Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

latent asymptomatic disease (non-pregnant)

1st line – observation

Back
ACUTE
|
latent asymptomatic disease (non-pregnant)
1st line – 

observation

In otherwise healthy people with small exposure to fungal spores, histoplasmosis manifests as an asymptomatic or clinically insignificant infection.

Localised, healed pulmonary histoplasmosis infection can calcify and persist long term as pulmonary nodules which are asymptomatic and are found incidentally during lung imaging. Antifungal therapy for pulmonary nodules is not recommended.[1]​

acute pulmonary disease (non-pregnant)

1st line – observation

Back
ACUTE
|
acute pulmonary disease (non-pregnant)
|
mild to moderate symptoms <4 weeks: immunocompetent
1st line – 

observation

In immunocompetent patients, the symptoms are mild, usually abate within weeks of onset, and tend to resolve without specific treatment.[1]

1st line – azole antifungal

Back
ACUTE
|
acute pulmonary disease (non-pregnant)
|
mild to moderate symptoms ≥4 weeks: immunocompetent
1st line – 

azole antifungal

Data for treatment of pulmonary histoplasmosis in immunocompetent patients with symptoms lasting ≥4 weeks are lacking. Itraconazole may be given, particularly in the presence of ongoing symptoms that raise concern for the development of progressive, disseminated histoplasmosis.[1] People with HIV who have a CD4 count ≥300 cells/mm3 should be managed in the same way an immunocompetent person without HIV.[25]

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.[25]​ They can be considered as alternatives for individuals intolerant to itraconazole.​[1]

Fluconazole demonstrates lower activity against the fungus and is less effective than itraconazole, and there have been reports of resistance emerging among patients receiving fluconazole therapy.[4] Fluconazole is therefore reserved for patients who are intolerant to other azoles.​​

Therapeutic drug monitoring is recommended with azole antifungals. Serum levels of itraconazole are generally higher with the solution formulation, and this should be used for treatment whenever possible.

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.

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

Treatment course: 6 to 12 weeks.

Primary options

itraconazole: children: 2.5 to 5 mg/kg orally twice daily, maximum 200 mg/dose; 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

OR

posaconazole: children: consult specialist for guidance on dose; adults: 300 mg orally (delayed-release tablet) twice daily on day 1, followed by 300 mg once daily

Tertiary options

fluconazole: children: 3-6 mg/kg orally once daily, maximum 200 mg/dose; adults: 800 mg orally once daily

1st line – azole antifungal

Back
ACUTE
|
acute pulmonary disease (non-pregnant)
|
mild to moderate symptoms of any duration: immunocompromised
1st line – 

azole antifungal

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. Itraconazole is the preferred option. 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.[4][25] 

Fluconazole demonstrates lower activity against the fungus, and there have been reports of resistance emerging among patients receiving fluconazole therapy.[4][25]​ Fluconazole is therefore reserved for patients who are intolerant of or refractory to other azoles. 

Therapeutic drug monitoring is recommended with azole antifungals. Serum levels of itraconazole are generally higher with the solution formulation, and this should be used for treatment whenever possible.

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.

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

Treatment course: 6 to 12 weeks for people without HIV.[1] People with HIV and acute pulmonary histoplasmosis who have a CD4 count <300 cells/mm3 are treated with itraconazole for at least 12 months.[25]​ People with HIV who have a CD4 count ≥300 cells/mm3 should be managed in the same way an immunocompetent person without HIV.[25]

Primary options

itraconazole: children (without HIV): 2.5 to 5 mg/kg orally twice daily, maximum 200 mg/dose; children (with HIV): 2-5 mg/kg orally three times daily for 3 days, followed by 2-5 mg/kg twice daily, maximum 200 mg/dose; adults: 200 mg orally three times daily for 3 days, followed by 200 mg 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

OR

posaconazole: children: consult specialist for guidance on dose; adults: 300 mg orally (delayed-release tablet) twice daily on day 1, followed by 300 mg once daily

Tertiary options

fluconazole: children: 3-6 mg/kg orally once daily, maximum 200 mg/dose; adults: 800 mg orally once daily

1st line – amphotericin-B

Back
ACUTE
|
acute pulmonary disease (non-pregnant)
|
severe symptoms of any duration
1st line – 

amphotericin-B

For these patients, intravenous amphotericin-B is required for 1 to 2 weeks before transitioning to an oral azole antifungal once stabilised.[1][25]​

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 amphotericin-B deoxycholate.[33][50]

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

Amphotericin-B is associated with nephrotoxicity, hypokalaemic, anaemia, and infusion-related adverse reactions.

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

OR

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

Plus – azole antifungal

Back
ACUTE
|
acute pulmonary disease (non-pregnant)
|
severe symptoms of any duration
Plus – 

azole antifungal

Treatment recommended for ALL patients in selected patient group

Patients should be transitioned to an oral azole antifungal once they have stabilised. Itraconazole is the preferred option.[1][25]​ 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]

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.[1][25]

Fluconazole has a reduced efficacy as chronic maintenance therapy, but can be used in patients intolerant of, or refractory to, other azoles.[1]

Therapeutic drug monitoring is recommended with azole antifungals. Serum levels of itraconazole are generally higher with the solution formulation, and this should be used for treatment whenever possible.

Azole antifungals are hepatotoxic. 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.

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

Primary options

itraconazole: children (without HIV) 2.5 to 5 mg/kg orally twice daily, maximum 200 mg/dose; children (with HIV): 2-5 mg/kg orally three times daily for 3 days, followed by 2-5 mg/kg twice daily, maximum 200 mg/dose; adults: 200 mg orally three times daily for 3 days, followed by 200 mg 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

OR

posaconazole: children: consult specialist for guidance on dose; adults: 300 mg orally (delayed-release tablet) twice daily on day 1, followed by 300 mg once daily

Tertiary options

fluconazole: children: 3-6 mg/kg orally once daily, maximum 200 mg/dose; adults: 800 mg orally once daily

Consider – ventilatory support

Back
ACUTE
|
acute pulmonary disease (non-pregnant)
|
severe symptoms
Consider – 

ventilatory support

Additional treatment recommended for SOME patients in selected patient group

Patients may become hypoxaemic and require ventilatory support.

chronic pulmonary disease (non-pregnant)

1st line – azole antifungal

Back
ACUTE
|
chronic pulmonary disease (non-pregnant)
|
mild to moderate
1st line – 

azole antifungal

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.

Treatment is the same for immunocompetent and immunocompromised patients. Chronic pulmonary histoplasmosis has not been described in paediatric populations.

For ambulatory patients with mild to moderate disease (i.e., those who do not require ventilator support), itraconazole has been found to be safe and effective in the treatment of chronic pulmonary histoplasmosis.[1][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. [1][25] Fluconazole can be used in patients intolerant of or refractory to other azoles.[4][25]

Therapeutic drug monitoring is recommended with azole antifungals. Serum levels of itraconazole are generally higher with the solution formulation, and this should be used for treatment whenever possible. Blood levels of itraconazole should be measured once steady state is reached (i.e., 2 weeks after initiation of therapy). Random serum concentrations should be between 1 and 10 micrograms/mL.[1]

Azole antifungals are hepatotoxic. 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.

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

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]

Primary options

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

Secondary options

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

OR

posaconazole: adults: 300 mg orally (delayed-release tablet) twice daily on day 1, followed by 300 mg once daily

Tertiary options

fluconazole: adults: 800 mg orally once daily

1st line – amphotericin-B

Back
ACUTE
|
chronic pulmonary disease (non-pregnant)
|
severe
1st line – 

amphotericin-B

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.

Treatment is the same for immunocompetent and immunocompromised patients. Chronic pulmonary histoplasmosis has not been described in paediatric populations.

For patients with severe disease (i.e., who become hypoxaemic and require ventilatory support (and are therefore hospitalised), intravenous amphotericin-B is recommended for 1 to 2 weeks before transitioning to an oral azole antifungal once stabilised.[33]

Liposomal amphotericin-B is the preferred formulation, although other formulations may be used if liposomal amphotericin-B is unavailable or not tolerated.[4]

Amphotericin-B is associated with nephrotoxicity, hypokalaemia, anaemia, and infusion-related adverse reactions.

Primary options

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

Secondary options

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

OR

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

Plus – azole antifungal

Back
ACUTE
|
chronic pulmonary disease (non-pregnant)
|
severe
Plus – 

azole antifungal

Treatment recommended for ALL patients in selected patient group

Patients should be transitioned toan oral azole antifungal once they have stabilised. Itraconazole is the preferred option.[1][25]​ 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]

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.[1][25]

Fluconazole has a reduced efficacy as chronic maintenance therapy, but can be used in patients intolerant of, or refractory to, other azoles.[1]

Therapeutic drug monitoring is recommended with azole antifungals. Serum levels of itraconazole are generally higher with the solution formulation, and this should be used for treatment whenever possible.

Azole antifungals are hepatotoxic. 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.

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

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

Primary options

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

Secondary options

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

OR

posaconazole: adults: 300 mg orally (delayed-release tablet) twice daily on day 1, followed by 300 mg once daily

Tertiary options

fluconazole: adults: 800 mg orally once daily

Consider – ventilatory support

Back
ACUTE
|
chronic pulmonary disease (non-pregnant)
|
severe
Consider – 

ventilatory support

Additional treatment recommended for SOME patients in selected patient group

Patients may become hypoxaemic and require ventilatory support.

disseminated disease (non-pregnant)

1st line – azole antifungal

Back
ACUTE
|
disseminated disease (non-pregnant)
|
mild to moderate
1st line – 

azole antifungal

Disseminated disease is defined as clinical illness that fails to improve after 3 weeks of observation and is accompanied by signs and symptoms of extrapulmonary involvement. Progressive disseminated histoplasmosis has a high fatality rate without therapy. Treatment is the same for immunocompetent and immunocompromised patients.[1][25]

Azole antifungals are recommended for patients with mild to moderate disseminated disease. Itraconazole for at least 12 months is the preferred treatment.[1][25]​

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.[1][25] 

Fluconazole demonstrates lower activity against the fungus and is less effective than itraconazole, and there have been reports of resistance emerging among patients receiving fluconazole therapy.[4][25]​ Fluconazole is therefore reserved for patients who are intolerant of or refractory to other azoles.

Therapeutic drug monitoring is recommended with azole antifungals. Serum levels of itraconazole are generally higher with the solution formulation, and this should be used for treatment whenever possible.

Azole antifungals are hepatotoxic. 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.

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

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]

Long-term treatment with itraconazole may be required after completion of treatment in immunocompromised patients.[1] In people with HIV, 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.[1][33][51][52]

Primary options

itraconazole: children (without HIV) 2.5 to 5 mg/kg orally twice daily, maximum 200 mg/dose; children (with HIV): 2-5 mg/kg orally three times daily for 3 days, followed by 2-5 mg/kg twice daily, maximum 200 mg/dose; adults: 200 mg orally three times daily for 3 days, followed by 200 mg 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

OR

posaconazole: children: consult specialist for guidance on dose; adults: 300 mg orally (delayed-release tablet) twice daily on day 1, followed by 300 mg once daily

Tertiary options

fluconazole: children: 5-6 mg/kg orally twice daily, maximum 600 mg/day; adults: 800 mg orally once daily

1st line – amphotericin-B

Back
ACUTE
|
disseminated disease (non-pregnant)
|
severe
1st line – 

amphotericin-B

Disseminated disease is defined as clinical illness that fails to improve after 3 weeks of observation and is accompanied by signs and symptoms of extrapulmonary involvement. Progressive disseminated histoplasmosis has a high fatality rate without therapy. Treatment is the same for immunocompetent and immunocompromised patients.[1][25]  Amphotericin-B for 1 to 2 weeks is the recommended initial treatment for patients with severe disseminated disease before transitioning to an oralzole antifungal once stabilised.[1][25]​

Liposomal amphotericin-B is the preferred formulation in adults, although other formulations may be used if liposomal amphotericin-B is unavailable or not tolerated.[1][4][25]​ 

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

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

Amphotericin-B is associated with nephrotoxicity, hypokalaemia, anaemia, and infusion-related adverse reactions.

Primary options

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

Secondary options

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

OR

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

Plus – azole antifungal

Back
ACUTE
|
disseminated disease (non-pregnant)
|
severe
Plus – 

azole antifungal

Treatment recommended for ALL patients in selected patient group

Patients should be transitioned to an oral azole antifungal once they have stabilised. Itraconazole is the preferred option.[1][25]​ 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]

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.[1][25]

Fluconazole demonstrates lower activity against the fungus and is less effective than itraconazole, 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.

Therapeutic drug monitoring is recommended with azole antifungals. Serum levels of itraconazole are generally higher with the solution formulation, and this should be used for treatment whenever possible.

Azole antifungals are hepatotoxic. 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.

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

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

Long-term treatment with itraconazole may be required after completion of treatment in immunocompromised patients.[1] In people with HIV, 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.[25][33][51][52]

Primary options

itraconazole: children (without HIV) 2.5 to 5 mg/kg orally twice daily, maximum 200 mg/dose; children (with HIV): 2-5 mg/kg orally three times daily for 3 days, followed by 2-5 mg/kg twice daily, maximum 200 mg/dose; adults: 200 mg orally three times daily for 3 days, followed by 200 mg twice daily

Secondary options

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

OR

posaconazole: children: consult specialist for guidance on dose; adults: 300 mg orally (delayed-release tablet) twice daily on day 1, followed by 300 mg once daily

Tertiary options

fluconazole: children: 5-6 mg/kg orally twice daily, maximum 600 mg/day; adults: 800 mg orally once daily

Consider – ventilatory support

Back
ACUTE
|
disseminated disease (non-pregnant)
|
severe
Consider – 

ventilatory support

Additional treatment recommended for SOME patients in selected patient group

Patients may become hypoxaemic and require ventilatory support.

mediastinal granuloma (non-pregnant)

1st line – observation

Back
ACUTE
|
mediastinal granuloma (non-pregnant)
|
asymptomatic
1st line – 

observation

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]

1st line – azole antifungal

Back
ACUTE
|
mediastinal granuloma (non-pregnant)
|
symptomatic: without mediastinal compression or fistulation
1st line – 

azole antifungal

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]

Therapeutic drug monitoring is recommended with azole antifungals. Serum levels of itraconazole are generally higher with the solution formulation, and this should be used for treatment whenever possible.

Azole antifungals are hepatotoxic. 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.

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

Primary options

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

1st line – corticosteroid + azole antifungal

Back
ACUTE
|
mediastinal granuloma (non-pregnant)
|
symptomatic: with mediastinal compression or fistulation
1st line – 

corticosteroid + azole antifungal

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.[53]

Therapeutic drug monitoring is recommended with azole antifungals. Serum levels of itraconazole are generally higher with the solution formulation, and this should be used for treatment whenever possible.

Azole antifungals are hepatotoxic. 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.

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

Primary options

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

and

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

Consider – surgery

Back
ACUTE
|
mediastinal granuloma (non-pregnant)
|
symptomatic: with mediastinal compression or fistulation
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 antifungal

Back
ACUTE
|
mediastinal fibrosis (non-pregnant)
1st line – 

observation + consideration of azole antifungal

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.

Consider – intravascular stent

Back
ACUTE
|
mediastinal fibrosis (non-pregnant)
Consider – 

intravascular stent

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
ACUTE
|
broncholithiasis (non-pregnant)
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)

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

Back
ACUTE
|
pericarditis (non-pregnant)
|
mild symptoms
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. NSAIDs are associated with an increased risk of cardiovascular thrombotic events and gastrointestinal toxicity (bleeding, ulceration, perforation). NSAIDs should be used at the lowest effective dose for the shortest effective treatment course. Gastroprotection (e.g., a proton-pump inhibitor) may be required.

Primary options

ibuprofen: adults: 600-800 mg orally every 8 hours or 600 mg every 6 hours initially for at least 24 hours until resolution of symptoms (typically up to 2 weeks), then decrease dose by 200-400 mg/dose every 1-2 weeks according to response, maximum 2400 mg/day

OR

aspirin: adults: 650-1000 mg orally every 8 hours for at least 24 hours until resolution of symptoms (typically up to 2 weeks), then decrease dose by 250-500 mg/dose every 1-2 weeks according to response, maximum 4000 mg/day

1st line – corticosteroid + azole antifungal

Back
ACUTE
|
pericarditis (non-pregnant)
|
moderate to severe symptoms
1st line – 

corticosteroid + azole antifungal

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]

Therapeutic drug monitoring is recommended with azole antifungals. Serum levels of itraconazole are generally higher with the solution formulation, and this should be used for treatment whenever possible.

Azole antifungals are hepatotoxic. 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.

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

Primary options

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

and

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

Consider – pericardiocentesis

Back
ACUTE
|
pericarditis (non-pregnant)
|
moderate to severe symptoms
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
ACUTE
|
rheumatological syndrome (non-pregnant)
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] NSAIDs are associated with an increased risk of cardiovascular thrombotic events and gastrointestinal toxicity (bleeding, ulceration, perforation). NSAIDs should be used at the lowest effective dose for the shortest effective treatment course. Gastroprotection (e.g., a proton-pump inhibitor) may be required.

Primary options

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

OR

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

OR

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

OR

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

2nd line – corticosteroid + azole antifungal

Back
ACUTE
|
rheumatological syndrome (non-pregnant)
2nd line – 

corticosteroid + azole antifungal

Corticosteroids are rarely needed but have been used for symptoms refractory to non-steroidal anti-inflammatory drugs (NSAIDs). If corticosteroids are given, itraconazole should be co-administered to prevent any dissemination of the infection.[58][59]

Therapeutic drug monitoring is recommended with azole antifungals. Serum levels of itraconazole are generally higher with the solution formulation, and this should be used for treatment whenever possible.

Azole antifungals are hepatotoxic. 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.

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

Primary options

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

and

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

meningoencephalitis (non-pregnant)

1st line – amphotericin-B

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ACUTE
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meningoencephalitis (non-pregnant)
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, followed by transition to an oral azole antifungal.[1][25]

Amphotericin-B is associated with nephrotoxicity, hypokalaemia, anaemia, and infusion-related adverse reactions.

Primary options

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

Plus – azole antifungal

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ACUTE
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meningoencephalitis (non-pregnant)
Plus – 

azole antifungal

Treatment recommended for ALL patients in selected patient group

Following completion of amphotericin-B treatment, transition to oral azole antifungal maintenance therapy is required for at least 1 year and until resolution of cerebrospinal fluid abnormalities, including Histoplasma antigen levels.[1][25]

The preferred option is itraconazole.[1][25] Voriconazole or fluconazole may be considered for patients who cannot tolerate itraconazole and are only moderately ill; clinical data is limited.[25]

Therapeutic drug monitoring is recommended with azole antifungals. Serum levels of itraconazole are generally higher with the solution formulation, and this should be used for treatment whenever possible. Blood levels of itraconazole should be obtained to ensure adequate drug exposure.[1]

Azole antifungals are hepatotoxic. 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.

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

Primary options

itraconazole: adults: 200 mg orally three times daily for 3 days, followed by 200 mg two to three times daily

Secondary options

voriconazole: adults: 400 mg orally twice daily on day 1, then 200 mg orally twice daily

Tertiary options

fluconazole: adults: 800 mg orally once daily

pregnant

1st line – amphotericin-B

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ACUTE
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pregnant
1st line – 

amphotericin-B

Azole antifungals are teratogenic in pregnancy; therefore, the preferred treatment for pregnant women is amphotericin-B for 4 to 6 weeks.[1][25] The baby should be monitored for clinical and laboratory evidence of histoplasmosis after birth.[1][62]

Liposomal or lipid formulations are recommended. The deoxycholate formulation is an alternative in patients who are at a low risk for nephrotoxicity.

Amphotericin-B is associated with nephrotoxicity, hypokalaemia, anaemia, and infusion-related adverse reactions.

Primary options

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

Secondary options

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

OR

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

Consider – ventilatory support

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ACUTE
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pregnant
Consider – 

ventilatory support

Additional treatment recommended for SOME patients in selected patient group

Patients may become hypoxaemic and require ventilatory support.

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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