Histoplasmosis infections worldwide: thinking outside of the Ohio River valley

Abstract

In the United States, histoplasmosis is generally thought to occur mainly in the Ohio and Mississippi River Valleys, and the classic map of histoplasmosis distribution reflecting this is second nature to many U.S. physicians. With the advent of the HIV pandemic reports of patients with progressive disseminated histoplasmosis and AIDS came from regions of known endemicity, as well as from regions not thought to be endemic for histoplasmosis throughout the world. In addition, our expanding armamentarium of immunosuppressive medications and biologics has increased the diagnosis of histoplasmosis worldwide. While our knowledge of areas in which histoplasmosis is endemic has improved, it is still incomplete. Our contention is that physicians should consider histoplasmosis with the right constellations of symptoms in any febrile patient with immune suppression, regardless of geographic location or travel history.

Introduction

Histoplasmosis, in the United States, is primarily seen in the Ohio and Mississippi River Valleys¹. The narrative regarding histoplasmosis is supported by solid epidemiologic evidence. By the mid-20^th century a geographic clustering of patients with histoplasmosis was noted,² and mapping of reactive histoplasmin skin tests was employed in patients with pulmonary calcifications on chest radiographs who did not react to tuberculin skin testing³. Edwards and colleagues constructed the now quite familiar map of histoplasmin skin reactivity among naval recruits⁴.

While the central United States seemed to have the greatest prevalence of Histoplasmosis capsulatum var. capsulatum, Brazil⁵, Argentina⁶, India⁷, and South Africa⁸ have all reported small case series, and Histoplasma capsulatum var. duboisii was thought to exist predominantly in West Africa. Additionally, sporadic cases have been reported from Central and South America, Oceania, northern sub-Saharan Africa, and Europe⁶. Histoplasmin skin test sensitivity analyses showed fairly high levels throughout Central America and parts of South America as well as Puerto Rico, Dominica, and Mexico in addition to the central United States with almost no skin test sensitivity in Europe, and scant information available from the rest of the world⁶. These skin test surveys appeared to support the idea that histoplasmosis exposure was infrequent in the rest of the world.

Over a number of years over which the authors have gained experience at multiple centers around the United States and Italy, it is extremely common for trainees at all stages to make assumptions about whether a diagnosis is even possible based on the geographical location alone. This review will focus on the truly global nature of histoplasmosis while acknowledging, the infection is certainly more common in certain areas, and that our current knowledge of endemicity is incomplete.

Pathogenesis and Immunity

The portal of entry for H. capsulatum is the lung, and following inhalation an area of pneumonitis develops. Neutrophils are unable to destroy the organism, although macrophages can ingest but cannot destroy the fungus⁹. Initially during the pre-immune phase, the fungus disseminates widely throughout the body⁹. Once T-cell mediated immunity develops, the entire process is arrested and recovery occurs⁹ – this allows for most infections to go un-noticed in persons without immune deficits. Primary infection by H. capsulatum is predominantly asymptomatic⁹; however, in patients exposed to a large infecting inoculum, symptomatic pulmonary infection is more common, and many patients require hospitalization¹⁰.

The degree to which infection is often sub-clinical is illustrated well by a 1964 outbreak in Mason City, Iowa. Of the estimated 6000, predominantly asymptomatic infections only 1 person developed progressive disseminated histoplasmosis and 87 persons developed acute pulmonary histoplasmosis¹¹. This attack rate in the context of the estimated number of sub-clinical infections was possible because an outbreak two years prior allowed for serial skin testing.)

In patients with faulty T-cell mediated immunity this localized containment does not occur and progressive dissemination may take place, leading to clinical illness⁹. Faulty T-cell mediated immunity may be innate (e.g. Job syndrome, severe combined immunodeficiency syndrome, etc.), caused by immunosuppressive medications, or may be caused by immunodeficiency states related to other diseases such as malignancy or HIV infection ⁹. Inadequate T-cell function allows progressive disseminated histoplasmosis due to reactivation of previous infection among patients with new immune compromise and has been particularly noted among immigrants from Latin America and sub-Saharan Africa in non-endemic geographic locales in Europe^12,13. Further evidence of the importance of T-cell function in controlling Histoplasma infection was provided in a recent retrospective analysis of ~1400 HIV-infected persons in French Guiana in which the authors found a hazard ratio for the development of progressive disseminated histoplasmosis of 47.2 in patients with CD4 T-lymphocyte counts of 0–50 cells/L, as compared to >500 cells/L, with an inverse relationship continuing between CD4 count and hazard ratio at higher CD4 counts¹⁴. Table 1 reviews the more typical clinical manifestations of H capsulatum infection as well as associated risk factors. Treatment varies by infection type^1,15–18.

Table 1.

Major clinical manifestations of histoplasmosis and associated risk factors

Manifestation	Risk factors
Acute pulmonary histoplasmosis	Young age, exposure to a large inoculum of Histoplasma
Chronic pulmonary histoplasmosis	Older age, chronic obstructive lung disease related to tobacco use
Mediastinal lymphadenitis, granuloma, fibrosis	Young age undefined inflammatory or immunologic factors in mediastinal fibrosis
Pericarditis or rheumatologic syndrome	Young age, immunocompetence, male sex and African American race in pericarditis and female sex in rheumatologic syndromes
Progressive disseminated histoplasmosis	Immunocompromising condition or medication, primary or acquired immunodeficiency, age < 1 or >55 years

The table above notes major categories of histoplasmosis and risk factors associated with development of this type of disease related to histoplasmosis.

Global Histoplasmosis and the advent of AIDS

In 1983, several patients who had been diagnosed with AIDS and progressive disseminated histoplasmosis were reported^19–23. While one report came from a known hyper-endemic area for histoplasmosis in Indiana²², other reports came from areas in the United States (Texas, Michigan,) where histoplasmosis was less common^19,21, or had not been thought to be present (New York, Colorado)^20,23. These reports rapidly increased across the United States in endemic and non-endemic areas alike^24,25. In addition, patients from around the world were reported from areas where histoplasmosis had been rarely or never reported such as Trinidad²⁶, Thailand²⁷, and the Democratic Republic of Congo²⁸. By 1990, Wheat and colleagues noted >100 cases of histoplasmosis in persons with AIDS,²⁹ and although many came from Indiana, a sizeable minority were from areas outside of traditional endemic zones. Most of the reported symptomatic cases were patients with progressive disseminated histoplasmosis,²⁹ as opposed to isolated pulmonary infections as had been the most common presentation in HIV-uninfected patients (when the infection did indeed lead to symptomatic clinical illness). In the decades since, numerous case series of progressive disseminated histoplasmosis associated with HIV infection have been reported around the globe in locations with few, if any, previous reported cases³⁰.

The widespread reporting of patients with progressive disseminated histoplasmosis since the advent of AIDS helped to identify previously unrecognized endemic areas where a great number of sub-clinical infections must have occurred but were not previously recognized. Similarly, for known outbreaks of histoplasmosis (including those reported in persons with AIDS), likely many more, sub-clinical, infections occur.

Ideally, antiretroviral therapy (ART) is started before immunocompromised occurs in HIV-infected persons and reverses the immune defect, reducing the likelihood of development of histoplasmosis. The idea of prevention is supported by a 2001 case-control study in which patients were matched for CD4 count among other factors – patients on ART had less risk all for developing disseminated histoplasmosis, even at low CD4 counts³¹. Interestingly, there have been reports of otherwise untreated histoplasmosis in persons with AIDS improving with ART alone³². In many high-income countries guidelines recommend that all HIV-infected persons are started on ART regardless of CD4 count³³, and so advanced immune suppression related to HIV infection and opportunistic infections such as histoplasmosis are less frequent in these countries. However in many parts of the world ART access is still not adequate and more cases of disseminated histoplasmosis are likely.

While AIDS illuminated many areas of hidden histoplasmosis endemicity, cases in areas not previously known to be endemic are still being reported and our knowledge regarding the distribution of histoplasmosis is expanding. With the incomplete nature of our understanding in mind, the reminder of the review will focus on the worldwide distribution of histoplasmosis and factors that might influence our understanding of histoplasmosis distribution in the future as HIV has done in the past and continues to do.

Global distribution of histoplasmosis

Our present knowledge of the worldwide distribution of Histoplasma capsulatum var. capsulatum relies most on the histoplasmin skin-test surveys with additional information coming from soil isolation of the fungus. Many of the pertinent studies were conducted in the 1950–70s^6,34,35. Notably a summary of skin-test studies by Mochi and Edwards in 1952⁶, highlighted that the “highest prevalence of histoplasmin sensitivity is found in east-central part of the USA, in southern Mexico, Central America and certain parts of South America. An isolated, low sensitivity area has been reported from South Africa⁶, and almost no histoplasmin sensitivity has been found in Europe, with the possible exception of Italy”⁶. Much of Asia and nearby nations were excluded from their “preliminary attempt” to map the geographical distribution of histoplasmosis due to the lack of any data from these areas⁶.

A review regarding soil isolation of H. capsulatum written in 1964 by Libero Ajello, added that in addition to well known endemic areas such as North America (USA, Mexico), Central (Panama) and South America (Brazil, French Guiana, Perù and Venezuela) a few countries in Africa (Congo, Tanzania-, and South Africa’s Guateng and Limpopo provinces), Asia (Malaysia) and the Caribbean (Trinidad)³⁶ also housed H. capsulatum within their borders.

It is worth noting that until now the geopolitical isolation of several countries as well as the lack of microbiological facilities in many low-income areas of the world might have contributed to the difficulty in constructing an accurate map of worldwide histoplasmosis distribution. Table 2 shows studies from outside of the USA^37–59, while Figure 1 shows a world map constructed with estimated areas endemic to histoplasmosis based on case reports primarily among HIV-infected patients.

Table 2.

Areas of endemicity for Histoplasma capsulatum outside United States of America (USA) according to histoplasmin skin reactivity

Country/year/Reference	Number tested/Population	Histoplasmin skin test positivity %
Asia
China
Hunan province 200135	101	8.9
Nanjing District 2001	292/healthy & pulmonary diseases	16.8
Sichuan province 199634	271 Healthy Students 28 TB patients	6–35
India 195533	962/NR	1.9
India (Delhi) 1962	8062/NR	6.8
India (Delhi riverine) 1960	162/NR	12.3
India (Calcutta) 1954	64/NR	4.7
India (Calcutta) 1956	4855/NR	0.7
Malaysia (Kuala Lumpur) 196433	227/Chest disease patients	10.5
Myanmar (Rangoon) 195233	1089/NR	27.1
Myanmar (Upper region) 1952	142/NR	8.4
Myanmar (Maguee) 1956	154/NR	86.4
Philippines (Manila) 1950–196433	3878/Navy recruits, TB patients, Medical & nurses students	4.1–6.4
Philippines (Luzon island) 200036	143/Healthy electric company employees	26
Taiwan (Nantou) 195633	444	49.8
Thailand (Bangkok) 196733	497/Medical & nurses students	5.6
Thailand 1961	329/Student nurses	4.0
Thailand (Northern region) 1987	NR/NR	7–14
Thailand (Central region) 1987	NR/NR	3–9
Thailand (Southern region) 198739	NR/NR	15–36
Vietnam (Saigon) 196033	303/NR	33.7
Central & South America
Argentina (Chaco province) 1996	315/Children	9.2
Brazil (Minas Gerais state) 199641	417/Miners	17.5
Brazil (Rio Grande Do Sul) 199643	354/Soldiers (17–19 years)	48–89
Brazil (Ceara State) 199242	138/Residents	61.5
Brazil (Amazonas state) 197844	495/Residents	37.8
Colombia (Department of Antioquia) 197145	NR/National survey	10
Mexico (Guerrero state) 199749	139/Cave guides, peasants	36.4–88.6
Mexico (Guerrero,, Queretaro, Tlaxcala state) 199448	253/NR	2 (Tlaxcala),83 (Guerrero),53 (Queretaro)
Venezuela (Bolivar state) 200546	182/Residents	34
Venezuela (Bolivar state) 200447	157/Farmers	42.7
Caribbean
Cuba (Ciego de Avila)199250	392/Poultry farmers	28.8
Barbados/198152	NR	4
Trinidad/1981	NR	42
Martinique & Guadeloupe 197253	454/Residents	7 Martinique; 4 Guadeloupe
Africa
Nigeria 199151	1087-226/Healthy-hospital patients	3.5 (Hcc):3.0 (Hcd) healthy
Nigeria (Anambra State) 199654	40/Cave guides, traders, farmers 620/Farmers, palm oil workers	8.85 (Hcc);6.6 (Hcd) hospital pts 35 (Hcd) 8.8 (Hcd)
Somalia (Mogadishu & Jilib) 197955	1014/NR	0.3
Uganda (Gulu, Jinja, Amudat, Fort Portal and Kasese, Kampala, Pakwach) 197038	1144/residents	0.4–12%

Hcc, Histoplasma capsulatum var. capsulatum; Hcd, Histoplasma capsulatum var. duboisii; NR, not reported

Figure 1.

Geographic distribution of Histoplasma capsulatum var. capsulatum (purple) and H. capsulatum var. duboisii (shadow area).

The circles indicate the number of published cases of autochthonous AIDS-associated histoplasmosis (via Scopus query). The majority of African cases have been observed outside Africa

An important example of a country in which the increasing rate of infections has been recognized in recent years is China. A 2013 review found that from 1990 to 2011, 300 cases were reported in China of which 75% occurred along the Yangtze river⁶⁰. Progressive disseminated histoplasmosis occurred in 257 of the 300 cases and immune suppression, HIV in most cases, was present in most patients⁶⁰. Studies from China report the prevalence of histoplasmin skin test reactivity ranging from 6% to 50%^37–39. Interestingly the distribution of H. capsulatum overlaps that of Penicillium marneffei⁶¹ in several areas of China.

The occurrence of histoplasmosis in Asia has not been fully appreciated until recent years despite the fact that in 1970 Randhawa reviewed 30 autochthonous cases from India, Malaysia, Indonesia, Singapore, Thailand, Vietnam and Japan³⁷. Histoplasma has been isolated from the soil from these countries ^62,63. Histoplasmin sensitivity was negligible in Japan, except in people working with soil and sand imported from overseas (including the USA)³⁷, and H. capsulatum has never been isolated from the environment nor detected by PCR in bat guano from Japan ⁶⁴.

In Thailand, the AIDS epidemic has been responsible of a dramatic upsurge of disseminated histoplasmosis with more than 1200 cases reported to the Ministry of Public Health from 1984 to 2010⁶⁵. A survey of histoplasmin sensitivity conducted in this country between 1966 and 1968 showed positivity rates of 7–14% in the northern region and 15–36% in the Southeast and Southern regions⁴³, overlapping with areas containing Penicillium marneffei as determined by PCR ⁶⁵.

Malaysia was the first country in Asia where H. capsulatum was successfully isolated from soil samples collected from bat-infested caves near Kuala Lumpur⁶⁶, and a survey of histoplasmin skin test sensitivity showed a prevalence of 10.5% in that country³⁷. Cases of histoplasmosis have been recognized both among HIV-positive and HIV-negative patients as well as among subjects travelling to Malaysia^67,68.

In India, histoplasmin sensitivity has been reported to be relatively high in Calcutta and Delhi (4.7–12.3%)³⁷ with most cases occurring in north-eastern India in West Bengal and Assam states. Fungal isolation from soil has also occurred. An increasing number of cases of progressive disseminated histoplasmosis have been recognized in recent years in India among HIV-positive and/or diabetic patients, and some have suggested that histoplasmosis might be under-recognized due to being mistaken for tuberculosis⁶⁹. In Australia, H. capsulatum has been cultured from different environmental sources (e.g. fowl yards and caves) in the States of Queensland and New South Wales. A recent review reported on 63 autochthonous cases from 1948 to 2009, including 11 with AIDS⁷⁰.

In South and Central American large numbers of patients, many in persons infected with HIV, have been reported in Brazil, French Guiana, Argentina, Colombia, Venezuela and Panama (Figure 1) ^14,71–74. Importantly, a recently published map of histoplasmosis endemic areas in the region did not include French Guiana⁷⁵. This would seem to have been an oversight as progressive disseminated histoplasmosis is the most common cause of AIDS-defining illness in that country with one retrospective study finding that ~41% of HIV-positive hospitalized patients with fever and a CD4+ count < 200 cells/L had disseminated histoplasmosis^14,71,72,76. Similarly, more than 70% of patients with histoplasmosis included in a survey conducted in Colombia from 1992 to 2008 had HIV/AIDS⁷⁷. Argentina has an area of endemicity for histoplasmosis in the north-eastern part of the country⁷⁸.

In Brazil, histoplasmosis is highly endemic especially in the northern (Amazona, Roraima, Parà, Amapà, Cearà, Rio Grande do Norte, Bahia), and mid-western states (Minas Gerais, Sao Paulo) as well as the south-eastern portions of the country. Histoplasmin positivity may be up to ~90% in some areas (although positivity varies widely by study, Table 2)^36,45–48. Moreover, a recent study from 1996 to 2006 showed 4.73 per 1000 deaths associated with AIDS were due to histoplasmosis⁷⁹.

A study conducted in metropolitan Caracas, Venezuela from 2000 to 2005 reported that AIDS was the risk factor in 33.5% of the 158 patients with histoplasmosis⁷³. Histoplasmosis seems to be present in much of the region (Figure 1) with HIV playing a crucial role in symptomatic infections.

The distribution of histoplasmosis in Africa is probably the most puzzling due to the lack of solid epidemiologic studies coupled with the limited laboratory capacity available in much of the continent^{55,58,59,80,81}. Complicating matters, there is the coexistence of two varieties of the fungus: H. capsulatum var. duboisii (“African histoplasmosis”) and H. capsulatum var. capsulatum on the continent. H capsulatum var. duboisii has been primarily noted in Nigeria, Niger, Congo, Democratic Republic of Congo, and Uganda^80–82 although a few cases have also been observed in Madagascar, Chad, Ivory Coast, Senegal^83–86. Only 17 cases of H. capsulatum var. duboisii have been described among HIV-infected patients in Europe; with all being described as imported¹². To the best of our knowledge only two studies, from Zimbabwe and South Africa, respectively, described 12 and 14 persons con-infected with AIDS and H. capsulatum var. capsulatum^87,88. The majority of published cases of histoplasmosis caused by H. capsulatum var. capsulatum among HIV-infected Africans were observed in Europe as imported infections^12,13,89. Although one study in Tanzania has identified patients with febrile illnesses that were likely due to histoplasmosis, the majority of patients tested were HIV-infected⁹⁰. In this study, the testing was done retrospectively as Histoplasma antigen testing, the most sensitive method of diagnosis, is not available in the region⁹⁰. Patients originated from Democratic Republic of Congo, Congo, Liberia, Ivory Coast, Gambia, Uganda, Central African Republic, Guinea Bissau, Senegal. In actuality, the majority of histoplasmosis cases in Africa are likely due to H. capsulatum var. capsulatum.

Travel, immigration, and histoplasmosis

The increasing number of persons travelling to endemic areas for tourism or international cooperation programs, or migrating for work is responsible of the growing number of reports of single or, more frequently, clusters of acute histoplasmosis. Numerous histoplasmosis cases among immigrants from Latin America and sub-Saharan Africa have occurred. Of particular importance in these populations are the potential to reactivate a previous infection when starting on immune suppressive therapy^12,13,89,91.

Table 3 shows cases related to international travel but not immigration^91–106. Sleeping outdoors or spelunking (where bats are present) are associated with the development of acute pulmonary histoplasmosis among tourists. However in an outbreak, involving more than 200 US students in Acapulco, Mexico, which is the largest reported outbreak among travellers, the infection source was soil from a hotel’s ornamental potted plants that had been fertilized with compost^94,107. More recently an outbreak with a high attack rate (61%) was observed among three mission groups that had travelled to El Salvador to renovate a church. Participation in dust-generating activities, such as digging or sweeping outdoors, were associated with an increased risk of symptomatic illness⁹³. Although the number of reports of travel-associated histoplasmosis increased steadily in recent years (Table 3), likely many cases go unnoticed, especially if not presenting as a cluster of patients.

Table 3.

Reports of cluster of acute imported histoplasmosis among travelers from 1988 to 2013

Author/year/Reference	N	Syndrome	Country of observation	Country of acquisition	Risk activity/ies
CDC, 198888	15	Pulmonary	USA	Costa Rica	Visiting bat-cave
Nasta, 199794	4	Pulmonary	Italy	Peru	Visiting bat-cave
Valdez, 199996	11	Pulmonary	USA	Ecuador	Visiting bat-cave
Gascon, 200087	7	Pulmonary	Spain	Santo Domingo (2); Perù; Guatemala (2); Nicaragua; Colombia	Visiting cave (Santo Domingo; Perù); sleeping in the forest (Nicaragua; Guatemala)
Buxton, 200297	14	Pulmonary	Canada	Belize	Visiting cave
Salomon, 200398	13	Pulmonary	France	Martinique (French West Indies)	Trekking (passage in a bat-infested tunnel)
Morgan, 200390	262	Pulmonary	USA	Mexico	Stay in hotel with minor construction activities
Weinberg, 200391	5	Pulmonary	USA	Nicaragua	Visiting bat-cave
Lyon, 200495	14	Pulmonary	Usa	Costa Rica	Visiting bat-cave
Garcia-Vazquez, 200593	9	Pulmonary	Spain	Guatemala	Renovation of an old school
Alonso, 200792	4	Rheumatologic	Spain	Ecuador	Agricultural activity
CDC, 200889	20	Pulmonary	USA	El Salvador	Construction activities (Church)
Norman, 2009102	5	Pulmonary	Spain	Peru; El Salvador; Panama; Ecuador; multiple exposure (Costa Rica; French Guiana; Ecuador; Argentina)	Visiting bat-cave (3); entomologist (1); agricultural activity (1)
Buitrago, 201099	9	Rheumatologic (4); pulmonary (3)	Spain	Ecuador (5); Nicaragua (1); Venezuela (1); Africa (2)	Visiting rural areas (4); visiting a cave (1); travelling to rural areas
Kajfastz, 2012101	4	Pulmonary	Poland	Ecuador	Visiting bat-caves
Cottle, 2013100	13	Pulmonary	UK	Uganda	Contact with bat-infested tree trunk

Medical immunosuppression and histoplasmosis

The number of patients receiving immunosuppressive and cyto-reductive therapies are increasing, particularly among patients who receive biologic medications to treat rheumatologic, gastrointestinal or dermatologic diseases^36,108–110. The fact that an intact immune system is important to prevent progressive dissemination of Histoplasma infection has been recognized^9,14 and so these patients are more susceptible to histoplasmosis. For example, since as early as the 1950s, immune suppression in the form of Hodgkin’s lymphoma was recognized as a risk factor allowing for progressive disseminated histoplasmosis¹¹¹.

Assi and colleagues conducted a large retrospective multi-center study of solid organ transplant patients with histoplasmosis in known endemic areas, reviewing 152 cases that occurred at 24 centers from 2003 to 2010¹¹⁰. Among 152 histoplasmosis infections, all patients were receiving immunosuppressive medications, most were receiving calcineurin inhibitors (138 of 152) and one or two other medications with mycophenolate preparations and corticosteroids being the most common¹¹⁰. Seventy eight patients had kidney transplantation, 24 had liver transplantation, 22 were pancreas/kidney transplant recipients, 14 received heart transplants, 8 lung transplants, and 3 received pancreas transplants while two other individual patients had kidney transplant combined with either heart or lung and one had a small bowel transplant¹¹⁰. In this population urine Histoplasma antigen was the most sensitive test detecting 132 of 142 cases and while the median time from transplant to diagnosis was 27 months, 34% of cases occurred in the first years after transplant¹¹⁰. Disseminated histoplasmosis occurred in 81% (122/152), and 10% (15/152) died¹¹⁰.

Patients with autoimmune conditions such as rheumatoid arthritis are also at risk for progressive disseminated histoplasmosis if immunosuppressive medications are used. In a single center study in an endemic area, 26 cases of patients with rheumatoid arthritis who were infected with Histoplasma were summarized. Progressive disseminated histoplasmosis was present in 46% (12/26) of patients with histoplasmosis¹⁰⁹, 11 of the 12 patients were receiving multiple immune suppressive medications. Of the 26 total patients, 16 were receiving methotrexate, 15 were receiving tumor necrosis factor (TNF)-α inhibitors, 15 corticosteroids (mean dose 9.1mg/day), 5 hydroxychloroquine and 5 leflunomide¹⁰⁹.

TNF-α inhibitors are particularly important as TNF-α is a key component of the granulomatous immune response to Histoplasma capsulatum^108,112. As of 2010, 88 cases of histoplasmosis had been reported in patients using TNF-α inhibitors, a majority of cases were disseminated¹⁰⁸. While many cases come from endemic areas, cases outside of endemic areas have been reported as well¹⁰⁸. Cases continue to be reported, particularly in those patients using infliximab¹⁰⁸. As an example, in Indiana, of 19 reported cases related to TNF-α inhibitor use, 13 patients were using infliximab¹⁰⁸. A final note, paradoxical immune reconstitution inflammatory syndrome (IRIS), which is a worsening of symptoms after successful microbiologic treatment upon improving a weakened immune system. Just as IRIS can occur in HIV-infected persons upon starting ART¹¹³, IRIS can also occur when TNF-α inhibitors or other immunosuppressive medications are stopped¹⁰⁸.

Conclusions

Histoplasmosis is a much more widespread than was once thought and current knowledge of its distribution is imcomplete³⁰. The AIDS pandemic has elucidated a worldwide risk for histoplasmosis, including areas previously unknown to be endemic. While ART access has improved to the point that histoplasmosis in the setting of HIV infection is rare in high-income countries, histoplasmosis remains a significant cause of AIDS-associated mortality in many parts of the world. Additionally, increased international travel and use of immune suppressive medications are likely to lead to additional emergence of histoplasmosis infection from areas not previously known to be endemic, and the non-HIV-related incidence may continue to increase for progressive disseminated histoplasmosis. Thus, we believe histoplasmosis should be considered as a possible diagnosis in much of the world. Areas of higher density of exposure exist, and the consideration should be stronger if a patient has been to or lived in these locations. We advocate physicians considering disseminated histoplasmosis in patients with immune suppression, regardless of the location of the hospital to which the patient presents although the weight which one considers progressive disseminated histoplasmosis might vary widely depending on the patient’s location. Currently, Histoplasma antigen testing is not available in many areas not previously thought to be endemic, and this may limit one’s ability to diagnose the condition properly as it is currently the most sensitive method of diagnosis^32,71,110. We look forward to the day when we no longer hear a presentation that includes, “well, they haven’t been to the Ohio River Valley so it can’t be histoplasmosis” from trainees.