IDSA 2025 Guidelines on Treatment of Histoplasma Pulmonary Nodules and Acute Histoplasmosis

Recommendation:

For both adults and children with asymptomatic, non-calcified pulmonary nodules due to histoplasmosis, with no signs of active disease elsewhere, or those with a known untreated prior infection, the panel advises against routine antifungal treatment to prevent reactivation (conditional recommendation, very low certainty of evidence).

Remarks:

• Individuals at increased risk for severe or disseminated histoplasmosis, especially those with immunosuppressive conditions categorized as moderate or high risk (as outlined in Table 1), should be closely monitored for any clinical or radiological progression, and antifungal therapy may be considered.
• Patients with calcified pulmonary nodules alone do not require treatment.
• In pregnant individuals, treatment should only be initiated after a careful risk-benefit assessment, ideally in consultation with both a maternal-fetal medicine specialist and an infectious disease expert. Since these cases are rare and highly variable, treatment decisions must be individualized. If therapy is necessary, azole antifungals should be avoided during the first trimester, and liposomal amphotericin B should be used instead.

Recommendation:

The panel suggests against routine antifungal therapy for immunocompetent adults and children with mild acute pulmonary histoplasmosis (conditional recommendation, very low certainty of evidence).

Remark:

• Antifungal treatment may be considered in cases where symptoms persist for an extended duration, pulmonary infiltrates worsen, or there is evidence of increasing hilar or mediastinal lymph node enlargement.
• A large outbreak study found that over 75% of affected individuals experienced symptoms for a week or less, with full recovery within two months without treatment.

Recommendation:

For immunocompetent adults and children with moderate acute pulmonary histoplasmosis, the panel suggests either initiating or withholding antifungal treatment, depending on symptom severity, duration, and the potential risks associated with antifungal therapy (conditional recommendation, very low certainty of evidence).

Remarks:

• Patients with moderate acute pulmonary histoplasmosis present with variable symptoms, and treatment should be prioritized in cases with prolonged illness, worsening symptoms, increasing pulmonary infiltrates, or progressive lymph node enlargement.
• When deciding on treatment, potential drug interactions, adverse effects, and financial costs should be considered and discussed with the patient.
• The primary goal of therapy is to shorten the illness duration and minimize the risk of dissemination, though data on treatment effectiveness in this group are lacking.
• Itraconazole is the preferred antifungal agent when treatment is indicated.
• Itraconazole dosing recommendations:
  • Standard itraconazole (capsules or oral solution):
    • Adults: 200 mg thrice daily for three days, followed by 200 mg twice daily for 6–12 weeks.
    • Children: 5 mg/kg per dose (max 200 mg/dose) three times daily for three days, then 5 mg/kg per dose twice daily (max 400 mg/day) for 6–12 weeks.
  • Super-Bioavailable (SUBA) itraconazole (capsules, currently approved for adults only):
    • 130 mg three times daily for three days, then 130 mg twice daily for 6–12 weeks.
    • Similar weight-based dosing may be considered off-label for children capable of swallowing capsules with pharmacist consultation.
• Therapeutic Drug Monitoring (TDM) is recommended for patients on itraconazole therapy.
  • Studies indicate that around 20% of patients require dose adjustments due to subtherapeutic or excessive drug levels, and approximately 28% experience side effects.
  • Target trough concentrations for itraconazole are >1 mg/L but <3–4 mg/L (measured by chromatographic assay) to balance efficacy and minimize toxicity risks.
  • Since itraconazole has a long half-life, random (non-trough) levels may also be used for monitoring.
  • Hydroxy-itraconazole, an active metabolite, has no established cutoff levels, but patients with a combined hydroxy-itraconazole and itraconazole level >2 mg/L may respond similarly to those with itraconazole levels >1 mg/L.
• Antifungal therapy should only be used in pregnant individuals after careful evaluation of risks vs. benefits, ideally involving maternal-fetal medicine and infectious disease specialists. Azoles should be avoided in the first trimester, and liposomal amphotericin B should be preferred instead.

Recommendation:

The panel recommends antifungal treatment for immunocompromised adults and children with mild to moderate acute pulmonary histoplasmosis who are at moderate to high risk of disease progression (conditional recommendation, very low certainty of evidence).

Remarks:

• Asymptomatic or mild cases in individuals with less severe immunosuppression may not require treatment.
• Itraconazole is the preferred antifungal agent when treatment is needed.
• Itraconazole dosing recommendations:
  • Standard itraconazole (capsules or oral solution):
    • Adults: 200 mg thrice daily for three days, then 200 mg twice daily for 6–12 weeks.
    • Children: 5 mg/kg per dose (max 200 mg/dose) three times daily for three days, then 5 mg/kg per dose twice daily (max 400 mg/day) for 6–12 weeks.
  • Super-Bioavailable (SUBA) itraconazole (capsules, currently approved for adults only):
    • 130 mg three times daily for three days, then 130 mg twice daily for 6–12 weeks.
    • With pharmacist consultation, similar weight-based dosing may be considered off-label for children capable of swallowing capsules.
• Therapeutic Drug Monitoring (TDM) is strongly recommended for patients on itraconazole therapy.
  • Studies indicate that around 20% of patients require dose adjustments due to subtherapeutic or excessive drug levels, and approximately 28% experience side effects.
  • The goal trough concentration for itraconazole is >1 mg/L but <3–4 mg/L (measured by chromatographic assay) to ensure effectiveness and minimize toxicity risks.
  • Random (non-trough) levels may also be used due to the long half-life of itraconazole.
  • The hydroxy-itraconazole metabolite has no definitive cutoff levels, but a combined hydroxy-itraconazole and itraconazole level >2 mg/L may yield similar responses as itraconazole >1 mg/L.
• Antifungal therapy should only be initiated during pregnancy after a careful risk-benefit assessment, ideally in consultation with maternal-fetal medicine and infectious disease specialists. Azoles should be avoided during the first trimester, and liposomal amphotericin B should be preferred instead.