Imported Histoplasmosis: Two Distinct Profiles in Travelers and Immigrants

Abstract

Background

Histoplasmosis is acquiring importance in nonendemic areas due to the increase in travel and immigration, being the most common systemic mycosis acquired by European travelers. Epidemiological studies show that the incidence of Histoplasma infection in these patients may be higher than previously believed and a wide clinical spectrum of disease may be observed.

Methods

Cases of histoplasmosis diagnosed at a Tropical Medicine Referral Unit in Madrid, Spain, during the period January 1996 to December 2006 were reviewed.

Results

Ten cases of histoplasmosis in travelers and immigrants are described. Five HIV‐positive patients (four immigrants and one expatriate) all presented with progressive disseminated disease. Five HIV‐negative patients (travelers) all presented with pulmonary disease: four with an acute pulmonary form (one with pleural involvement) and one patient was found to have residual pulmonary disease (lung nodule). Three of the travelers also had rheumatologic manifestations (arthromyalgias or arthritis).

Conclusions

Clinicians in nonendemic areas may be faced with patients with a diagnosis of histoplasmosis and although Histoplasma infection can have a varied and nonspecific clinical presentation, imported histoplasmosis may have two distinct profiles. Previously, healthy travelers may be exposed in endemic areas and mainly develop acute forms of the disease with a favorable outcome. Immigrants or expatriates from endemic areas who may be immunosuppressed due to HIV infection may experience reactivation of latent disease developing disseminated forms with high mortality rates. This infection should be considered in the differential diagnosis of diseases affecting travelers and immigrants.

Histoplasmosis is a fungal infection acquired following inhalation of the microconidia of Histoplasma capsulatum, endemic in specific areas of North and Latin America. Cases have also been described in Asia, Africa, and Europe. Most cases in North America have occurred in the Mississippi and Ohio River valleys. Although the endemic area for histoplasmosis may be wider than previously reported, in Europe, most autochthonous cases have been described in Italy, where the organism has been found in the soil of the Po river valley,¹ with very few suspected autochthonous cases published from Spain. The microorganism requires a humid and temperate climate for its growth, and the mycosis is associated with activities where soil is disturbed such as archaeology, ploughing, and construction work. An increased risk for tourists is associated with visits to caves as soil enriched with bird/bat excrement enhances the growth of the organism.^2,3 Flying bats may also disperse pathogens, and the possibility of infection at the cave entrance has been reported recently.⁴

In recent years, the increase in travel to endemic areas, due to the growth in tourism, international cooperation programs, and immigration, has led to diagnosis of cases in nonendemic areas, mainly in immunosuppressed individuals. A recent survey reports under 120 cases identified in Europe over a 5‐year period and only eight were considered to have been acquired locally (Italy, Germany, or Turkey).⁵ However, an epidemiological study in first‐time European travelers to Latin America reports the incidence of Histoplasma infection may be as high as 20% as reflected by positive histoplasmin skin tests.⁶ The severity of H capsulatum infection depends on intensity of exposure and host immunological status and may have a wide spectrum of disease, from subclinical infection to progressive disseminated forms. Many infections are asymptomatic and even symptomatic disease tends to be mild and self‐limiting in healthy individuals.⁷ Diagnosis may be complex, and a high index of suspicion and knowledge of the epidemiology of this infection may be necessary when attending patients arriving from endemic areas.

Methods

A review of cases of histoplasmosis diagnosed at a Tropical Medicine Referral Unit in Madrid, Spain during the period January 1996 to December 2006 was performed. For diagnosis, all patients fulfilled the following criteria: (1) positive epidemiological risk factor (history of exposure or residence in endemic area); (2) symptoms suggestive of histoplasmosis; and (3) positive serology (immunodiffusion) or positive histopathological findings revealing typical yeast structures of H capsulatum and/or positive culture (Saubouraud medium). Polymerase chain reaction and urinary Histoplasma antigen determination were not performed (these techniques are not readily available in our setting).

Results

Table 1 summarizes clinical/epidemiological findings and treatment regimes and outcome. Four of the patients were immigrants (two from South America and two from West Africa). One was a Spanish expatriate (living for over 10 y in Mexico). The other five patients were Spanish travelers (two short‐term travelers to Peru and Ecuador and three long‐term travelers: Panama, El Salvador, and one patient had lived in Costa Rica, French Guyana, Ecuador, and Argentina).

Table 1

Clinical and epidemiological findings; treatment regimes and outcome in patients with histoplasmosis

Case no.	1	2	3	4	5	6	7	8	9	10
Age (years), Gender	42, Male	33, Male	43, Male	31, Male	34, Male	59, Male	59, Male	26, Female	26, Male	27, Female
Country  of origin	Equatorial  Guinea	Liberia	Peru	Ecuador	Spain	Spain	Spain	Spain	Spain	Spain
Epidemiological  risk factor	Immigrant,  1 mo in Spain	Immigrant,  5 y in Spain	Immigrant, 23 y  in Spain,  return trips  to country  of origin	Immigrant,  8 y in Spain	Expatriate, >10 y,  Mexico and  south USA,  past history  untreated  histoplasmosis	STT, 1 mo,  Peru,  exposure:  bat cave	LTT, 8 mo,  Costa Rica,  French  Guyana,  Ecuador,  Argentina,  entomologist	LTT, 1 y,  El Salvador,  exposure:  birds, bat  caves,  humanitarian  work	LTT, 6 mo,  Panama,  agricultural  project,  exposure:  birds	STT, 1 mo,  Ecuador,  exposure:  bat cave
HIV status	+	+	+	+	+	−	−	−	−	−
CD4 count (cells/μL)	<10	<10	<50	<10	<50	ND	ND	ND	ND	ND
Clinical form	PDH	PDH	PDH	PDH	PDH	Acute  pulmonary	Residual  pulmonary  disease	Acute  pulmonary  and  rheumatologic  syndrome	Acute  pulmonary  and pleural	Acute pulmonary
Clinical  presentation	Submandibular  mass, weight  loss, fever,  dyspnea,  skin lesions,  HS	Fever, weight  loss, HS	Fever, cough,  weight  loss, HS	Fever, weight  loss, GI  symptoms, HS	Fever, weight loss, respiratory symptoms, HS	Fever,  respiratory  symptoms,  myalgia, H	Relapsing fever	Fever, headache,  myalgia,  arthritis, H	Fever, R‐sided  chest pain	Fever, respiratory  symptoms,  chest pain,  arthromyalgia
Diagnosis	Serology: ND,  LN biopsy:  culture–,  histopath+,  Skin biopsy:  culture+,  histopath+	Serology: ND,  BM biopsy:  culture+,  histopath+,  Blood  cultures+	Serology: −, BM  biopsy:  histopath+,  culture−	Serology: −, BM  aspirate:  culture+,  histopath+,  LN culture+,  histopath+	Serology: −, LN biopsy: culture+, histopath+	Serology: +,  Histoplasmin  skin test: +	Serology: +	Serology: +	Serology: +,  Pleural  fluid:  culture−,  histopath−,  hemorrhagic  exudate	Serology: +
Treatment	Lipo ampho B,  single dose	Ampho B* (950 mg),  itraconazole  400 mg/d  maintenance.  HAART	Lipo ampho B* (1,000 mg),  itraconazole  400 mg/d  maintenance.  TB treatment.  HAART	Lipo ampho  B* (2,150 mg),  itraconazole  200 mg/d  maintenance.  HAART	Ampho B* (900 mg),  itraconazole  400 mg/d  maintenance.  HAART	Itraconazole, 3  mo, 400 mg/d	None	Itraconazole, 6  mo, 400 mg/d	Itraconazole,  8 mo,  200 mg/d	None
Outcome	Died: pulmonary  hemorrhage	Improved	Improved	Died 5 mo  after diagnosis,  possible  adrenal  insufficiency	Improved. Died unrelated cause 3 y later	Improved	Improved	Improved	Improved	Improved

STT = short‐term travel; LTT = long‐term travel; += positive; −= negative; PDH = progressive disseminated histoplasmosis; LN = lymph node; H = hepatomegaly; S = splenomegaly; GI = gastrointestinal; ND = not done; ampho B = amphotericin B; lipo ampho B = liposomal amphotericin B;*= expressed as cumulated dose; BM = bone marrow; histopath = histopathology; HAART = highly Active Anti‐Retroviral Therapy; TB = tuberculosis.

Five patients (5/10) including all the immigrants and the Spanish expatriate (no. 5, who referred a possible past history of partially treated histoplasmosis) were infected with HIV‐type 1. All the HIV‐negative patients (5/10) were travelers who referred activities typically associated with risk of exposure to H capsulatum: two patients had visited bat caves during short‐term travel abroad (Peru and Ecuador), one patient had been exposed to birds/bat caves during a long‐term stay in El Salvador, and one patient had contact with birds in Panama (agricultural project), and the last patient had been working as a field entomologist in South and Central American countries.

All the HIV‐positive patients presented with progressive disseminated disease. Of the five non‐HIV patients, four presented with acute pulmonary forms (one with pleural involvement) and one patient was found to have residual pulmonary disease (lung nodule), diagnosed incidentally when investigated for another travel‐related illness. Three travelers referred nonspecific arthromyalgia and one of these had associated arthritis. Duration of symptoms varied according to the type of presentation ranging from a few days for no. 10, a traveler who presented with symptoms of acute pulmonary histoplasmosis, which resolved spontaneously, to 4 months for no. 1, an HIV‐positive patient with progressive disseminated histoplasmosis (PDH).

All the HIV‐negative patients (5/5) had positive serology for Histoplasma sp. Three of the HIV‐infected patients had negative serology and in the other two this technique was not performed. In four of the five HIV‐infected patients, H capsulatum var. capsulatum was identified. For no. 3, intracellular inclusions typical of Histoplasma sp were identified in the bone marrow sample, but culture was subsequently negative. In three patients, H capsulatum was found in lymph node biopsies (both lymph node and bone marrow aspirate cultures were positive in no. 4; no. 1 also had positive skin biopsies), another (no. 2) had a positive bone marrow biopsy (culture and histopathology) and positive blood cultures. Following presentation, diagnosis was obtained after an average of 15 to 20 days.

In total, 8 of 10 patients received treatment, and in the majority (6/8), this was initiated once diagnosis was confirmed. Amphotericin B was used in all the HIV‐infected patients and in four this was followed by suppressive treatment with oral itraconazole. One patient (no. 1) died after receiving only a single dose of amphotericin B due to acute pulmonary hemorrhage. In three other HIV‐infected patients, histoplasmosis responded to treatment: two remained well at follow‐up but one died 3 years later of an unrelated cause. The other HIV‐infected patient died 5 months after diagnosis of histoplasmosis having presented with hypotension, fever, vomiting, hypokalemia, and hyponatremia possibly due to adrenal insufficiency. Three of the non‐HIV patients were treated with oral itraconazole with a good outcome. The other two HIV‐negative patients with pulmonary disease did not require treatment: one presented with acute self‐limiting pulmonary disease and one had residual disease.

Discussion

Clinicians in nonendemic areas may be challenged with the diagnosis of histoplasmosis, an infrequent infection that should be included in the differential diagnosis of diseases affecting travelers and immigrants. Special emphasis should be made on careful history taking that focuses on areas visited, contact with birds/bats in their natural environments, and other risk activities.

As demonstrated by this series of cases, Histoplasma infection may have a varied and nonspecific clinical presentation. The majority of infections may be asymptomatic, but immunosuppressed patients, such as those infected with HIV, may develop lethal disseminated forms of the disease. Other diseases prevalent among both immigrants and HIV patients, which share certain clinical features with histoplasmosis such as tuberculosis (TB) should be ruled out. Although it is less common and no cases were diagnosed in this series, African histoplasmosis, caused by H. capsulatum var. duboisii, should also be considered especially as many immigrants of African origin currently reside in European countries. Methods such as serology do not readily distinguish between the two varieties of H capsulatum and identification is based on typical appearances of the yeast phase in infected tissues.⁸

All HIV‐1 infected patients in this series presented with PDH, which occurs most often in patients with underlying immune suppression. Fever, weight loss, respiratory symptoms, and hepatosplenomegaly were frequent clinical findings and although nonspecific should alert the clinician to the possibility of disseminated histoplasmosis. Gastrointestinal tract involvement in disseminated histoplasmosis is common but tends to be asymptomatic unlike the presentation in no. 4 with vomiting, abdominal pain, and diarrhea.⁹ For no. 4, adrenal insufficiency resulting in death may have been secondary to adrenal destruction, which, although rare, has been described more frequently with histoplasmosis than with other disseminated mycoses. Of note, one patient (no. 3) had PDH and suspected disseminated TB, although the latter was not confirmed microbiologically. In HIV‐infected patients with disseminated histoplasmosis, the association with TB has been well documented as both infections may arise as a consequence of a common immunological deficit. According to published series from South and Central America, up to 15% of HIV patients with disseminated histoplasmosis may have associated TB,¹⁰ although rates are lower for other geographical areas.

Among the travelers, fever with/without respiratory symptoms were the most frequent symptoms, and diagnosis was suspected based on travel history and risk factors. Two patients had additional features, which occur infrequently in patients with acute histoplasmosis. Pleural effusions are rare during pulmonary histoplasmosis and are generally culture‐negative, hemorrhagic exudates as found in the case described (no. 9). Atypically, this case did not have associated pericarditis. Rheumatologic manifestations are also rare. Polyarthritis/arthralgia and even histoplasmosis‐associated erythema nodosum as described recently in three female travelers, may occur, and appear to result from systemic immunological reactions to recent Histoplasma sp infection.^1,9,11

Most healthy patients remain relatively asymptomatic, and thus infection is most probably underdiagnosed in travelers. Recent outbreaks of acute infection have followed identification of index patients with ensuing investigations identifying additional subjects. In 2003, an outbreak (262 clinically confirmed and 148 laboratory confirmed cases) among American students who stayed in a specific hotel in Mexico was identified after a group reported an acute febrile respiratory illness on return.¹² Increased awareness of clinical manifestations of histoplasmosis is necessary and testing may even be extended to include relatively asymptomatic fellow travelers as cases may otherwise remain undetected.

Conclusions

In conclusion, histoplasmosis may be considered an emerging disease in nonendemic countries. Although manifestations are varied, imported histoplasmosis appears to have two distinct profiles. The disease may be acquired by travelers to endemic areas exposed to organic material, who mainly develop acute forms of the disease and have favorable outcomes. The second group includes immigrants or expatriates from endemic areas who may be immunosuppressed due to HIV infection and may experience reactivation of latent disease even years after initial exposure developing disseminated forms with high mortality rates (up to 50%).¹³ Histoplasmosis should be considered in travelers from endemic areas presenting with acute respiratory symptoms or recognized associated manifestations and in their travel companions. HIV‐positive immigrants with febrile illnesses of unknown origin should also be tested for this mycosis. If exposure can be anticipated pretravel, avoidance of specific activities or use of protective equipment should be recommended, especially in high‐risk patients.

Dr F Norman is the recipient of a grant (C‐45/07) from the Fundación Biomédica para la Investigación Hospital Ramón y Cajal, Madrid, Spain. The clinical research team acknowledges the support provided by the Red de Investigación de Centros de Enfermedades Tropicales (RICET), RD06/0021/0020.

Declaration of interests

The authors state that they have no conflicts of interest.