Histoplasmosis: An Overview Treatment of Histoplasmosis

Abstract

In 2000, the Infectious Diseases Society of America (IDSA) published a clinical practice guideline on managing patients with histoplasmosis and, in 2020, the first global guideline for diagnosing and managing disseminated histoplasmosis in people living with HIV (PLHIV). The classification of pulmonary histoplasmosis is done after clinical presentation and imaging. The optimal treatment depends on the patient’s clinical syndrome: acute mild/moderate, acute moderately/severe, chronic cavitary pulmonary, mediastinal lesions, or broncholithiasis. Asymptomatic patients or patients with mild cases of histoplasmosis with symptoms lasting less than four weeks do not usually require antifungal treatment. When necessary, itraconazole is the treatment of choice in mild to moderate acute forms of the disease, often for six weeks. For severe histoplasmosis, amphotericin B is recommended as initial therapy, followed by itraconazole as consolidation therapy. Long-term treatment for at least 12 months is recommended in patients with chronic cavitary histoplasmosis.

1. Introduction

Pulmonary histoplasmosis is a lung disease caused by infection with the fungus Histoplasma capsulatum (HC), first described by Dr. Samuel Darling in 1906 [1, 2].

The causative species is comprised of three taxonomic varieties, but only two distinct varieties are known to be pathogens for humans: H. capsulatum var. capsulatum (HC) and H. capsulatum var. duboisii with different geographic distributions, clinical manifestations, and morphologies [3, 4]. The management of the patients varies according to the severity disease and the status of the host’s immunity. H Capsulatum is a thermally dimorphic fungus, present as a mold in its natural reservoir, found in soil, caves, and abandoned constructions contaminated with bird droppings. After inhalation of microconidia or mycelial fragments, it converts to a budding yeast form in tissues during the invasive disease [1, 5]. Given this mode of transmission, respiratory infection is the most common manifestation. Yeast multiplies within airspaces and then spreads to adjacent alveoli and subsequently to hilar and mediastinal lymph nodes. In the setting of immunocompetent status, the activated macrophages kill phagocytosed yeast, and even disseminated forms are usually self-limitated [6]. In immunosuppressed patients, the disease severity increase could be fatal and need different treatment’ strategies [6, 7].

Although histoplasmosis is well-known in endemic regions and found worldwide in temperate zones of the world, it remains rare in Western Europe [1, 5]. Air currents carry the spores for miles, exposing individuals unaware of contact with the contaminated site, making histoplasmosis a diagnostic challenge for doctors worldwide [7]. Infection usually occurs by inhalation of environmental spores and can occur in both immunocompetent and immunocompromised hosts. Recently, histoplasmosis has raised increasing attention in immunocompetent travelers (the most common endemic mycosis acquired by European travelers) [8]. In this situation, the epidemiological context (visiting endemic county) and type of exposure (bat-infested caves, cleaning of chicken coops, demolition of old buildings, and excavation) could increase the diagnosis suspicion. Therefore, in the presence of clinical and paraclinical pictures, susceptible of pulmonary mycosis histoplasmosis has to be taken into account even in patients that do not have immune disorders and even in non-endemic regions as treatment in some forms is essential. It is important to emphasize that H. capsulatum infection is not transmissible through person-to-person contact [9]. Severity of illness after exposure varies, depending on the exposure intensity, the virulence of the stains and the host immune status. The spectrum of disease ranges from asymptomatic patients to severe, life-threatening disseminated disease, especially in immunocompromised individuals [7, 8]. The population at risk of developing clinically significant histoplasmosis has grown substantially with patients treated with an ever-expanding variety of immunosuppressive medications and/or with immunosuppressive medical conditions [6, 10]. In the general population, primary H. capsulatum infection is asymptomatic in 99% of cases, and only a small proportion of exposed individuals (<0.1%) may develop disseminated disease. Even when it manifests in immunocompetent individuals, the disease is mild, mostly subclinical, often undiagnosed with varying degrees of pneumonia and influenza-like symptoms [11]. On the contrary, in immunocompromised patients with disabled cellular immunity (particularly conditions with compromised cellular immunity affecting T cells), infection cannot be cleared, and the organism continues to reproduce intracellularly and disseminates via lymphatic and hematogenous circulation, cumulating in a state called disseminated histoplasmosis [2]. Dissemination may involve various organs, including the oropharynx, lung, lymph nodes, liver, spleen, skin, brain, and adrenal glands. Considering these different kinds of histoplamosis manifestation with varied symptoms, severity, the management and duration of treatment require a personalized approach [10, 11]. Disseminated progressive disease is more frequent in persons with cell-mediated immunological defects like hematological malignancies, HIV, transplant recipients, hepatitis C, HTLV-1, renal failure, prolonged use of corticosteroids, or biological therapies [2, 12]. In these patients, the disease can occur due to primary infection, reinfection, or dissemination of latent foci persisting after remote infection. If reactivation occurs, a large population of immunosuppressed persons would be at risk (approximately 20% of the U.S. population has had prior subclinical histoplasmosis). Reactivation of latent infections may complicate recipients of solid organ transplants and patients receiving immunosuppressive therapy for other reasons [6, 12]. Exposure to H. capsulatum does not confer immunity to reinfection [12]. Up to 40% of patients presenting with disseminated histoplasmosis do not have any obvious risk factors [2].

Histoplasmosis could be divided into several clinical forms [11]:

1. histoplasmosis in the normal host, subdivided into asymptomatic primary infection and acute pulmonary infection;

2. chronic pulmonary histoplasmosis (acute disease, after progression from pulmonary infiltrates to fibrosis and finally cavitation);

3. histoplasmosis in the immunocompromised individuals, corresponding to acute or subacute disseminated histoplasmosis;

4. immunologically mediated disease (latent form).

These distinct clinical syndromes vary by clinical course and wide range of presentation, degrees of severity, extent of disease, delay of diagnosis, and radiographic findings. Therefore, treatment depends on the severity of the clinical syndrome as well as the host immune status [11, 13].

2. Treatment options

Multiple organizations have published treatment guidelines for histoplasmosis: the National Institutes of Health (NIH), the Infectious Diseases Society of America (IDSA), and the Centers for Disease Control and Prevention (CDC) in collaboration with the HIV Medical Association (HIVMA) and the IDSA; the American Thoracic Society; and the World Health Organization (WHO)/Pan American Health Organization (PAHO). Recommendations from these four sets of guidelines are similar and are updated when new data or publications might change a prior recommendation or when the panel feels clarification or additional guidance is warranted [6, 7, 10].

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.

	Immunocompetent	Imunosupresions (HIV/imunossupresive terapy)
Acute mild; asymptomatic	Antifungal treatment is generally not required
Symptoms lasting >1 month; Mild to moderate acute histoplasmosis	initial therapy; Itraconazole, (200 mg x 3 orally for the first three days); maintenance regimen; (200 mg orally once or twice daily) for 6 to 12 weeks	Itraconazole 200 mg twice daily after a loading dose of 200 mg three times daily for three days is used to treat mild to moderate histoplasmosis.
Moderately severe to severe progressive disseminated H	initial 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); Maintenance therapy; 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 (at least six months)	Induction therapy: Liposomal amphotericin B, 3.0 mg/kg for two weeks.; Maintenance therapy: Itraconazole 200 mg twice daily for 12 months (treatment less than 12 months is envisageable when the person is clinically stable, receiving antiretroviral treatment, has suppressed viral load, and the immune status has improved); Alternative azole options include; posaconazole 300 mg x2 for 1 day, then 300 mg daily; voriconazole 400 mg x2 for 1 day, then 200 mg bid; or the least desirable option, fluconazole 800 mg daily For long-term suppressive therapy,; itraconazole. IDSA advises a dose of 200 mg daily, whereas the CDC/NIH recommends 200 mg x2.; Alternative options in rank order include posaconazole 300 mg extended-release capsule daily; voriconazole 200 mg x2; or fluconazole 400 mg daily
Acute respiratory distress syndrome	Methylprednisolone (0.5 to 1.0 mg/kg/day intravenously) for one to two weeks	IRIS while receiving effective antiretroviral therapy at the time of diagnosis should continue it and begin treatment for histoplasmosis with amphotericin B or itraconazole Intravenous fluids and oxygen therapy Various anti-inflammatory agents
Chronic Histoplasmosis; nodules; cavity	Initial therapy; Oral itraconazole 200 mg orally x 3 for the first three days); The maintenance dose (200 mg orally once or twice daily) for at least one year until 24 months	Initial treatment; Oral itraconazole 200 mg orally x 3 for the first three days); The maintenance dose; (200 mg orally once or twice daily) for at least one year until 24 months

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, 18, 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 AIDS-defining 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.

2.2.1 Histoplasmosis treatment in HIV patients

Histoplasmosis is an AIDS-defining illness presenting as an invasive form [20]. The most frequent disease in these patients is progressive disseminated histoplasmosis (PDH), where the fungus spreads to other body parts, resulting in high mortality if not treated early [19, 20].

Patients with HIV may require life-long therapy depending on CD4 counts and the status of anti-retroviral treatment [7, 10]. The immunosuppression state is a factor that predisposes the infection due to the CD4+ T-lymphocyte-mediated immunity being compromised [19].

In the first few years of the AIDS pandemic, histoplasmosis carried a high risk for mortality because of the lack of efficacy of ketoconazole. Amphotericin B was effective initially, but in 60% cases experienced relapsed after stopped of treatment. Two treatment phases are recommended: initial induction and long-term maintenance therapy [6].

The IDSA recommended treatment is: a one-to-two-week induction therapy, with liposomal amphotericin B, 3 mg/kg/day for severe disease or itraconazole, a 3-day loading dose of 3x200mg, and then long-term maintenance itraconazole therapy, 200 mg daily, for a minimum period of 12 months [7].

The CDC/NIH and WHO/PAHO guidelines recommend induction for two weeks rather than the 1-to-2-week period advised by the IDSA [7, 20].

In the 2021 Guideline Development Group for Diagnosing And Managing Disseminated Histoplasmosis Among People Living With HIV, three recommendations address the induction and maintenance therapy for histoplasmosis among PLHIV. “The preferred treatment for severe or moderately severe disease is liposomal amphotericin B, 3.0 mg/kg for two weeks” (GRADE classified this recommendation as conditional with very-low-certainty evidence).

“For mild and moderate histoplasmosis, the preferred treatments are itraconazole 200 mg twice a day after an initial dose of 200 mg three times per day for three consecutively days” (GRADE classified this recommendation as conditional with very-low-certainty evidence). For maintenance therapy, the recommended doses are itraconazole 200 mg twice daily for 12 months (GRADE classified this recommendation as conditional with very-low-certainty evidence). Shorter treatment duration can be considered in clinically stable patients that receive antiretroviral treatment that suppressed the viral load with improvement in immune status. (GRADE classified this recommendation as conditional with very-low-certainty evidence) [20].

Global guidelines for the diagnosis and management of endemic mycoses recommended L-AmB as the drug of choice for induction therapy for patients with advanced HIV and moderate-to-severe histoplasmosis, or patients who are sufficiently ill to require hospitalization. However, when L-AmB is not available, other AmB formulations are acceptable alternatives [20].

Liposomal or deoxycholate amphotericin B was more effective in AIDS patients with histoplasmosis (excluding those with CNS involvement) than amphotericin B lipid complex, with one-year survival of 81% and 56%, respectively [22, 23].

Alternative azole options recommended by the NIH/CDC include posaconazole 300 mg x2 for one day, then 300 mg daily; voriconazole 400 mg x2 for one day, then 200 mg bid; or the least desirable option, fluconazole 800 mg daily [6].

Global guideline for the diagnosis and management of endemic mycoses, in individuals with less severe disease, voriconazole is not routinely recommended, and fluconazole has a lower success rate than itraconazole and highlighted the fluconazole resistance in patients receiving fluconazole therapy [21, 23].

Isavuconazole is a newer antifungal triazole used for the treatment of both invasive aspergillosis and mucormycosis with in vitro demonstrated activity against H. capsulatum. It could be the best alternative to posaconazole because of its excellent sensitivity, including isolates resistant to fluconazole or voriconazole [24].

A recent Cochrane analysis concluded that the optimum maintenance regimen for histoplasmosis had not been determined (no published study has compared <12 months to >12 months of maintenance treatment) but 95% were relapse-free after 1 year for patients treated with itraconazole, 200 or 400 mg daily [25]. Because of potential toxicity and the need for intravascular access, weekly or biweekly amphotericin B deoxycholate has rarely been used [20, 25, 26].

A complex presentation of disseminated histoplasmosis infection involves the central nervous system (CNS). CNS manifestations can include meningitis involving the basilar meninges, acute meningitis, encephalitis, small ring-enhancing lesions, abscess, and stroke due to infected emboli [27]. Meningitis poses additional challenges in treatment. Liposomal amphotericin B for 4–6 weeks, followed by itraconazole for at least one year, is recommended [27, 28]. IDSA guidelines recommend prophylaxis with itraconazole for as long as the CD4 count remains low (> 150/mm³⁾ in areas where the incidence of histoplasmosis is of >10 cases per 100 person-years. When efavirenz and itraconazole are administered together, itraconazole levels fall by 40%, so higher doses are required [7], and thus, their administration should be closely monitorized.

HIV-associated immune reconstitution inflammatory syndrome (IRIS) is an essential early complication of antiretroviral therapy initiation, associated with considerable morbidity and mortality, particularly in patients who start antiretroviral treatment with advanced immunosuppression [29, 30].

Numerous infective and noninfective conditions are associated with IRIS in HIV infection, including histoplasmosis. Some authors described a higher incidence of disseminated histoplasmosis among patients that recently started antiretroviral therapy, suggesting that this treatment can lead to unmasking IRIS [29]. Patients who manifest findings of IRIS while receiving effective antiretroviral therapy at the time of diagnosis should continue it and begin treatment for histoplasmosis with amphotericin B or itraconazole [29].

Supportive management may be required, including intravenous fluids and oxygen therapy. Various anti-inflammatory agents have been used to treat paradoxical and unmasking IRIS, including corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs). The role of corticosteroids remains unclear but could be appropriate in patients with more severe manifestations [29, 30].

In 2019, the WHO included Histoplasma antigen tests as an essential diagnostic in endemic areas or non-endemic areas as a reference test for imported cases of histoplasmosis, and by 2025, every country should have access to rapid testing for histoplasmosis. Additionally, itraconazole and both formulations of amphotericin B should be available in the public sector [23, 26].

In the first year, levels of antigenuria and antigenemia should be monitored for early diagnosis of failure or relapse. After successful immune reconstitution and an increase in CD4 count (to more than 150/μL), secondary prevention can be stopped if the patient has received a minimum six-month course of antiretroviral treatment and at least 12 months of antifungal therapy, antigen, and blood culture-negative [7, 11, 29]. However, literature data recommend continuing prophylaxis until the clinical and laboratory results normalize [29]. Monitoring drug interaction in patients with HIV under antiretroviral treatment and histoplamosis is necessary, as these interactions are sometimes diminish efficacy and safety in patients taking these drugs, and they are at risk of toxicity or ineffectiveness from drug interactions. This observation might be useful for patients with advanced disease where possible resistant viruses with limited antiretroviral options [31].

2.2.2 Histoplasmosis secondary to immunosuppressive treatment

Histoplasmosis secondary to TNF-α inhibitor therapy requires discontinuation of the tumor necrosis factor-α blocker during antifungal treatment [22, 32, 33].

Pharmacological immunosuppression with TNF-α inhibitor might be reinstituted after an excellent clinical response after 12 months of anti-histoplasmosis therapy and a negative antigen test [23]. Oral itraconazole, as an antifungal for H. capsulatum, could inhibit the CYP3A4 pathway and could decrease steroid metabolites [32]. A growing number of biologics targeting cytokines are available, including inhibitors of the pro-inflammatory mediators such as tumor necrosis factor-alpha (anti-TNF α), interleukin (IL)-1b (canakinumab), IL-1R (anakinra), IL-6R (tocilizumab), as well as T-cell co-stimulation (abatacept) and B-cells (rituximab) but with an increased risk for development of opportunistic infections [34]. TNF is essential for the formation of granuloma and the prevention of granulomatous infections such as tuberculosis and histoplasmosis [32, 33].

For long-term suppressive therapy, each of the four guidelines recommends itraconazole. A dose of 200 mg daily is advised by IDSA, whereas the CDC/NIH recommends 200 mg x2. Alternative options in rank order include posaconazole 300 mg extended-release capsule daily; voriconazole 200 mg x2; or fluconazole 400 mg daily [7].

2.2.3 Histoplasmosis in solid organ transplant recipients

In the field of solid organ transplantation (SOT), T-cell immune dysfunction can also be significant, and the infection can be difficult to predict but remains a rare infection in post-transplant settings, even in endemic areas [34].

Solid organ transplant (SOT) recipients and other immunocompromised hosts have a propensity for severe infection, inclusive of extrapulmonary and disseminated disease. The infections in SOT recipients are best categorized as mild, moderate, or severe [35].

Clinical disseminated histoplasmosis in solid organ transplant (SOT) recipients is nonspecific and rare, with the highest risk period in the first year after transplant, although cases have been reported up to 20 years after transplantation [36]. One-third occurred in the first year, and almost half in the first two years after the transplant [34].

Given the low incidence of histoplasmosis in healthy donors and the rarity of reported donor transmission events, routine donor screening is not indicated, nor the pre-transplant screening for histoplasmosis in transplant candidates, nor even in endemic areas [36]. Donor-derived histoplasmosis is rare, but this confirmed transmission has been reported [34]. Even without clear evidence of dissemination, SOT recipients with histoplasmosis should generally be treated as disseminated disease [5].

The American Society of Transplantation (AST) guidelines recommend at least 1 to 2 weeks of amphotericin B and step down to oral itraconazole. ITZ monotherapy could be used in mild to moderate disease, and longer courses of AmB therapy are recommended for patients with central nervous system (CNS) disease (i.e., 4 to 6 weeks). Irrespective of initial disease severity, antifungal therapy should be continued for a minimum of 12 months or more in patients necessitating continued high-level immunosuppression after a relapsed disease or in CNS involvement. Fluconazole (FCZ) or newer-generation azoles, including voriconazole (VCZ), isavuconazole (ISZ), and posaconazole (PCZ), has been used as an alternative in patients with ITZ intolerance [35]. Once the diagnosis of histoplasmosis is made, immunosuppressive medication should be reduced, although the optimal timing and strategy in this regard are unknown [36]. In patients taking concomitant itraconazole and tacrolimus, concentrations should be assessed to ensure that concentrations are within the narrow therapeutic window or to avoid increased tacrolimus serum levels with potential side effects because of excessive immunosuppression and toxicity (nephrotoxicity and neurotoxicity). Additional pharmacokinetic (PK) and drug–drug interaction considerations must be assessed in kidney transplant patients. Treatment of histoplasmosis with L-AmB comes with nephrotoxicity concerns and possible allograft loss. In the presence of subsequent acute kidney injury, treatment with liposomal amphotericin B (L-AmB) should be associated with concomitant administration of renin-angiotensin system blockers, catecholamines, or immunosuppressants, L-AmB doses ≥3.5 mg/kg/day, and serum potassium <3.5 mEq/L immediately before L-AmB administration [37].

2.3 Treatment in particular forms of histoplasmosis

2.3.1 Mediastinal granuloma, mediastinal lymphadenitis, and fibrosing mediastinitis

A relatively rare complication of pulmonary histoplasmosis is mediastinal granuloma, characterized by enlarging mediastinal lymph nodes. No treatment is recommended for patients with asymptomatic mediastinal granuloma because the active infection is no longer present [7, 11].

Most often, the granuloma is symptomatic secondary to compression of adjacent structures (the esophagus, pulmonary vessels, and trachea), and in these situations, itraconazole for 6–12 weeks is prescribed frequently. Surgical resection of obstructive masses should be considered in the setting of obstruction or in whom a fistula to adjacent structures with drainage of necrotic material has occurred [38, 39].

Fibrosing mediastinitis is a rare disorder characterized by an excessive fibrotic reaction in the mediastinum, which results from an exaggerated host response to a prior infection located at mediastinal lymph nodes [39].

The symptoms are due to the vascular, esophageal, and central airway compression, and fibrosing mediastinitis represents the most severe complication of pulmonary histoplasmosis [38].

2.4 Other manifestations of pulmonary histoplasmosis

1. Broncholithiasis occurs when a calcified node adjacent to a bronchus erodes into the bronchus, causing obstruction, inflammation, and subsequent bronchial scarring; antifungal treatment is not necessary unless the presence of massive hemoptysis or fistula formation when bronchoscopy is required [38].

2. A small proportion of patients with acute pulmonary histoplasmosis develop pericarditis as a complication of the infection that responds to treatment with nonsteroidal anti-inflammatory agents [17, 18].

3. Pleural disease is uncommon during pulmonary histoplasmosis except for the exudative, culture-negative pleural effusions associated with

4. Infection of the central nervous system with histoplasmosis was first recognized in an infant in 1934. Central nervous system histoplasmosis occurs in 5 to 10% of individuals with disseminated diseases, not restricted to immunocompromised individuals, with a high rate of relapse (50%), and increased morbidity and mortality (20–40%) [40, 41].

With the development of effective antifungal therapy, histoplasmosis of SNC has been transformed from a universally fatal illness to a manageable condition if diagnosed early. Aggressive and prolonged antifungal therapy is indicated in all cases of CNS histoplasmosis. However, there is no definitive treatment for CNS histoplasmosis [42].

The Infectious Disease Society of America (IDSA) guideline for the treatment of CNS histoplasmosis recommends an initial course of liposomal amphotericin B because it is known to penetrate CNS structure well (5 mg/kg daily for a total of 175 mg/kg over 4–6 weeks) followed by itraconazole (200 mg 2–3 times daily) for at least one year and until resolution of CSF abnormalities, including negative histoplasma antigen [4, 41, 43].

Because of the risk of relapse, it is recommended to re-evaluate CSF parameters before discontinuation of itraconazole at 12 months and should be followed for at least three years for recurrence.

1. Pregnant patients with histoplasmosis should consider efficacy and safety data carefully. Treatment with amphotericin B for a total of 4–6 weeks, since azoles are teratogenic, particularly in the first trimester, is indicated in moderately severe or severe acute pulmonary disease, chronic pulmonary disease, or disseminated disease and any involving the central nervous system [44, 45].

3. Conclusions

Histoplasmosis is an underdiagnosed infection that affects both immunocompromised and healthy individuals, and early diagnosis requires a high clinical suspicion by clinicians. Management decisions in these patients must balance the severity and localization of the disease, the degree of immunosuppression, the necessity of immunosuppression, the interaction of antifungal drugs, the side effect, the tolerance, and the adherence to treatment. Systematically statements and guidelines assist practitioners and patients in making decisions about appropriate health care for specific clinical circumstances.

Conflict of interest

The authors declare no conflict of interest.