*3.1.3 Life cycle of* H. capsulatum

The life cycle of the fungus does not necessarily require the yeast-phase transition and infection of a mammalian host. Rather, human infections are believed to be accidental, the resulting systemic mycoses being an unfortunate consequence of the fungus ability to adapt during its evolution as a species when encounter the hostile environment of the human body [61–63].

In the soil, the mold form of *H. capsulatum* may reproduce by either sexual or asexual process. In sexual reproduction, the haploid nuclei of two opposite mating types, if encountered, fuse to form a diploid nucleus, which then divides by meiosis and produces ascospores. The mycelia are also able to asexually reproduce by mitotic division, the process being known as conidiation. As a result of conidiation is the production of vegetative budding spores: macroconidia and microconidia. These conidia can germinate in the soil and further, depending on temperature, can adopt either the mold or the yeast form [64]. When the soil is disrupted, conidia and fragments of hyphal mycelia become aerosolized and are inhaled by a susceptible host. Once entered the lungs of the host, triggered by the warmer body temperature, these infectious propagules germinate within distal bronchioles and pulmonary alveoli and convert to budding yeast. The yeast is phagocytized by immune cells and reaches the regional lymph nodes, from where it can spread to other parts of the body through the bloodstream (**Figure 4**) [48, 62, 64].

#### **Figure 4.**

*Life cycle of H. capsulatum. The environmental form of H. capsulatum is a mold (1) with aerial hyphae, producing saprophytic spores (2) which are aerosolized and inhaled by the susceptible host (3). In the lungs (4), their transformation into the parasitic form of yeast takes place and, consequently, their dissemination through the lymphatic system (5) and then through the blood (6) to other organs. https://www.cdc.gov/fungal/diseases/ histoplasmosis/causes.html*

## **3.2 Host**

The incubation period of the disease is not known with certainty [65], but some authors suggest an interval between 3 to 21 days [46, 66].

The extent and severity of the clinical picture of the disease are determined by the amount of conidia inhaled, the effectiveness of the host's cell-mediated immunity and the virulence of the infective strain of Histoplasma [48, 62, 67].

In most immunocompetent individuals, the infection is mildly symptomatic or even asymptomatic. About 95–99% of the primary infections in endemic areas have never been diagnosed as being histoplasmosis. However, acute severe pneumonia and chronic progressive pulmonary histoplasmosis can also occur in a healthy person if many conidia are inhaled. In individuals with impaired cell-mediated immunity, even a small inoculum or a previously considered avirulent strain can cause lifethreatening to fatal disease [41, 48, 54, 62, 67, 68]. *H. capsulatum* primary infection can remain in a latent, quiescent state, without any symptoms, even for decades, and can reactivate if the host's immunosuppression occurs [48, 49, 68].

Patients at high risk for reactivating latent infection and developing disseminated histoplasmosis are those chronically receiving corticosteroids or chemotherapy, those receiving anti-cytokine therapies (tumor necrosis factor alpha or gamma interferons antagonists), individuals who have received solid organ transplantation, and patients with advanced HIV infection [63, 67]. Additional risk factors for histoplasmosis include smoking [69], COPD [70], extreme ages (infants younger than 2 years old, elderly older than 50 years old) [71], and genetics deficiencies (IFN-γ receptor 1 deficiency or histocompatibility complex haplotypes) [72, 73].

Histoplasmosis is reported among wild animals (rodents, marsupials, sloths, spotted skunks, opossums, baboons) and domestic animals such as cats, dogs, and horses [52, 65].

Some animal reservoirs could be used as sentinels in epidemiological surveillance of the disease in a defined territory, due to potentially wider environmental exposures and limited travel [74].

### **3.3 Environment**

### *3.3.1 Natural habitat*

The existence of *H. capsulatum* has been reported on all continents, including recently in Antarctica [39].

Although, in the past, histoplasmosis was reported in tropical and subtropical areas between latitudes 45°N and 35°S, autochthonous cases have been reported, in recent decades, in both Canada and Patagonia, demonstrating a geographical dispersion at extreme latitudes of *H. capsulatum*. The wide geographic spread of the fungus may be the result of behavioral changes in its natural reservoirs and dispersers as well as climatic changes in its natural habitat [75].

The natural habitat for *H. capsulatum* is soil enriched with bat guano or bird droppings, which favors the growth of its mycelial phase. Once contaminated, the fungus persists for many years in the soil under black bird roosts and chicken farms, even after the birds no longer stay in the area [15, 49]. Numerous other species of birds were strongly associated with *H. capsulatum* habitats: grackles, pigeons, starlings, and oil birds [76].

The fungus prefers the dark areas where temperatures are 22–29°C, near watercourses with humidity above 60%, and with porous, slightly acidic soil, high in nitrogen, and phosphorus elements [45, 68]. These conditions allow this geophilicsaprotrophic fungus to absorb the required nutrients from organic matter in soil and to unimpeded proliferate in the environment [47, 62]. Conidia of *H. capsulatum* were also isolated from air and water specimens [76].

### *3.3.2 Transmission routes*

Typically, the portal of entry of *H. capsulatum* is the lung and the main transmission mode is indirect, through the inhalation of airborne infectious propagules from the environment. However, few cases of histoplasmosis have been attributed to indoor transmission of Histoplasma spores through building air handling systems or cleaning air ducts [77], through inhaling contaminated cocaine [78] and aerosolized conidia produced by composed organic fertilizers [79].

The infection is not contagious, airborne transmission by nasal secretions or direct host-to-host transmission of the fungus have never been established [61, 64, 75, 80]. Although exceptional, the vertical transmission route has been reported in newborns of mothers who manifested the disease in the last trimester of pregnancy, while receiving anti-TNF therapy or in the setting of HIV infection [80].

Also, donor-to-recipient fungal transmission through an infected allograft has been clearly documented [81, 82]. The incidence is rare (1 case per 1000 personyears) most infections occurring within 1–2 years after transplantation [83].

The transcutaneous route of transmission has also been suggested, especially in *H. capsulatum* var. duboisii, but the evidence is sparse, supported in some studies by the appearance of lesions at acupuncture needle pricks after mud baths and tattoos [65, 67, 84], or by sharing needles with an infected patient [85].
