**2. Epidemiology**

Histoplasmosis has been reported worldwide in tropical and subtropical, but most frequently, in temperate areas where this dimorphic fungus has found the perfect condition to thrive as mold (saprophytic form): nitrogen-rich soil at temperatures of 37°C or greater with moisture (95–100% humidity), containing bird droppings (composed of nutrients that promote growth and also substances that discourage the growth of competitive organisms), or bat guano.

However, what has significantly changed the global epidemiology of histoplasmosis was precisely the HIV pandemic, especially because of patients in the AIDS stage. In fact, HIV-infected patients often serve as sentinel markers for histoplasmosis outbreaks [6, 7].

Starting with 1983, several case reports have been published about HIV-infected patients who have been diagnosed with progressive disseminated histoplasmosis (PDH) [7]. Some of them came from endemic areas but a lot of cases have been discovered in places considered as non-endemic areas, which was not expected. In United States, reports have come from hyper-endemic areas such as Indiana [8, 9] as well as from areas where histoplasmosis has never been reported [10, 11] such as Denver or California.

Outside the United States, histoplasmosis incidence is driven by the AIDS pandemic [12]. In French Guyana, PDH is considered to be the most common AIDSdefining illness [12, 13], detected in 41% of HIV hospitalized patients with fever and CD4 less than 200 cell/mm3 . In the hyper-endemic area of Rio Grande do Sul, Brazil, 47% of patients diagnosed with histoplasmosis are HIV positive and have PDH [12, 14]. Between 1992 and 2008 in Columbia, 70.7% of the patient diagnosed with histoplasmosis had AIDS [12, 15, 16]. Two different studies estimated the incidence of histoplasmosis in Latin America to 1.48 cases per 100 PLWA, which amounts to over 22,000 cases per year [17, 18] (the first) and 0.15 per 100,000 person-years [18, 19] (the second), both estimation for 2012 and 2011. In the first study, countries with the highest histoplasmosis incidence in people living with HIV (≥1.5 cases per 100 people living with HIV) follow the same geographical distribution as histoplasmosis prevalence hotspots in the general population: Central America, Argentina, and the northernmost part of South America (Venezuela and the Guiana Shield) [17].

In parts of Asia [20], Southeast Asia [21], and India [22] where histoplasmosis is endemic, the most described and reported cases are in people living with HIV/AIDS. In China, 75% of cases are reported along the Yangtze River, most of them in association with AIDS [23].

In Africa, where HIV continues to be a major global public health issue [24], the estimated rate of histoplasmosis is not established due to the lack of solid epidemiologic studies and the limited possibility of detection in the laboratory. Cases of HIV patients have been reported in South Africa (Transvaal and Cape Province) [25], Zimbabwe [25], Uganda [26], Nigeria [27], and Tanzania [28]. Both strains of Histoplasma capsulatum are isolated in Africa. African histoplasmosis caused by H. capsulatum var. duboisii is prevalent in Western and Central Africa (Mali, Chad, Niger, Nigeria, Democratic Republic of Congo, and Ghana), and in the island of Madagascar [25]. Meanwhile, in South Africa and Zimbabwe, only the classical histoplasmosis caused by Histoplasma capsulatum var. capsulatum is known to occur [25] as is the case in the United States, Latin America, Asia, and Australia. Cases confirmed in HIV travelers who are returning home from these areas are diagnosed in Italy, Spain, the UK, the Netherlands, etc., as imported infections [29].

In Australia, where H. capsulatum has been found in Queensland and New South Wales from different samples (caves and fowl yards), only 63 cases have been

### *HIV-Associated Histoplasmosis DOI: http://dx.doi.org/10.5772/intechopen.111389*

diagnosed, but 41% of disseminated disease occurred in patients with human immunodeficiency virus [30].

In Europe, a non-endemic area, only a few cases of histoplasmosis in HIV-infected patients have been reported. Most of them are imported (mainly from Central and South America), but there were also rare autochthonous cases (Italy and Israel). The time span between leaving the endemic area and the diagnostic could reach up to four decades. Due to the scarce knowledge of this disease, the prognosis is poor with a high mortality rate (32%) [29] as the delay of diagnostic is detrimental in the course of disseminated histoplasmosis.

Due to the PDH form recognized by clinicians, reports about this disease came from across the world in places where histoplasmosis had been rarely or never present: Thailand, where this disease is observed almost exclusively among HIV-infected patients as this country is facing a high HIV prevalence (1253 cases reported from 1984 to 2010) [31, 32], Trinidad (only two cases also in HIV men) [33], and the Democratic Republic of Congo [18]. These reports of HIV patients are proving to be very useful in order to identify previously unrecognized areas where histoplasmosis could generate different forms of disease. Conversely, detecting a case of histoplasmosis in an area considered non-endemic must require the patient's testing for a possible HIV infection.

If prior to the advent of HAART approximately 5% of AIDS patients living in endemic area developed histoplasmosis [34] with a peak of incidence during the Indianapolis outbreak of 27% [6], nowadays initiating cART rapidly proves to be the game changer for this comorbidity in HIV patients [35, 36]. As the "test and treat" intervention strategy provides good results with 79% of people living with HIV aware of their status and 62% receiving treatment in 2018, and as guidelines recommend that all HIV-patient must start cART regardless of CD4 count [37–39], and it is expected that the global epidemiology of histoplasmosis in HIV patients will be changing in the future, except in countries where ART access is still not widely available or the patients are non-adherent.

Occupational risk factors identified to be associated with histoplasmosis in AIDS-patients were working with birds [35] or history of exposure to chicken coops [40]. Among case patients who had worked with soil contaminated with chicken or bat droppings and who could recall the date of their most recent exposure, the median time from their last exposure to the onset of symptoms was of 1.6 years [35]. A notable risk factor was smoking; although not historically associated with progressive disseminated histoplasmosis, smoking has been recognized as a risk factor for the chronic pulmonary form of the disease [41]. Recipients of antifungal agents as any triazole in the 2 months prior to the diagnosis of histoplasmosis seem to have a lower risk, as well as history of Pneumocystis jiroveci pneumonia (PCP) [35, 42].

Several risk factors are associated with the progressive disseminated form: low CD4 lymphocytes count (less than 150) and low nadir CD4 count [40, 42], low CD8 count [42], history of chronic medical condition and history of herpes simplex infection [35], and male gender [42]. Receiving treatment with TMP-SMZ was associated with a decreased risk of poor outcomes [35]. Other described factors associated with severe manifestations of histoplasmosis are: a level of creatinine higher than 2.1 mg/ dL and hypoalbuminemia (less than 3/5 g/dL) [43].
