Histoplasmosis

Back

1st line –

azole antifungals

Immunocompromised patients should be started on antifungal therapy as soon as active histoplasmosis infection is suspected, due to their high risk of progression to disseminated histoplasmosis and the attendant complications.

Azole antifungals are recommended for these patients. Serum levels of itraconazole are generally higher with the solution formulation, and this should be used for treatment whenever possible. Voriconazole and posaconazole show good in vitro activity against histoplasmosis, and have been successfully used to treat a more limited number of immunocompromised patients with acute disease. They can be considered as alternative agents for individuals who cannot tolerate itraconazole. Therapeutic drug monitoring is advised.[25]

Fluconazole demonstrates lower activity against the fungus, and there have been reports of resistance emerging among patients receiving fluconazole therapy.[4] Fluconazole is therefore reserved for patients who are intolerant of or refractory to these azoles. Should be used in consultation with infectious disease expert.

Azole antifungals are hepatotoxic. Therefore, liver enzymes should be checked before initiation of therapy; at weeks 1, 2, and 4 after initiating treatment; and every 3 months thereafter (if applicable) until end of therapy.

Itraconazole levels should be therapeutically monitored at least 2 weeks after initiation of therapy, and random serum itraconazole levels of ≥1 microgram/mL are recommended for effective therapy.

Azole antifungals have a number of potential drug-drug interactions; review the patient's medication history prior to administration.

Treatment course: 6 to 12 weeks.

Primary options

itraconazole: children (HIV negative): 2.5 to 5 mg/kg (maximum 200 mg/dose) orally twice daily; children (HIV positive): 2-5 mg/kg (maximum 200 mg/dose) orally three times daily for 3 days, followed by 2-5 mg/kg (maximum 200 mg/dose) twice daily; adults: 200 mg orally three times daily for 3 days, followed by 200 mg once or twice daily

Secondary options

voriconazole: children: consult specialist for guidance on dose; adults: 400 mg orally twice daily on day 1, followed by 200 mg twice daily

posaconazole: children: consult specialist for guidance on dose; adults: 300 mg orally twice daily on day 1, followed by 300 mg once daily

Tertiary options

fluconazole: children: 10-12 mg/kg orally once daily, maximum 400 mg/day; adults: 800 mg orally once daily

severe symptoms

Back

1st line –

amphotericin B

For these patients, intravenous amphotericin B is required for 1 to 2 weeks before switching to an oral agent once stabilised. Liposomal amphotericin B is the preferred formulation in adults, although other formulations may be used if liposomal amphotericin B is unavailable or not tolerated.[4]

In patients with HIV, liposomal amphotericin B has been associated with a higher response rate and lower mortality than the deoxycholate formulation.[33][50]

Amphotericin B deoxycholate is well tolerated in children and lipid formulations are not necessarily preferred.[1]

Primary options

amphotericin B liposomal: children and adults: 3-5 mg/kg/day intravenously

Secondary options

amphotericin B lipid complex: children and adults: 5 mg/kg/day intravenously

amphotericin B deoxycholate: children and adults: 0.7 to 1 mg/kg/day intravenously

Back

Consider –

ventilatory support

Additional treatment recommended for SOME patients in selected patient group

Patients may become hypoxaemic and require ventilatory support.

mild to moderate symptoms

Back

Plus –

itraconazole maintenance

Treatment recommended for ALL patients in selected patient group

Patients may be transitioned to itraconazole once they have stabilised. After discharge from hospital, patients require continued treatment with itraconazole for at least 12 weeks or until the pulmonary infiltrates have resolved on chest x-ray.[1]

Fluconazole has a reduced efficacy as chronic maintenance therapy.[1]

Azole antifungals have a number of potential drug-drug interactions; review the patient's medication history prior to administration.

Primary options

acute pulmonary disease: >4 weeks (non-pregnant)

Back

1st line –

azole antifungals

Azole antifungals are recommended for these patients. Serum levels of itraconazole are generally higher with the solution formulation, and this should be used for treatment whenever possible. Voriconazole and posaconazole have good in vitro activity against histoplasmosis. They have been successfully used to treat a limited number of immunocompromised individuals with histoplasmosis. They can be considered as alternatives for individuals intolerant to itraconazole. Therapeutic drug monitoring is advised.[25]

Fluconazole demonstrates lower activity against the fungus, and there have been reports of resistance emerging among patients receiving fluconazole therapy.[4] Fluconazole is therefore reserved for patients who are intolerant to these other azoles. Should be used in consultation with infectious disease expert.

Azoles are hepatotoxic. Therefore, liver enzymes should be checked before initiation of therapy; at weeks 1, 2, and 4 after initiating treatment; and every 3 months thereafter (if applicable) until end of therapy.

Itraconazole levels should be therapeutically monitored at least 2 weeks after initiation of therapy, and random serum itraconazole levels of ≥1 microgram/mL are recommended for effective therapy.

Azole antifungals have a number of potential drug-drug interactions; review the patient's medication history prior to administration.

Treatment course: 6 to 12 weeks.

Primary options

Secondary options

voriconazole: children: consult specialist for guidance on dose; adults: 400 mg orally twice daily on day 1, followed by 200 mg twice daily

posaconazole: children: consult specialist for guidance on dose; adults: 300 mg orally twice daily on day 1, followed by 300 mg once daily

Tertiary options

fluconazole: children: 10-12 mg/kg orally once daily, maximum 400 mg/day; adults: 800 mg orally once daily

severe symptoms

Back

1st line –

amphotericin B

In patients with HIV, liposomal amphotericin B has been associated with a higher response rate and lower mortality than the deoxycholate formulation.[33][50]

Amphotericin B deoxycholate is well tolerated in children and lipid formulations are not necessarily preferred.[1]

Primary options

amphotericin B liposomal: children and adults: 3-5 mg/kg/day intravenously

Secondary options

amphotericin B lipid complex: children and adults: 5 mg/kg/day intravenously

amphotericin B deoxycholate: children and adults: 0.7 to 1 mg/kg/day intravenously

Back

Consider –

ventilatory support

Additional treatment recommended for SOME patients in selected patient group

Patients may become hypoxaemic and require ventilatory support.

Back

Plus –

itraconazole maintenance

Treatment recommended for ALL patients in selected patient group

Fluconazole has a reduced efficacy as chronic maintenance therapy.[1]

Azole antifungals have a number of potential drug-drug interactions; review the patient's medication history prior to administration.

Primary options

chronic pulmonary disease (non-pregnant)

ambulatory

Back

1st line –

azole antifungals

In contrast to other infections, the distinction between acute and chronic histoplasmosis is determined by the presence or absence of underlying lung disease rather than duration of symptoms. Chronic histoplasmosis arises in a pre-existing lung cavity, and symptoms take months to years to become clinically obvious.

Chronic pulmonary histoplasmosis has not been described in paediatric populations.

For ambulatory patients, itraconazole has been found to be safe and effective in the treatment of chronic pulmonary histoplasmosis.[24] However, relapse rates are high (9% to 15%); hence, long-term treatment is recommended.

Voriconazole and posaconazole show good in vitro activity against histoplasmosis, and have been successfully used to treat a limited number of immunocompromised patients with acute disease. They can be considered as alternative agents for individuals who are unable to tolerate itraconazole. Therapeutic drug monitoring is advised.[25] Fluconazole can be used in patients intolerant of or refractory to other azoles. Should be used in consultation with infectious disease expert.

Itraconazole levels should be therapeutically monitored at least 2 weeks after initiation of therapy, and random serum itraconazole levels of ≥1 microgram/mL are recommended for effective therapy.

Liver enzymes should be checked before initiation of therapy; at weeks 1, 2, and 4 after initiating treatment; and every 3 months thereafter (if applicable) until end of therapy.

Chest x-ray should be obtained at 4- to 6-month intervals, and treatment should be continued for at least 12 months or until complete resolution on chest x-ray, whichever comes later.[1]

Azole antifungals have a number of potential drug-drug interactions; review the patient's medication history prior to administration.

Primary options

itraconazole: 200 mg orally three times daily for 3 days, followed by 200 mg once or twice daily

Secondary options

voriconazole: 400 mg orally twice daily on day 1, followed by 200 mg twice daily

posaconazole: 300 mg orally twice daily on day 1, followed by 300 mg once daily

Tertiary options

fluconazole: 800 mg orally once daily

hospitalised

Back

1st line –

amphotericin B

Chronic pulmonary histoplasmosis has not been described in paediatric populations.

For these patients, intravenous amphotericin B is required for 1 to 2 weeks before switching to an oral agent once stabilised. Liposomal amphotericin B is the preferred formulation, although other formulations may be used if liposomal amphotericin B is unavailable or not tolerated.[4]

Primary options

amphotericin B liposomal: 3-5 mg/kg/day intravenously

Secondary options

amphotericin B lipid complex: 5 mg/kg/day intravenously

amphotericin B deoxycholate: 0.7 to 1 mg/kg/day intravenously

Back

Consider –

ventilatory support

Additional treatment recommended for SOME patients in selected patient group

Patients may become hypoxaemic and require ventilatory support.

Back

Plus –

itraconazole maintenance

Treatment recommended for ALL patients in selected patient group

Patients may be transitioned to itraconazole once they have stabilised. After discharge from hospital, patients require continued treatment with itraconazole for at least 12 months or until the pulmonary infiltrates have resolved on chest x-ray.[1]

Fluconazole has a reduced efficacy as chronic maintenance therapy.[1]

Due to high rates of relapse, patients should be closely monitored for at least 1 year after treatment is discontinued.

Azole antifungals have a number of potential drug-drug interactions; review the patient's medication history prior to administration.

Primary options

itraconazole: 200 mg orally three times daily for 3 days, followed by 200 mg once or twice daily

disseminated disease (non-pregnant)

ambulatory

Back

1st line –

azole antifungals

Azole antifungals are recommended for these patients. Serum levels of itraconazole are generally higher with the solution formulation, and this should be used for treatment whenever possible. Voriconazole and posaconazole show good in vitro activity against histoplasmosis, and have been successfully used to treat a limited number of immunocompromised patients with acute disease. They can be considered as alternative agents for individuals who cannot tolerate itraconazole. Therapeutic drug monitoring is advised.[25]

Fluconazole demonstrates lower activity against the fungus, and there have been reports of resistance emerging among patients receiving fluconazole therapy.[4] Fluconazole is therefore reserved for patients who are intolerant of or refractory to other azoles. Should be used in consultation with infectious disease expert.

Itraconazole levels should be therapeutically monitored at least 2 weeks after initiation of therapy, and random serum itraconazole levels of ≥1 microgram/mL are recommended for effective therapy.

Liver enzymes should be checked before initiation of therapy; at weeks 1, 2, and 4 after initiating treatment; and every 3 months thereafter (if applicable) until end of therapy.

Chest x-ray should be obtained at 4- to 6-month intervals, and treatment should be continued for at least 12 months or until complete resolution on chest x-ray, whichever comes later.[1]

In HIV-infected patients, itraconazole can safely be discontinued after at least 1 year if they are receiving highly active antiretroviral therapy, CD4 count is >150 cells/mL, blood culture results are negative, and Histoplasma serum and urine antigen levels are <2 nanograms/mL.[33][51][52]

Azole antifungals have a number of potential drug-drug interactions; review the patient's medication history prior to administration.

Primary options

Secondary options

voriconazole: children: consult specialist for guidance on dose; adults: 400 mg orally twice daily on day 1, followed by 200 mg twice daily

posaconazole: children: consult specialist for guidance on dose; adults: 300 mg orally twice daily on day 1, followed by 300 mg once daily

Tertiary options

fluconazole: children: 10-12 mg/kg orally once daily, maximum 400 mg/day; adults: 800 mg orally once daily

hospitalised

Plus – ventilatory support

Back

1st line –

amphotericin B

In patients with HIV, liposomal amphotericin B has been associated with a higher response rate and lower mortality than the deoxycholate formulation.[33][50]

Amphotericin B deoxycholate is well tolerated in children and lipid formulations are not necessarily preferred.[1]

Primary options

amphotericin B liposomal: children and adults: 3-5 mg/kg/day intravenously

Secondary options

amphotericin B lipid complex: children and adults: 5 mg/kg/day intravenously

amphotericin B deoxycholate: children and adults: 0.7 to 1 mg/kg/day intravenously

Back

Plus –

ventilatory support

Treatment recommended for ALL patients in selected patient group

Patients may become hypoxaemic and require ventilatory support.

1st line – observation only

Back

Plus –

itraconazole maintenance

Treatment recommended for ALL patients in selected patient group

Patients may be transitioned to itraconazole once they have stabilised. After discharge from hospital, patients require continued treatment with itraconazole for at least 12 months or until the pulmonary infiltrates have resolved on chest x-ray.[1]

Fluconazole has a reduced efficacy as chronic maintenance therapy.[1]

Due to high rates of relapse, patients should be closely monitored for at least 1 year after treatment is discontinued.

Azole antifungals have a number of potential drug-drug interactions; review the patient's medication history prior to administration.

Primary options

mediastinal granuloma (non-pregnant)

asymptomatic

Back

1st line –

observation only

In some patients, mediastinal lymph nodes can coalesce over months to years to form a large, caseating, encapsulated mass following acute pulmonary histoplasmosis. Treatment is not indicated for asymptomatic patients.[1]

symptomatic: without mediastinal compression or fistulation

symptomatic: with mediastinal compression or fistulation

Back

1st line –

azole antifungals

In some patients, mediastinal lymph nodes can coalesce over months to years to form a large, caseating, encapsulated mass following acute pulmonary histoplasmosis. Symptomatic patients can be treated with itraconazole.[1] Azole antifungals have a number of potential drug-drug interactions; review the patient's medication history prior to administration.

Primary options

itraconazole: 200 mg orally three times daily for 3 days, followed by 200 mg once or twice daily for 6-12 weeks

1st line – corticosteroids + azole antifungals

Back

1st line –

corticosteroids + azole antifungals

Reactive structures can cause symptoms secondary to compression of mediastinal structures or form fistulous tracts with a bronchus, the oesophagus, or skin. In this situation, treatment with a corticosteroid such as prednisone in combination with itraconazole is required. Surgery may be indicated to relieve obstructive symptoms.[53]

Azole antifungals have a number of potential drug-drug interactions; review the patient's medication history prior to administration.

Primary options

prednisolone: 0.5 to 1 mg/kg/day orally once daily, taper dose gradually over 1-2 weeks, maximum 80 mg/day

and

itraconazole: 200 mg orally three times daily for 3 days, followed by 200 mg once or twice daily for 6-12 weeks

Consider – surgery

Back

Consider –

surgery

Additional treatment recommended for SOME patients in selected patient group

Surgery may be indicated to relieve obstructive symptoms.[53]

mediastinal fibrosis (non-pregnant)

1st line – observation + consideration of azole antifungals

Back

1st line –

observation + consideration of azole antifungals

Invasive fibrosis can sometimes encase mediastinal or hilar lymph nodes and cause airway and great vessel occlusion. Bilateral disease is uncommon but highly fatal.[54]

Antifungal and anti-inflammatory treatments are generally not considered helpful. Some clinicians recommend a 12-week course of itraconazole, although efficacy is not demonstrated.[55]

Corticosteroids are not recommended and the role of antifibrotics is unknown.

Azole antifungals have a number of potential drug-drug interactions; review the patient's medication history prior to administration.

Consider – intravascular stents

Back

Consider –

intravascular stents

Additional treatment recommended for SOME patients in selected patient group

Intravascular stents can be used to ameliorate symptoms of superior vena cava compression.[1][55]

broncholithiasis (non-pregnant)

1st line – bronchoscopic or surgical removal of stones

Back

1st line –

bronchoscopic or surgical removal of stones

Calcified lymph nodes from prior histoplasmosis infection can sometimes erode into the adjacent bronchus, causing haemoptysis and spitting of small chalk-like pieces (lithoptysis).[56]

Bronchoscopic and sometimes surgical removal of stones is the treatment of choice.[56] Antifungal therapy is not indicated.[1][55]

pericarditis (non-pregnant)

mild symptoms

1st line – non-steroidal anti-inflammatory drug (NSAID)

Back

1st line –

non-steroidal anti-inflammatory drug (NSAID)

Symptoms are typically caused by the host inflammatory response to pulmonary infection, rather than due to infection of the pericardial sac itself.[57] Treatment with NSAIDs is sufficient for mild symptoms.

Primary options

ibuprofen: 400-800 mg orally every 6-8 hours when required, maximum 2400 mg/day

aspirin: 300-900 mg orally every 4-6 hours when required, maximum 4000 mg/day

Secondary options

indometacin: 25-50 mg orally (immediate-release) two to three times daily when required, maximum 200 mg/day

moderate to severe symptoms

1st line – corticosteroids + azole antifungals

Back

1st line –

corticosteroids + azole antifungals

Patients with moderate to severe symptoms require treatment with a corticosteroid; in this circumstance, itraconazole should be co-administered to prevent any dissemination of the infection that may result from the immunosuppression.[1]

Azole antifungals have a number of potential drug-drug interactions; review the patient's medication history prior to administration.

Primary options

prednisolone: 0.5 to 1 mg/kg/day orally once daily, taper dose gradually over 1-2 weeks, maximum 80 mg/day

and

itraconazole: 200 mg orally three times daily for 3 days, followed by 200 mg once or twice daily for 6-12 weeks

Consider – pericardiocentesis

Back

Consider –

pericardiocentesis

Additional treatment recommended for SOME patients in selected patient group

Pericardiocentesis may be needed in patients with haemodynamic compromise.[1]

rheumatological syndrome (non-pregnant)

1st line – non-steroidal anti-inflammatory drug (NSAID)

Back

1st line –

non-steroidal anti-inflammatory drug (NSAID)

The host inflammatory response to acute pulmonary histoplasmosis can cause polyarthritis or arthralgia in up to 10% of patients.[58] Affected patients may also develop erythema nodosum.

Treatment is usually with NSAIDs alone.[1]

Primary options

ibuprofen: 400-800 mg orally every 6-8 hours when required, maximum 2400 mg/day

naproxen: 250-500 mg orally twice daily when required, maximum 1250 mg/day

diclofenac potassium: 50 mg orally (immediate-release) two to three times daily when required, maximum 150 mg/day

indometacin: 25-50 mg orally (immediate-release) two to three times daily when required, maximum 200 mg/day

2nd line – corticosteroids + azole antifungals

Back

2nd line –

corticosteroids + azole antifungals

Corticosteroids are rarely needed but have been used for symptoms refractory to NSAID treatment. If corticosteroids are given, itraconazole should be co-administered to prevent any dissemination of the infection.[58][59]

Azole antifungals have a number of potential drug-drug interactions; review the patient's medication history prior to administration

Primary options

prednisolone: 0.5 to 1 mg/kg/day orally once daily, taper dose gradually over 1-2 weeks, maximum 80 mg/day

and

itraconazole: 200 mg orally three times daily for 3 days, followed by 200 mg once or twice daily for 6-12 weeks

meningoencephalitis (non-pregnant)

Back

1st line –

amphotericin B

Up to 20% of patients with disseminated histoplasmosis demonstrate signs and symptoms of central nervous system involvement that include meningitis, encephalitis, and mass lesions of the brain or spinal cord.[60] Initial treatment is with liposomal amphotericin B for 4 to 6 weeks.

Primary options

amphotericin B liposomal: 3-5 mg/kg/day intravenously for 4-6 weeks

Back

Plus –

itraconazole maintenance

Treatment recommended for ALL patients in selected patient group

Following completion of amphotericin B treatment, itraconazole maintenance therapy is required for at least 1 year and until resolution of cerebrospinal fluid abnormalities, including Histoplasma antigen levels. Blood levels of itraconazole should be obtained to ensure adequate drug exposure.[1]

Azole antifungals have a number of potential drug-drug interactions; review the patient's medication history prior to administration.

Primary options

itraconazole: 200 mg orally three times daily for 3 days, followed by 200 mg once or twice daily

pregnant

Back

1st line –

amphotericin B

Azole antifungals are teratogenic in pregnancy; therefore, pregnant women should be treated with amphotericin B preparations for 4 to 6 weeks, and the baby should be monitored for clinical and laboratory evidence of histoplasmosis after birth.[62]

Lipid formulation is recommended.

Deoxycholate formulation is an alternative in patients who are at a low risk for nephrotoxicity.

Primary options

amphotericin B liposomal: 3-5 mg/kg/day intravenously

Secondary options

amphotericin B lipid complex: 5 mg/kg/day intravenously

amphotericin B deoxycholate: 0.7 to 1 mg/kg/day intravenously