Approach

In immunocompetent patients, influenza-like symptoms are mild, and most acute forms of histoplasmosis resolve without specific treatment. For patients with more persistent symptoms, chronic pulmonary histoplasmosis, or disseminated disease, or for immunocompromised patients (from primary immunodeficiency or secondary to immunosuppressive therapy), systemic antifungal treatment is indicated.

Latent asymptomatic histoplasmosis, non-pregnant

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. These nodules are asymptomatic and are found incidentally during lung imaging. They may be difficult to distinguish from malignancy or infection without biopsy. Antifungal therapy for pulmonary nodules is not recommended.[1]

Acute pulmonary histoplasmosis, non-pregnant

In immunocompetent patients, the symptoms are mild, usually abate within 4 weeks of onset, and tend to resolve without specific treatment. Therefore, immunocompetent patients with mild to moderate symptoms for <4 weeks can be observed without specific treatment.[1]

Data for treatment of pulmonary histoplasmosis in immunocompetent patients with mild to moderate symptoms lasting ≥4 weeks are lacking. Itraconazole for 6 to 12 weeks may be given, particularly in the presence of ongoing symptoms that raise concern for the development of progressive, disseminated histoplasmosis. Other azole antifungals (i.e., voriconazole, posaconazole, fluconazole) can be considered alternatives in patients who are intolerant to itraconazole.[1][4]

Immunocompromised patients are at risk for progressive and life-threatening disseminated disease.[2][49]​ Therefore, immediate antifungal therapy is warranted in immunocompromised patients where infection is suspected or with any manifestation of histoplasmosis infection.

For immunocompromised patients with mild to moderate symptoms (of any duration), itraconazole for 6 to 12 weeks is recommended.[4][25]​ 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]​

Voriconazole and posaconazole have been successfully used to treat immunocompromised individuals with histoplasmosis, and these drugs can be considered as alternative agents to itraconazole.[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, resulting in treatment failure.[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 have a number of potential drug-drug interactions; review the patient's drug history prior to administration.

Azole antifungals are hepatotoxic. Therefore, liver enzymes should be checked before initiation of therapy; at weeks 1, 2, and 4 after treatment is initiated; and every 3 months thereafter 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 drug history prior to administration.

For patients with severe disease, regardless of immune status and duration of symptoms, intravenous amphotericin-B should be used initially, followed by a transition to itraconazole (or an alternative azole antifungal) once the patient has stabilised.[1][25] Ventilatory support with oxygen may be required for those with respiratory distress.

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

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]

Chronic pulmonary histoplasmosis, non-pregnant

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.

Patients with underlying lung disease may develop chronic pulmonary infection following exposure to the fungus. Without treatment the disease is progressive and may result in death. Chronic pulmonary histoplasmosis has not been described in paediatric populations. Treatment is the same for immunocompetent and immunocompromised patients in this group.

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. 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]

Voriconazole and posaconazole have been successfully used to treat immunocompromised individuals with histoplasmosis, and these drugs can be considered as alternative agents to itraconazole.[1][25] Fluconazole can be used in patients intolerant of or refractory to these other azoles.[4]​ [25]

For patients with severe disease (i.e., who become hypoxaemic and require ventilatory support and are therefore hospitalised), amphotericin-B is recommended for 1 to 2 weeks. This can be transitioned to oral therapy with itraconazole (or an alternative azole antifungal) to complete the 12-month therapy when the patient is stable and becomes ambulatory.[33] Due to high rates of relapse, patients should be closely monitored for at least 1 year after treatment is discontinued.

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]

Disseminated histoplasmosis, non-pregnant

This 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 in this group.[1][25]

Patients with mild to moderate disseminated disease should be treated with itraconazole for at least 12 months.[1][25] 

Voriconazole and posaconazole have been successfully used to treat immunocompromised individuals with histoplasmosis, and these drugs can be considered as alternative agents for those individuals unable to 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.

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.

Urine Histoplasma capsulatum antigen levels should be taken monthly to monitor response to therapy and followed for 12 months to detect disease relapse. Up to 10% to 15% of patients experience relapse despite treatment, which is an indication for long-term maintenance therapy with itraconazole.[24]

For patients with severe disseminated disease, the recommended initial treatment is amphotericin-B.[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.[25][33][50]​ Amphotericin-B induction therapy should be followed by treatment with itraconazole (or an alternative azole antifungal) for at least 12 months.[1][25][33]

Therapeutic drug monitoring is recommended with azole antifungals.[1][25]​ In patients with disseminated disease, random itraconazole levels should be measured after 2 weeks and should be 1-2 micrograms/mL.[25]​ Target trough levels are 1-5 micrograms/mL for voriconazole and >1 microgram/mL for posaconazole after 5 days of therapy.[25]​ Of note, these levels are based upon extrapolations from studies of other fungal diseases and histoplasmosis specific data is generally limited.

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 H capsulatum serum and urine antigen levels are <2 nanograms/mL.[25][33][51][52]

Mediastinal granuloma, non-pregnant

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. Symptomatic patients can be treated with itraconazole.[1] 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]

Mediastinal fibrosis, non-pregnant

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 anti-fibrotics is unknown. Intravascular stents can be used to ameliorate symptoms of superior vena cava compression.[1][55]

Broncholithiasis, non-pregnant

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] Computed tomography scans are useful for making this diagnosis. Bronchoscopic and sometimes surgical removal of stones is the treatment of choice.[56] Antifungal therapy is not indicated.[1][55]

Pericarditis, non-pregnant

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 non-steroidal anti-inflammatory drugs (NSAIDs) is sufficient for mild symptoms. Patients with moderate to severe symptoms require treatment with a corticosteroid; in this circumstance, itraconazole should be co-administered for 6 to 12 weeks to prevent any dissemination of the infection which may result from the immunosuppression.[1] Pericardiocentesis may be needed in patients with haemodynamic compromise.[1]

Rheumatological syndrome, non-pregnant

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] 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]

Meningoencephalitis, non-pregnant

Up to 20% of patients with disseminated histoplasmosis have 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 treatment with itraconazole (or a suitable alternative azole antifungal) for at least 1 year and until resolution of cerebrospinal fluid abnormalities, including Histoplasma antigen levels.[1][25]​ Blood levels of itraconazole should be obtained to ensure adequate drug exposure.[1]

Pregnant women

Due to the risk of transplacental transmission of infection to the developing fetus, H capsulatum infections during pregnancy should be treated with antifungal agents.[1][61] 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]

Children

Manifestations of acute pulmonary histoplasmosis in children are similar to those in adults; however, chronic pulmonary histoplasmosis has not been described in paediatric populations. The same therapies are used in children and adults. However, amphotericin-B deoxycholate is well tolerated in children and lipid formulations are not necessarily preferred.[1]

The management of mediastinal granuloma, mediastinal fibrosis, broncholithiasis, pericarditis, rheumatological syndrome, and meningoencephalitis in children is beyond the scope of this topic. These manifestations are rarely seen in children. Progressive disseminated histoplasmosis is the most common reason for treatment in children.[1]

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