**2.1 Histoplasmosis treatment in immunocompetent host**

In immunocompetent individuals, the disease is usually mild, asymptomatic, or experiences a self-limiting condition with nonspecific symptoms (fever, malaise, chills, weight loss, night sweats, respiratory, rheumatologic, or gastrointestinal symptoms) and may require only symptomatic measures [7, 9, 11]. For most individuals, signs typically resolve without intervention, and only 5% of *Histoplasma* infections are estimated to require clinical management [11, 14].

Disseminated disease although more frequent among immunocompromised patients can be seen occasionally even in immunocompetent patients, when they have traveled in endemic county and have been infected with a large quantity of *H capsulatum*, or have been exposed to a highly virulent strain.

Antifungal treatment is indicated for certain forms of histoplasmosis, including acute moderate to severe histoplasmosis, chronic disease, and extrapulmonary histoplasmosis. The Infectious Diseases Society of America (IDSA) guidelines state that antifungals could be considered for patients with symptoms lasting >1 month [7]. In **Table 1**, we summarized histoplasmosis treatment considering the immune status and disease severity in acute and chronic forms of histoplasmosis.


#### **Table 1.**

*Treatment in histoplasmosis considering the immune status and disease severity in acute and chronic histoplasmosis [7, 11, 12, 15].*

In vitro activities of current antifungal drugs (the polyene, azole, and echinocandin classes) used clinically have been established for dimorphic fungi [11]. Antifungal treatment is generally not required in mild to moderate diseases if they do not have symptoms for more than four weeks. The initial therapy should be itraconazole, given as a loading dose (200 mg orally three times daily for the first three days) followed by a maintenance dose (200 mg orally once or twice daily) for 6 to 12 weeks [10].

For moderate form to severe progressive disseminated histoplasmosis cases, the IDSA guidelines recommend initial amphotericin B treatment (liposomal amphotericin B dosed 3 mg/kg/day intravenously or amphotericin B lipid complex dosed 5 mg/kg/day intravenously or amphotericin B deoxycholate dosed 0.7 to 1 mg/kg/ day intravenously) followed by itraconazole (200 mg orally three times daily for the first three days, then 200 mg orally twice daily) for a minimum of 12 weeks up to an additional three months [2, 7, 11].

Antifungal treatment in non-immunosuppressed patients is suggested for at least six months, although the severity and site of the disease need to be considered before determining the duration of therapy [11].

In patients with severe dyspnea, hypoxemia, and/or development of acute respiratory distress syndrome, the addition of methylprednisolone (0.5 to 1.0 mg/kg/d intravenously) for one to two weeks has been used in some patients with clinical benefit [16, 17].

All patients with chronic pulmonary histoplasmosis should be treated due to most patients` progressive loss of pulmonary function. Oral itraconazole is given as a loading dose (200 mg orally three times daily for the first three days) followed by a maintenance dose (200 mg orally once or twice daily) for at least one year until 24 months because of the substantial risk of relapse (after treatment stopped up to 10 to 20% of patients with chronic pulmonary histoplasmosis could relapse within two years of stopping therapy) [7, 18]. Chronic cavitary pulmonary histoplasmosis developed after the acute form is marked by low-grade chronic symptoms, development of persistent cavitation, pulmonary fibrosis and pulmonary insufficiency [19].

In chronic pulmonary histoplasmosis, the cavities should be monitored with chest radiography, and if they persist over a 2- to 4-month period, antimicrobial treatment is recommended, especially if there are also symptoms [19].

Chest radiography should be performed every six months for the first year and then annually for four years to monitor for relapse. Without therapy, pulmonary function progressively declines to respiratory insufficiency, the disease will progress, and the patients will die [7, 11, 17–19].

More recent series have emphasized that pulmonary nodules are a more common manifestation of chronic histoplasma infection that can persist a long time and should be differentiated from symptomatic patients who have multiple diffuse nodules and require acute pulmonary histoplasmosis treatment [7, 11].

## **2.2 Histoplasmosis treatment in immunocompromised patients**

An immunocompromised state (due to HIV or other sources of immunosuppression) increases the risk of systemic infection with histoplasmosis. In addition, the immune system dysregulation in autoimmunity and immunosuppressive medications increases serious infection risk as histoplasmosis [17, 20].

After invading the lungs, the infection progressively spreads to other organs. Immunocompromised patients are 10 to 15 times more likely to develop a disseminated form of the disease [7, 20, 21]. The disseminated disease is often fatal if it is not promptly recognized, particularly in patients with HIV infection (histoplasmosis is an AIDSdefining condition), stem cell or solid organ transplantation receivers, and requires a high index of suspicion for timely diagnosis and treatment. In HIV-infected patients, symptomatic illness has been observed in 55% of cases of primary histoplasmosis, and progressive disseminated histoplasmosis occurred in 97–100% of cases of symptomatic histoplasmosis before the availability of highly active antiretroviral therapy [6].

Severely immunocompromised patients often present acutely with fever, pancytopenia, severe respiratory distress, circulatory shock, coagulopathy, and multiorgan failure involving the liver and kidneys. In these patients, histoplasmosis is a life-threatening condition that may require a multi-disciplinary approach to care [20]. Patients with mild immune deficiencies produced by several factors (older age, advanced age, alcoholism, diabetes *mellitus*, solid tumors, corticotherapy, or lymphomas) are more prone to develop chronic histoplasmosis [19].

Histoplasmosis in the immunocompromised host has some particularities. One of the more severe forms of the disease, disseminated histoplasmosis, is a progressive extrapulmonary infection often seen in immunocompromised patients (e.g., AIDS, those on immunosuppressive medications, etc.) or at extremes of age.
