What is the recommended management for a patient with vision changes suspected to be related to histoplasmosis, particularly in those with a history of immunocompromise?

Management of Vision Changes in Histoplasmosis

Antifungal therapy is NOT recommended for presumed ocular histoplasmosis syndrome (POHS), as it has been shown to be ineffective and the condition is not clearly caused by active Histoplasma capsulatum infection 1. However, if vision changes occur in an immunocompromised patient with evidence of disseminated or CNS histoplasmosis, aggressive systemic antifungal therapy is mandatory.

Critical Distinction: POHS vs. True Ocular Histoplasmosis

Presumed Ocular Histoplasmosis Syndrome (POHS)

• Classic triad: discrete atrophic choroidal scars ("histo spots"), peripapillary atrophy, and choroidal neovascularization (CNV) 2
• Not an active infection: represents focal defects in Bruch membrane without active inflammation 2
• Amphotericin B is ineffective: one report demonstrated no response to amphotericin B treatment 1
• Management is ophthalmologic, not infectious disease: laser photocoagulation for extrafoveal/juxtafoveal CNV, photodynamic therapy with verteporfin for subfoveal CNV, or intravitreal bevacizumab 3, 2

True Intraocular Histoplasmosis (Disseminated Disease)

• Occurs only in immunocompromised patients: particularly those with HIV/AIDS, on TNF-α inhibitors, or other systemic immunosuppression 4, 5
• Presents as panuveitis or chorioretinitis: with active inflammation, not just atrophic scars 4
• Part of progressive disseminated histoplasmosis (PDH): requires evidence of systemic involvement (fever, hepatosplenomegaly, mucosal ulcers, CNS involvement) 1

Management Algorithm for Immunocompromised Patients

Step 1: Assess for Disseminated Disease

Look for:

• Systemic symptoms: fever, weight loss, malaise lasting >3 weeks 1
• Physical findings: hepatosplenomegaly, mucosal ulcers, skin lesions 1
• Laboratory abnormalities: pancytopenia, elevated LDH, elevated ferritin, progressive hepatic enzyme elevation 1
• CNS involvement: chronic meningitis or focal brain lesions (occurs in 5-20% of disseminated cases) 1

Step 2: Obtain Diagnostic Testing

• Histoplasma antigen in urine and blood: persistent antigenuria/antigenemia indicates dissemination 1
• Culture from aqueous humor or vitreous: if true intraocular involvement suspected 4
• Blood cultures and tissue biopsy: to demonstrate granulomas with H. capsulatum yeasts 1
• Molecular testing (Hc100-PCR): can detect H. capsulatum DNA in peripheral blood 3

Step 3: Initiate Antifungal Therapy for Disseminated Disease

For severe disseminated histoplasmosis with ocular involvement:

• Liposomal amphotericin B 5.0 mg/kg IV daily for 4-6 weeks (total dose 175 mg/kg) 1
• Followed by itraconazole 200 mg PO 2-3 times daily for at least 12 months 1
• Monitor itraconazole blood levels: ensure adequate drug exposure (therapeutic range typically >1.0 mcg/mL) 1

For CNS involvement (including optic nerve or retinal involvement with CNS disease):

• Liposomal amphotericin B 5.0 mg/kg IV daily for total of 175 mg/kg over 4-6 weeks 1
• Followed by itraconazole 200 mg PO 2-3 times daily for at least 1 year and until CSF abnormalities resolve, including Histoplasma antigen levels 1

Step 4: Consider Intravitreal Therapy for Refractory Cases

• Intravitreal amphotericin B: may be necessary for persistent anterior segment or vitreous involvement despite systemic therapy 4
• Difficult to eradicate from anterior chamber: particularly in severely immunocompromised patients 4
• Vitrectomy: may be required for severe vitritis 4

Critical Pitfalls to Avoid

Do NOT Use Fluconazole as First-Line

• Inferior efficacy: only 64-70% response rate compared to itraconazole 1
• Higher relapse rates: fluconazole resistance can develop in treatment failures 1
• Not acceptable for prophylaxis: due to inferior activity against H. capsulatum 6
• Only use if itraconazole contraindicated: requires higher doses (400-800 mg daily) and close monitoring 1, 6

Do NOT Stop Immunosuppression Abruptly

• May not be necessary: in the case series of ocular inflammation patients who developed histoplasmosis on immunomodulatory therapy, most did not require stopping their immunosuppression 5
• Coordinate with infectious disease: ensure adequate antifungal coverage before making decisions about immunosuppression 5

Do NOT Treat POHS with Antifungals

• Explicitly not recommended: POHS is listed under "Not recommended, unknown efficacy or ineffective" in IDSA guidelines 1
• Refer to ophthalmology: for laser photocoagulation, photodynamic therapy, or anti-VEGF injections 2

Monitoring During Treatment

• Quarterly clinical assessments: for patients on systemic antifungal therapy 6
• Urine and blood Histoplasma antigen levels: monitor every 3 months to assess treatment response 6
• Itraconazole blood levels: check to ensure therapeutic concentrations 1, 7
• Renal function, liver enzymes, electrolytes: particularly potassium and magnesium if on amphotericin B 8
• Ophthalmologic follow-up: serial examinations to assess response of chorioretinal lesions 4

Special Populations

HIV/AIDS patients:

• Can discontinue suppressive therapy: if CD4 count increases to >150 cells/mm³ on antiretroviral therapy and remains there for ≥6 months 1
• Resume suppressive therapy if: CD4 drops below 150 cells/mm³, antiretroviral therapy fails, or patient becomes nonadherent 1

Pregnancy:

• Amphotericin B is the only option: lipid formulations are safe 1
• Azoles are contraindicated: teratogenic and embryotoxic in animals 1