster of Differentiation 4) count of 114, indicating impaired immune function, likely due to Human Immunodeficiency Virus (HIV) infection?

Most Likely Opportunistic Infection: Disseminated Histoplasmosis

In a patient with CD4 count of 114 cells/μL presenting with granulomatous lymphadenitis, pleural effusion, tender hepatomegaly, and cholestatic liver function tests, disseminated histoplasmosis is the most likely diagnosis and requires immediate diagnostic workup with urine and serum Histoplasma antigen testing, blood cultures, and consideration of tissue biopsy, followed by prompt initiation of amphotericin B therapy if confirmed. 1

Clinical Reasoning Based on CD4 Count and Manifestations

CD4 count of 114 cells/μL places this patient at high risk for disseminated histoplasmosis, which typically occurs when CD4+ counts fall below 150 cells/μL. 1 This level of immunosuppression creates the perfect environment for reactivation of latent Histoplasma infection or progression of acute infection to disseminated disease.

Classic Presentation Matches Disseminated Histoplasmosis

The constellation of findings is highly characteristic:

• Hepatosplenomegaly and lymphadenopathy are among the most common manifestations of disseminated histoplasmosis in AIDS patients, occurring alongside fever, fatigue, and weight loss. 1

• Granulomatous hepatitis with cholestasis is a well-documented presentation of histoplasmosis, particularly in immunodeficient hosts where the organism disseminates from pulmonary sites to involve the liver. 2

• Pleural effusion has been specifically reported as a manifestation of histoplasmosis in AIDS patients, with organisms identifiable on Wright-Giemsa stained smears of pleural fluid cells. 3, 4

• Respiratory symptoms (cough, chest pain, dyspnea) occur in approximately 50% of patients with disseminated histoplasmosis, even though the primary presentation may be extrapulmonary. 1

Immediate Diagnostic Approach

First-Line Rapid Diagnostic Tests

• Order urine and serum Histoplasma antigen testing immediately - this is the most sensitive rapid diagnostic method, detecting antigen in urine of 95% and serum of 85% of AIDS patients with disseminated histoplasmosis. 1

• Obtain blood cultures for fungi and mycobacteria - H. capsulatum can be cultured from blood in >85% of AIDS patients with disseminated disease, though organisms may require several weeks to grow. 1

• Examine peripheral blood smear - in severe disseminated histoplasmosis, organisms can be seen engulfed by white blood cells on routine blood smears. 1

Tissue Diagnosis

• Perform liver biopsy if initial tests are negative or diagnosis remains uncertain - histopathologic examination demonstrates characteristic 2-4 μm budding yeast forms and provides rapid diagnosis when methenamine silver stain is applied. 1, 5

• Consider bone marrow biopsy and culture - this appears to be one of the best diagnostic studies in immunocompromised patients with disseminated histoplasmosis. 6

Critical Differential Diagnoses to Exclude

Mycobacterium tuberculosis

Tuberculosis must be actively excluded as it can occur at any CD4 level and presents with similar manifestations including lymphadenopathy, pleural effusion, and hepatic involvement. 1 Obtain three sputum specimens for AFB smear and culture immediately, and consider tuberculosis blood cultures (mycobacterial blood cultures). 7

Mycobacterium avium Complex (MAC)

While MAC typically occurs at CD4 <50 cells/μL, this patient's CD4 of 114 is close enough to warrant consideration. 7 However, MAC more commonly presents with mycobacteremia and diffuse lymphadenopathy without the prominent pleural effusion and cholestatic pattern seen here. 1

Cryptococcosis

Cryptococcosis typically occurs with CD4 <100 cells/μL and can cause hepatic involvement, but the granulomatous lymphadenitis and pleural effusion pattern is less characteristic. 7 Consider serum cryptococcal antigen testing as part of the workup.

Immediate Treatment Recommendations

If Histoplasmosis is Confirmed or Highly Suspected

• Initiate intravenous amphotericin B immediately for moderately severe to severe disseminated histoplasmosis, particularly given the hepatic involvement with cholestasis and multiple organ systems affected. 1, 3, 5

• Plan for at least 2 weeks of amphotericin B induction therapy (or until clinical improvement), followed by transition to oral itraconazole 200 mg three times daily for 3 days, then 200 mg twice daily for at least 12 months. 1

• Monitor closely for clinical deterioration - delay in diagnosis and treatment can be life-threatening in this immunocompromised population. 2, 6

Antiretroviral Therapy Timing

• Initiate or optimize ART within 2 weeks of starting antifungal therapy for most opportunistic infections at this CD4 level, as early ART reduces mortality despite increased IRIS risk. 8

• Monitor for IRIS manifestations within the first 3-6 months after ART initiation, which may present as paradoxical worsening with fever, enlarging lymphadenopathy, or worsening hepatic inflammation. 8

Critical Pitfalls to Avoid

• Do not delay empiric amphotericin B therapy if clinical suspicion is high while awaiting culture results, as the interval from symptom onset to diagnosis directly affects prognosis and mortality. 6

• Do not assume negative serologic tests exclude histoplasmosis - serologic tests are less useful than antigen assays in AIDS patients with disseminated disease. 1

• Do not overlook tuberculosis coinfection - obtain AFB cultures even if histoplasmosis is confirmed, as dual infections can occur in this population. 1

• Do not discontinue antifungal therapy prematurely - patients require lifelong suppressive therapy with itraconazole after completing initial treatment, which can only be discontinued if CD4 count recovers to >150 cells/μL and remains there for >6 months on ART. 1