**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 (batinfested 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 influenzalike 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]:


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].
