*3.3.3 Risk factors for epidemiological process*

Bats play a more important role than terrestrial mammal hosts in dispersion and transmission of the infection because of their ability to cross long distances and to spread the mycelia. The infected bats are also natural reservoirs of *H. capsulatum*, returning the fungus to the environment through their urine, feces, and carcasses. Although immune to disease, starlings and black birds contribute to the spreading of spores on their feathers, beaks, claws, and feet over short distances and, on the other hand, favor the mycelial growth in the soil through their droppings rich in nitrogen and phosphorus [48, 49, 75]. Wind, storms, airstreams in bat caves, and other natural environmental phenomenon are promoting factors for the epidemiological process. Poorly protected water supply basins or wells can be contaminated by water from sanitary and storm sewers that have washed away the soil, manure, dust, and decayed wood harboring *H. capsulatum* [86].

Studies performed to investigate the longevity of *H. capsulatum* in composed organic fertilizers obtained from hens and chicken manure demonstrated that some of them are associated with an important risk of infection by fungal-aerosolized conidia [75, 79].

Invasion and deforestation of the natural habitats of bats and birds and accelerated urbanization by disrupting the environment by excavation and construction are significant risk factors for producing air-borne conidiospores of *H. capsulatum*, and consequently infections [46, 75]. Once predominant in rural areas, histoplasmosis

### *Epidemiology of Histoplasmosis DOI: http://dx.doi.org/10.5772/intechopen.110901*

became more prevalent in urban areas and was classified as an occupational and recreational disease. Builders, constructors, housekeepers, farmers, gardeners, tree cutters, hunters, speleologists, archeologists, and microbiology laboratory workers are at increased risk of acquiring occupational histoplasmosis. Outdoor recreational activities such as traveling in endemic areas, cave exploration, bird and bat watching, golf and tennis courses, and visiting amusement parks could be at risk of acquiring the fungus [45, 66, 79].

Histoplasmosis appears to affect all age groups from 13 months to 70 years [65], with a predominance of cases in men (2:1 male-to-female ratio), which might be related to outdoor occupational exposure [87].

### *3.3.4 Forms of manifestation of the epidemiological process*

An "*endemic* disease" is, by definition, one "occurring frequently in a particular region or population." Histoplasmosis occurs, with low or greater endemicity, in some known areas, more frequently in some populations (e.g., up to 25% of people living with HIV in hyper-endemic areas develop manifest histoplasmosis) [88]. In certain locations from Americas, and parts of Asia and of Africa, skintest surveys indicate that more than half of the population acquired histoplasmosis early in life [89].

The *epidemic* form of histoplasmosis is usually associated with outbreaks. An outbreak is defined as involving at least two cases, usually originating from the same known source [77].

Outbreaks of histoplasmosis are closely related to exposure, especially of immunocompetent individuals, to a large amount of aerosolized conidia of *H. capsulatum* during occupational activities that disturb vegetation and soil, containing bird or bat droppings, or during recreational trips to abandoned archeological sites or bat caves [45, 90, 91]. Although most infections are not outbreak-associated [91], individuals acquiring histoplasmosis during an outbreak may experience more intense exposures and thus potentially develop more severe disease than persons sporadically infected [90]. Due to high dose exposure during outbreaks, attack rates have been estimated at 50–100% [92].

During outbreaks and in high-risk groups, the incidence of cases is higher than 100 per 100,000 inhabitants [52]. The epidemic form of manifestation of the epidemiological process is mainly described in some Latin American countries, but numerous reports also described outbreaks of histoplasmosis in the US and Canada prior to the 1980s [77]. In recent years, this type of exposure affects more people due to the shift of outbreaks from rural to urban areas [4].

*Sporadic* or isolated cases are related to passive exposure during normal daily activities, are usually diagnosed outside areas recognized as endemic, and cannot be associated with a specific situation or known source of infection [48, 74]. Estimative data suggest that only 1% of sporadic infections are symptomatic [92].

Histoplasmosis occurs infrequently in persons living in non-endemic areas, but increasingly imported cases are recognized and diagnosed in immigrants or after traveling in endemic locations, especially in individuals with impaired cellular immunity [89].

## *3.3.5 Distribution and burden of the disease*

Histoplasmosis has a wide distribution around the globe, being reported on all continents excepting Antarctica.

The real burden of the disease seems to be underestimated because it is frequently misdiagnosed as tuberculosis [52], community-acquired pneumonia or other acute lower respiratory tract infections [93], and underdiagnosed due to poor availability of diagnostic tests [94]. In addition, the incidence of the disease is poorly described even in areas known to be endemic, since histoplasmosis is not a nationally notifiable condition by the clinicians, even in the USA [93]. However, recent global estimates found almost 500,000 cases of histoplasmosis and approximately 100,000 cases of disseminated histoplasmosis occurring annually [12].

Although exposure to *H. capsulatum* was initially thought to be limited to the traditional area described by the well-known Edwards' map, with the onset of the HIV pandemic in 1980s and the emergence of new cases outside this area, this theory has been challenged [69].

Consequently, an increasing number of reported cases, both from areas previously known and from areas not known to be endemic, disclosed a wider geographic distribution of the fungus than historically described (**Figure 5**) [69, 94].

According to Global Action for Fungal Infections (Gaffi), the case fatality rate of disseminated histoplasmosis is 15–30%, if timely treated, and more than 80,000 deaths with this diagnostic were estimated annually [95].

Since 1987, the disseminated form of histoplasmosis is considered an AIDSdefining event [96]. In people living with HIV (PLHIV) in endemic areas, the annual incidence of progressive disseminated histoplasmosis (PDH) is about 5%, with mortality rates remaining high, even with the availability of antiretroviral therapy (ART) [97].

In hyper-endemic areas up to 25% of PLHIV develop clinical histoplasmosis [88] and an estimated 20% will develop PDH, with fatal prognosis without timely diagnostic and therapy [97]. The annual incidence of the disease was estimated from 0.1 to 100 cases per 100,000 inhabitants, with the lowest rates described in temperate territories and the highest in tropical areas [52]. The incidence varies within continents and territories, histoplasmosis being known to be highly endemic in central and eastern areas of North America (in the Ohio and Mississippi River Valleys), Central and South America, and parts of sub-Saharan Africa [46, 62, 63]. The disease is also endemic in patchy regions of Southeast Asia and Australia [98, 99] and sporadically

#### **Figure 5.**

*World map estimating regions most likely to have histoplasmosis based on literature review (2020) [94]. https:// link.springer.com/article/10.1007/s11046-020-00431-2.*

### *Epidemiology of Histoplasmosis DOI: http://dx.doi.org/10.5772/intechopen.110901*

reported in the remained continents, except Antarctica. Recently, the fungus has been detected in soil and penguin droppings even in the Antarctic peninsula [39].

The geographic distribution of *H. capsulatum* in the North America remains still unclear and requires further investigations [100].

In highly endemic areas around the US river valleys, population skin delayed type hypersensitivity to histoplasmin is around 90%, meaning that residents of these areas were exposed to the primary infection at some point in their lifetime [16, 69].

In most of them the infection is inapparent, asymptomatic and only less than 1% of them will develop the disease [101].

Extrapolating these figures to the entire population, nearly 50 million Americans are latently infected with *H. capsulatum* [16]. Epidemiological reports and studies have shown many cases of histoplasmosis diagnosed in humans or animals outside historically recognized endemic areas. The distribution of these cases extends beyond the originally defined boundaries of the US river valleys [43, 94], encompassing states in the north (Minnesota, Wisconsin, Michigan), northeast (New York), and west (California, Arizona, Idaho, and Montana) [74].

However, the real picture of Histoplasma geographic distribution, potential exposure, and relevant host factors is still incomplete in the USA, histoplasmosis not being part of the diseases with mandatory national notification, being voluntary reported only in 13 states. These states do not necessarily include the relevant ones where histoplasmosis has traditionally been diagnosed. A recent CDC report summarizes 2019 US surveillance data on histoplasmosis and confirmed that Histoplasma causes substantial illness in the USA, with the high rates of hospitalization and death. Reported data rely on the national case definition established in 2017 by the Council of State and Territory Epidemiologists (CSTE), which classifies histoplasmosis cases as confirmed or probable based on laboratory, and clinical and epidemiological criteria. The findings showed that the overall incidence of histoplasmosis was 1.8 cases per 100,000 population, 54% of patients were hospitalized, and 5% died. Three northeastern states were accountable for 65% of the cases: Minnesota (19%) with an incidence rate of 3.8, and Michigan (20%) and Illinois (26%) with a rate of 3.2 each [93]. Using county-level data on histoplasmosis cases reported between 2011 and 2014 in 12 states (covering the eastern half of the USA), a recent estimate from 2022 supports the hypothesis of a shift in the presence of *H. capsulatum* toward the northeastern and central states around the Great Lakes and the Atlantic coast [100].

In a retrospective study performed between 2002 and 2017 in PLHIV in the USA, the overall mortality rate proved to be 37% with an early mortality of 14.8% and late mortality of 22.2%, with no statistically significant difference in survival in those treated with HAART [102].

In the USA, there are estimated 25,000 cases of life-threatening Histoplasma infections [18] and over 5000 histoplasmosis-related hospitalizations annually [70, 87]. Between 2001 and 2012, the proportion of histoplasmosis-related hospitalizations in people with diabetes, transplanted or receiving biologic agents had increased, while in people living with HIV/ AIDS had decreased from 21.5% to 17.3%. The mean length of histoplasmosis-associated hospitalizations is almost double compared with that non-histoplasmosis related. In 2012, the total burden for histoplasmosis-related hospitalizations was estimated at \$371 million [70].

In Canada, histoplasmosis is considered endemic in the regions adjacent to the St. Lawrence River and the Great Lakes, especially Quebec and Ontario. A northward expansion of the disease has been observed, evidenced by a continued increase (0.05 to 0.25 per 100,000 people) in confirmed cases of histoplasmosis in Alberta between 1990 and 2015 [43, 94, 103].

Histoplasmosis is endemic in Central and South America [94], excepting the western part of the two continents (west Mexico and Peru, and most of Chile) [43]. Histoplasmin skin test sensitivity average is 32% in the general population of Latin America [94]. High-endemicity areas are Guatemala, Brazil, Venezuela, Ecuador, Uruguay, Paraguay, and Argentina [16].

The variability of histoplasmin test results is high in the states of Latin America, with rates of nearly 90% in Guatemala, some areas of Mexico [69] and Southeastern Brazil, 63% in Midwestern Brazil [16], 42% in Trinidad and Tobago and Venezuela, and 37% in Costa Rica and Nicaragua [94].

Histoplasmosis is an increasing challenge for the Latin American population, especially the disseminated form of the disease occurring in HIV-positive patients [68]. In PLHIV histoplasmosis is as widespread as tuberculosis [94]. Some studies estimate more than 15,000 new histoplasmosis cases occurring annually [104] and up to 30% mortality rate [105].

In a large prospective cohort study, conducted in Guatemala between 2005 and 2009, which enrolled HIV-positive patients with suspected histoplasmosis, crude mortality in patients with histoplasmosis was 43.6 versus 30.8% among no-histoplasmosis patients. Also, early mortality rate was 24.8% among histoplasmosis cases, statistically significantly higher than non-histoplasmosis ones (9.3%). Coinfection with *Mycobacterium tuberculosis* was found in 9.9% of patients [106], data which is similar with other findings from some Latin America countries where mycobacterial coinfection was reported in 8% (in French Guiana) to 15% (Panama) of HIV+ patients with Histoplasma infection [107].

Interestingly, patients infected with Histoplasma alone had lower survival rates than those coinfected with Histoplasma and *M. tuberculosis* [106].

A robust study of more than 58% of the newly diagnosed HIV patients, reported by the national HIV program during 2017–2018, in Guatemala found that histoplasmosis was the most common opportunistic infection, with an overall incidence of 7.9%, varying from 1.1 to 19.7% in patients with CD4 cell counts higher than 350 cells/mm3 and lower than 50 cells/mm3 , respectively. Of all patients enrolled, 18.1% had opportunistic infections, of which 36.4% was histoplasmosis. In those with two underlying opportunistic infections, histoplasmosis was frequently associated with cryptococcal disease and tuberculosis in 35.5 and 32.3% of cases, respectively. Mortality rates in disseminated histoplasmosis were significantly statistical higher than in non-disseminated cases (32.7 versus 13.3%) [108].

A screening program for histoplasmosis in HIV-positive patients in Guatemala showed an increasing trend in the number of newly diagnosed cases of histoplasmosis, with the annual incidence rising from 6.5% in 2017 to 8.8% in 2019. As a result of early diagnosis and rapid initiation of treatment, 180-day mortality rates showed an annual downward trend, from 32.8% in 2017 to 21.2% in 2019, underscoring the importance of implementing screening programs in endemic areas and populations at risk for decreasing mortality [109].

In a cohort of HIV-infected patients from French Guiana followed between 2010 and 2019, disseminated histoplasmosis was the most common opportunistic infection with an early case fatality rate of 3.9 within 1 month of diagnosis. It is important to emphasize that the analysis of the evolution of histoplasmosis cases showed that as diagnosis rates improved and, consequently due to treatment, the huge early fatality rate (40%) from 1992 to 1997 decreased more than 10 times in this cohort, leading to better outcomes in most patients with disseminated form of disease [110].

## *Epidemiology of Histoplasmosis DOI: http://dx.doi.org/10.5772/intechopen.110901*

A systematic review of 3530 published cases of disease and isolates of *H. capsulatum* from environmental and animal sources between 1939 and 2018 in Brazil showed that histoplasmosis is endemic throughout Brazil, especially in Northeastern, Central-Western Southeastern, and Southern areas. Disseminated histoplasmosis was the prevalent form of disease, described in more than 80% of reported cases in Brazil. The main underlying condition was HIV infection, found in 97.2% of patients with immunosuppression. Coinfection with *M. tuberculosis* was found in 10.37% patients, these findings being like those found in Guatemala and other Latin American countries. Mortality rate was 33.1% [111]. The north-eastern state of Brazil, the estate of Ceará, is a highly endemic area of histoplasmosis, with many disseminated histoplasmosis cases in people living with HIV, being considered the area with the highest mortality rate due to histoplasmosis (33–42%) [45, 112].

Genetic diversity among isolates and sexual reproduction of *H. capsulatum* in Brazilian population support the hypothesis that Brazil is the center of origin of Histoplasma spp. in Latin America, most likely with the contribution of migratory birds and bats [52].

On African continent, despite the significant number of people living with HIV, histoplasmosis remains an underdiagnosed and neglected disease. The lack of skin tests surveys necessary to develop a much more detailed geographic understanding of the distribution of the disease has impeded the clear delimitation of areas of hyperendemicity.

An exhaustive review on histoplasmosis cases reported from 32 African countries between 1952 and 2017, performed by Oladele and her colleagues, reveals a comprehensive picture of the disease distribution across the continent. Both varieties of *H. capsulatum* coexist in the African territory, *H. capsulatum* var. capsulatum (Hcc) being found predominantly in Southern and Northern Africa and *H. capsulatum* var. duboisii (Hcd) being prevalent in the West, Central, and East of the continent. Moreover, Hcc is found mostly in HIV-positive adults, while Hcd is reported especially in immunocompetent children [113]. Although less common in the African AIDS patients, Hcd is more likely to produce the disseminated form of the disease [94, 113] with a case fatality rate around 23% [65].

The disease is more prevalent in Western Africa (especially Nigeria), Southern Africa (South Africa and Zimbabwe), and Central-Eastern countries (Congo, Uganda) with a nonuniform distribution of isolated cases in many other states across the continent [94, 113].

Of the total number of cases reported in Africa, Nigeria accounts for more than a quarter (26.4%), all exclusively involving Hcd and, with an overwhelming majority (96.7%), in HIV-negative patients [113]. Interestingly, Nigeria has high variable rate in the histoplasmin reactivity test between rural (35%) and urban areas (4.4%) [94, 113].

Hcc was the exclusive causative microorganism, affecting almost equally the HIV-positive and the negative population in South Africa, which had 13% of the cases of histoplasmosis in Africa. In Zimbabwe, the percentage of cases was 12% of mainland cases, diagnosed exclusively in HIV-positive patients, all but one caused by Hcc [113].

The prognosis of disseminated histoplasmosis in Africa is poor, fatality rates varying between 23% for *H. capsulatum* var. duboisii and 50% for *H. capsulatum* var. capsulatum infections [84, 114, 115].

Within Asia, histoplasmosis is endemic in China, especially along the Yangtze River [116], Thailand, South Korea, and India [17].

A study of hospitalized patients and healthy residents in China found overall values of histoplasmin reactivity of 9.0%, with higher values in Jiangsu province (15.1%) [117].

In Sichuan Province, histoplasmin test positivity was found between 21.8% in healthy adults and 28.6% in hospitalized TB patients [118].

A review of 300 cases of histoplasmosis recorded in China between 1990 and 2011 found three quarters of cases in southeastern territory, along the Yangtze River. More than 85% were patients with disseminated histoplasmosis, most of them with underlying immunocompromising conditions such as HIV infection, diabetes, and liver disease [116].

A study of 4211 lifelong residents of Thailand found uneven distribution in the 8 regions studied, with histoplasmin sensitivity ranging from rates of 4.8% in the north and northeast to 34.4% in the south and center, which are among the highest reported in Asia. Due to the endemicity of Talaromyces marneffei in the region, the hypothesis of overestimation of the sensitivity to histoplasmin through cross-reactivity with this fungal antigen was issued [119].

In Thailand, histoplasmosis is reportable to the Ministry of Public Health, and between 1984 and 2010, a total of 1253 cases were documented among exclusively patients living with HIV in this country [120].

In Myanmar, a study of histoplasmin skin test sensitivity in prisoners and their families showed rates ranging from 8.4 to 27.1% [98, 121].

Cases of histoplasmosis have also been reported in other Southeast Asian countries, where histoplasmin reactivity ranges from 2.7–63.6% in Indonesia, 11.8% in Malaysia, 33.7% in Vietnam, and 6.4–26% in the Philippines, supporting the hypothesis of the endemicity of histoplasmosis in these areas [94, 98].

Histoplasma has been known to be present in India for many years since it was first reported to be present in the soil of Gangetic Plain in 1975 [122]. Most cases of histoplasmosis were reported in north-eastern areas, especially West Bengal and Assam states, crossed by the Ganges, Yamuna, and Brahmaputra Rivers. Yet, it is very likely that the number of cases is underestimated, due to misdiagnosis as tuberculosis or leishmaniasis [123, 124]. The histoplasmin test positivity rate reported in a study between 1950 and 1970 was 12.3% in northern India [125].

In a retrospective analysis of cases published between 2001 and 2015, it was found that most of them were reported in the north-eastern part of India, six times more frequently in men than in women, and were associated with agricultural activity. Patients with underlying immunocompromising conditions were around 33% of cases, of which HIV infection was the main cause of immunosuppression. The mortality rate was 27.5% in immunosuppressed versus 10% in immunocompetent patients with histoplasmosis [124].

In Japan, histoplasmosis is rarely reported, and most diagnosed cases are considered imported from endemic areas [44]. A study on 187 bat guano samples collected from 67 bat-inhabited caves in Japan was unable to detect *H. capsulatum*, by either method [126].

Isolated and scattered cases of locally acquired histoplasmosis have been reported since 1948 in all Australian states except Tasmania. Endemic areas are Queensland and northern New South Wales, regions traversed by the long Dumaresq and Macintyre rivers. In a report of cases and literature review of cases in Australia, 41% of disseminated form was found in HIV infected patients. The prognosis of patients with disseminated disease was poor, this form being associated with a 30% recurrence rate and a 37% mortality rate [99].

### *Epidemiology of Histoplasmosis DOI: http://dx.doi.org/10.5772/intechopen.110901*

Europe is a non-endemic area for histoplasmosis, and the disease is rarely reported and is considered a predominantly imported disease. The majority of cases are linked to travel in endemic areas or immigration [127].

In a review of 118 cases of histoplasmosis diagnosed in Europe between 1995 and 1999, more than 93% of patients had a history of migration or travel to a known endemic area. The remaining 6.8% were considered autochthonous European cases, and these patients having no travel history outside their country of origin (Italy, Turkey, and Germany). Notably in this survey, cases of disseminated histoplasmosis were diagnosed among elderly residents of the United Kingdom who fought in India and Myanmar during World War II and who had not left their country of origin for over 50 years after returning from the war. Out of 8 non-imported cases, Italy was the country with the most cases diagnosed as autochthonous [128]. This is consistent with the isolation of *H. capsulatum* in the soil [129] and dogs [130] in the Po Valley area in Italy and with the histoplasmin positivity rate of 1.2% in the population of this area. Few sporadic cases of autochthonous histoplasmosis have also been described in Spain [131].

A more recent systematic review of histoplasmosis cases in the literature identified 223 patients diagnosed between 2005 and 2020 in 17 European countries and Israel. Only eight cases were classified as autochthonous (four in Italy, two in Spain, one in Ireland, and one in Israel), the remaining majority of 96.4% being imported, especially from Latin America and Sub-Saharan Africa. More than 64% of imported cases of histoplasmosis were diagnosed in 3 European countries: Spain (36.7%), France (19.5%), and Italy (7.9%). The other countries reporting the remaining cases of imported histoplasmosis were the Netherland, Germany, Switzerland, United Kingdom, Poland, Austria, Slovenia, Portugal, Greece, Ireland, Sweden, Belgium, Finland, Denmark, and Israel. Most of the cases were recorded in HIV-infected patients (over 51.1%), in whom progressive disseminated histoplasmosis was the most common form of clinical presentation (89.47%). The patients with other immunocompromising diseases were 12.5%, histoplasmosis manifesting in its disseminated form in 57.1% of these cases. In a smaller percentage (6.2%), the picture of progressive disseminated histoplasmosis was also encountered in immunocompetent individuals. The worst outcome of histoplasmosis (32% mortality rate) was registered in patients with other than HIV underlying immunocompromised conditions, while in patients living with HIV infection the mortality rate was 24.3% [132].

In conclusion, doctors from non-endemic areas must consider in certain cases the differential diagnosis with histoplasmosis in immunosuppressed patients and especially in those with HIV infection, because early diagnosis and rapid institution of therapy improve the outcome of the disease and patient's survival [97].
