Definitions of the levels of evidence (I-III) and grades of recommendation (A-C) are repeated at the end of the "Major Recommendations" field.
Indications for Antifungal Therapy
Definite Indication, Proven or Probable Efficacy
- Acute diffuse pulmonary, moderately severe or severe symptoms
- Chronic cavitary pulmonary
- Progressive disseminated
- Central nervous system infection
Uncertain Indication, Unknown Efficacy
- Acute focal pulmonary, asymptomatic or mild symptoms persistent >1 month
- Mediastinal lymphadenitis
- Mediastinal granuloma
- Inflammatory syndromes, treated with corticosteroids
Not Recommended, Unknown Efficacy or Ineffective
- Mediastinal fibrosis
- Pulmonary nodule
- Broncholithiasis
- Presumed ocular histoplasmosis syndrome
What Is the Treatment for Acute and Chronic Pulmonary Histoplasmosis?
Moderately Severe To Severe Acute Pulmonary Histoplasmosis
- Lipid formulation of amphotericin B, 3.0 to 5.0 mg/kg/day (d) intravenously (IV), for one to two weeks, followed by itraconazole, 200 mg 3 times daily for 3 days and then 200 mg twice daily, for a total of 12 weeks is recommended (AIII).
- The deoxycholate formulation of amphotericin B 0.7 to 1.0 mg/kg/d is an alternative to a lipid formulation in patients who are at a low risk for nephrotoxicity (AIII).
- Methylprednisolone, 0.5 to 1.0 mg/kg/d given intravenously, during the first 1 to 2 weeks of antifungal therapy is recommended for patients who develop respiratory complications, including hypoxemia or significant respiratory distress (BIII).
Mild to Moderate Acute Pulmonary Histoplasmosis
- Treatment is usually unnecessary (AIII). Itraconazole, 200 mg 3 times daily for 3 days and then 200 mg once or twice daily, for 6 to 12 weeks is recommended in those patients who continue to have symptoms for longer than a month (BIII).
Chronic Cavitary Pulmonary Histoplasmosis
- Itraconazole, 200 mg 3 times daily for 3 days and then once or twice daily for at least one year is recommended, but some prefer 18 to 24 months in view of the risk for relapse (AII).
- Blood levels of itraconazole should be obtained after the patient has been on this agent for at least two weeks to ensure adequate drug exposure (AIII).
What Is the Treatment for the Complications from Pulmonary Histoplasmosis (e.g., pericarditis, arthritis/erythema nodosum, mediastinal lymphadenitis, mediastinal granuloma, mediastinal fibrosis, broncholithiasis, and pulmonary nodule)?
Pericarditis
- Non-steroidal anti-inflammatory therapy is recommended in mild cases (BIII).
- Prednisone 0.5 to 1.0 mg/kg/d (maximum 80 mg daily) in tapering doses over 1 to 2 weeks is recommended in patients with evidence for hemodynamic compromise or unremitting symptoms after several days of therapy with non-steroidal anti-inflammatory therapy (BIII).
- Pericardial fluid removal is indicated in patients with hemodynamic compromise (AIII).
- Itraconazole, 200 mg 3 times daily for 3 days and then once or twice daily for 6 to 12 weeks is recommended if corticosteroids are administered (BIII).
Rheumatologic Syndromes
- Non-steroidal anti-inflammatory therapy is recommended in mild cases (BIII).
- Prednisone 0.5 to 1.0 mg/kg/d (maximum 80 mg daily) in tapering doses over 1 to 2 weeks is recommended in severe cases (BIII).
- Itraconazole, 200 mg 3 times daily for 3 days and then once or twice daily for 6 to 12 weeks is recommended only if corticosteroids are administered (BIII).
Mediastinal Lymphadenitis
- Treatment is usually unnecessary (AIII).
- Itraconazole, 200 mg 3 times daily for 3 days and then 200 mg once or twice daily, for 6 to 12 weeks is recommended in patients who have symptoms that warrant treatment with corticosteroids and in those who continue to have symptoms for longer than a month (BIII).
- Prednisone 0.5 to 1.0 mg/kg/d (maximum 80 mg daily) in tapering doses over 1 to 2 weeks is recommended in severe cases with obstruction or compression of contiguous structures. (BIII).
Mediastinal Granuloma
- Treatment is usually unnecessary (AIII).
- Itraconazole, 200 mg 3 times daily for 3 days and then once or twice daily for 6 to 12 weeks is recommended for symptomatic cases (BIII).
Mediastinal Fibrosis
- Antifungal treatment is not recommended (AIII).
- The placement of intravascular stents is recommended for selected patients with pulmonary vessel obstruction (BIII).
- Itraconazole, 200 mg once or twice daily, for 12 weeks is recommended if clinical findings cannot differentiate mediastinal fibrosis from mediastinal granuloma (CIII).
Broncholithiasis
- Antifungal treatment is not recommended (AIII).
- Bronchoscopic or surgical removal of the broncholith is recommended (AIII).
Pulmonary Nodules (Histoplasmomas)
- Antifungal treatment is not recommended (AIII).
What Is the Treatment for Progressive Disseminated Histoplasmosis?
- For moderately severe to severe disease, liposomal amphotericin B, 3.0 mg/kg/d is recommended for 1 to 2 weeks, followed by oral itraconazole, 200 mg 3 times daily for 3 days and then 200 mg twice daily for a total of at least 12 months (AI).
- Substitution of another lipid formulation, at a dosage of 5.0 mg/kg/d, may be preferred in some patients because of cost or tolerability (AIII).
- The deoxycholate formulation of amphotericin B 0.7 to 1.0 mg/kg/d is an alternative to a lipid formulation in patients who are at a low risk for nephrotoxicity (AIII).
- For mild to moderate disease, itraconazole, 200 mg 3 times daily for 3 days and then twice daily for at least 12 months is recommended (AII).
- Lifelong suppressive therapy with itraconazole 200 mg daily, may be required in immunosuppressed patients if immunosuppression cannot be reversed (AII), and in patients who relapse despite appropriate therapy (CIII).
- Blood levels of itraconazole should be obtained to ensure adequate drug exposure (BIII).
- Antigen levels should be measured during therapy and for 12 months after therapy is ended to monitor for relapse (BIII). Persistent low-level antigenuria may not be a reason to prolong treatment in patients who have completed appropriate therapy and have no evidence for active infection.
Is Prophylaxis Recommended for Immunosuppressed Patients?
- Prophylaxis with itraconazole 200 mg daily is recommended in patients with HIV infection with CD4 counts <150 cells/mm3 in specific endemic areas in which the incidence of histoplasmosis is >10 cases per 100 patient years (AI).
- Prophylaxis with itraconazole 200 mg daily may be appropriate in specific circumstances in other immunosuppressed patients (CIII).
What Is the Treatment for Central Nervous System Histoplasmosis?
- Liposomal amphotericin B, 5.0 mg/kg/d for total of 175 mg/kg given over 4 to 6 weeks followed by itraconazole, 200 mg 2 or 3 times daily for at least one year and until resolution of cerebrospinal fluid abnormalities, including Histoplasma antigen levels, is recommended (BIII).
- Blood levels of itraconazole should be obtained to ensure adequate drug exposure (BIII).
What Is the Treatment for Histoplasmosis in Pregnancy?
- Lipid formulation amphotericin B, 3.0 to 5.0 mg/kg/d, for 4 to 6 weeks is recommended (AIII).
- The deoxycholate formulation of amphotericin B, 0.7 to 1.0 mg/kg/d is an alternative to a lipid formulation in patients who are at a low risk for nephrotoxicity (AIII).
- If the newborn shows evidence for infection, treatment is recommended with amphotericin B deoxycholate 1.0 mg/kg/d for 4 weeks (AIII).
What Treatment Is Recommended for Histoplasmosis in Children?
Acute Pulmonary Histoplasmosis
- Treatment indications and regimens are similar to adults, except that amphotericin B deoxycholate, 1.0 mg/kg/d is usually well tolerated, and the lipid preparations are not preferred (AIII).
- Itraconazole dosage in children is 5.0 to 10.0 mg/kg/d in two divided doses, not to exceed 400 mg daily, generally using the solution formulation (AIII).
Progressive Disseminated Histoplasmosis
- Amphotericin B deoxycholate, 1.0 mg/kg/d for 4 to 6 weeks is recommended (AIII)
- Amphotericin B deoxycholate, 1.0 mg/kg/d for 2 to 4 weeks, followed by itraconazole 5.0 to 10.0 mg/kg/d in two divided doses, not to exceed 400 mg daily, to complete 3 months of therapy is an alternative (AIII).
- Longer therapy may be needed in patients with severe disease, immunosuppression or primary immunodeficiency syndromes (AIII).
- Lifelong suppressive therapy with itraconazole 5.0 mg/kg/d up to 200 mg daily, may be required in immunosuppressed patients if immunosuppression cannot be reversed (AII), and in patients who relapse despite appropriate therapy (CIII).
- Blood levels of itraconazole should be obtained to ensure adequate drug exposure (BIII).
- Antigen levels should be monitored during therapy and for 12 months after therapy is ended to monitor for relapse (BIII). Persistent low-level antigenuria may not be a reason to prolong treatment in patients who have completed appropriate therapy and have no evidence for active infection.
Performance Measures
- Itraconazole is the preferred azole for initial therapy of patients with mild to moderate histoplasmosis and as step-down therapy after amphotericin B. When other azole agents are used, the medical record should document the specific reasons that itraconazole was not used and why other azoles were used.
- Patients with severe or moderately severe histoplasmosis should be treated with an amphotericin B formulation initially. When amphotericin B is used, the patient's electrolytes, renal function, and blood counts should be monitored several times a week and documented in the medical record.
- Itraconazole drug levels should be measured during the first month in patients with disseminated or chronic pulmonary histoplasmosis and these levels should be documented in the medical record, as well as the physician's response to levels that are too low.
- Itraconazole should not be given to patients receiving the contraindicated medications: pimozide, quinidine, dofetilide, lovastatin, simvastatin, midazolam, triazolam. Reasons for deviation from this practice should be documented in the medical record.
Definitions:
Quality of Evidence
- Evidence from ≥1 properly randomized, controlled trial
- Evidence from ≥ well-designed clinical trial without randomization, from cohort or case-control analytic studies (preferably from ≥ center), from multiple time-series, or from dramatic results from uncontrolled experiments
- Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees
Strength of Recommendation
- Good evidence to support a recommendation for use
- Moderate evidence to support a recommendation for use
- Poor evidence to support a recommendation
