samuel darling   in 1906  is a dimorphic fungal organism found in moist fertile soil contaminated by bird or bat droppings . although endemic in east and central us states bordering the ohio river valley and the lower mississippi river , in europe some rare autochthone cases in italy , near the po valley , have been described . transmission regularly occurs via inhalation of h. capsulatum spores from the soil , and primary infections in the immunocompetent host are generally asymptomatic or present as a self - limiting flu - like illness . if infection can not be cleared , as in immunocompromised patients with disabled cellular immunity , the organism continues to reproduce intracellularly and disseminates throughout the body via lymphatic and hematogenous circulation , cumulating in a state called disseminated histoplasmosis . disseminated histoplasmosis manifests most prominently in the digestive tract , from mouth to anus , beside its well - described symptoms and manifestations , such as pulmonary disease , skin lesions , fever , and encephalopathy . untreated disseminated histoplasmosis usually leads to death within a few weeks . therefore , accurate diagnosis and appropriate treatment , we present the case of an obviously nonimmunocompromised patient from a nonendemic area infected by h. capsulatum , and we thus describe the first case with a disseminated disease course in austria . a 67-year - old man was referred to our department of otorhinolaryngology in december 2014 for the evaluation of anorexia , painful dysphagia , hoarseness , diarrhea , and a history of unintentional weight loss of about 15 kg ( equaling approximately 20% of his previous body weight of roughly 80 kg ) in the last 3 months , accompanied by intermittent fever , night sweats , and chills . his past medical history consisted of stable coronary heart disease and well - controlled chronic obstructive pulmonary disease caused by long - term tobacco smoking ( about 30 pack - years ) . he was a retired engineer employed at a local steel company , operative in africa and middle and south america , where the patient was involved in construction work and soil - disruptive activities for several months . however , there was no history of far distance travelling during the last 6 years . on admission , the patient was in an alarming general condition , cachectic with a wasting syndrome , requiring intermittent parenteral nutrition . the most obvious clinical observation was an extremely painful stomatitis and angular cheilitis with ulcers involving the tongue and the palate ( fig 1a , b ) . laboratory data on admission included an unremarkable blood count with slightly elevated c - reactive protein of 3.8 mg / dl , an increased lactate dehydrogenase of 264 u / l , and a mildly elevated angiotensin - converting enzyme level of 64 screening for tumor markers and autoimmune disease as well as testing results for hiv , hepatitis , and tuberculosis were negative . chest x - ray demonstrated an emphysematous lung with reticulonodular parenchymal changes ( fig 2a ) . further evaluation for a suspected occult malignant disease , bearing in mind the long - term tobacco consumption , included a whole - body positron emission tomography scan , which detected an additional hypermetabolic process in the ascending colon ( fig 2b ) . this prompted us to perform an endoscopic evaluation of the colon and the terminal ileum . macroscopically , rather small ulcerous lesions and erosions presented on a diffuse edematous mucosa with capillary congestion in the terminal ileum and ascending colon upon endoscopic examination ( fig 2c ) . histological examination of the biopsies excluded a malignant process but rather described a polypoid mucosa infiltrated by a kind of granulomatous inflammatory process with the presence of prominent histiocytes . intracellularly , these  foam cells  harbored abundant intracellular round - shaped fungal elements with a characteristic halo sign , about 24 m in diameter , highly indicative of h. capsulatum ( fig 2d ) . biopsies of the tongue and a computed tomography - guided puncture of the lung confirmed the presence of round intracellular fungal forms using periodic acid - schiff staining ( fig 1c , d ) . diagnosis was finally established from an oral re - biopsy by panfungal polymerase chain reaction , performed at a reference center at the medical university of vienna , confirming positivity for h. capsulatum . liposomal amphotericin b ( 1 mg / kg body weight ) was administered to the patient , and constitutional symptoms markedly improved during the next few days . after 4 weeks of treatment , the patient was discharged from hospital and switched to oral itraconazole . on follow - up 6 months later ( fig 3 ) , the patient continued to improve and subjectively reported that his voice was much stronger and that his dysphagia and gastrointestinal symptoms had completely resolved . particularly , conditions with compromised cellular immunity affecting t cells are prone to propagation of the disease , a scenario often resembling miliary tuberculosis . only a small proportion of exposed individuals ( < 0.1% ) may develop disseminated disease . aids , htlv-1 , hepatitis c , renal failure , long - term corticosteroid use or therapy with biologicals , and older age   are well - characterized risk factors . notably , up to 40% of patients presenting with disseminated histoplasmosis do not have any obvious risk factors . endogenous reactivation of old foci during an immunocompromised state might be the trigger of dissemination . in our patient , the underlying chronic obstructive pulmonary disease might have been a risk factor for primary infection of the lung ; however , we could not delineate any commonly acquired or inherited immune deficiency states often associated with disseminated histoplasmosis . thus , reactivation years after the last stay in endemic areas , performing  soil - disruptive activities  , might just be attributed to an age - related immune system  rundown  , an already previously described promoting factor for dissemination . in clear contrast to the initial presentation of acute histoplasmosis , which almost exclusively involves the respiratory tract , disseminated histoplasmosis most prominently affects the gastrointestinal tract . typical sites with abundant lymphatic tissue , such as the terminal ileum , are mostly affected , presenting on endoscopic examination as segmental inflammation , ulcerative lesions , and also polypoid masses , often incorrectly attributed to malignancy , inflammatory bowel disease ( e.g. , crohn 's disease and ulcerative colitis ) , or appendicitis . in the majority of patients , gastrointestinal manifestation takes a subclinical disease course . nonetheless , endoscopy is an important diagnostic tool for the assessment of dissemination . therefore , it appears crucial for clinicians to be aware that an oropharyngeal or laryngeal presentation of histoplasmosis may be the only apparent clinical sign of dissemination . in addition , a differential diagnostic consideration should include tuberculosis , other fungal diseases , such as coccidioidomycosis and blastomycosis , and viral infection , such as coxsackievirus or herpes virus infection . microscopically , diffuse lymphohistiocytic infiltrates with fungal elements about 24 m in size detected within the cytoplasm of macrophages are pathognomonic . granulomatous inflammatory processes are often associated with elevated angiotensin - converting enzyme serum levels , and previous reports even suggested exclusion of histoplasmosis , especially during acute disease states , before establishing the diagnosis of sarcoidosis . although serological testing for antibodies to h. capsulatum revealed a negative result in our case , this seems to be in accordance with previously published reports of diminished sensitivity of serological tests in disseminated disease , especially during immunocompromised states . periodic acid - schiff staining is considered the gold - standard technique for microscopically based diagnosis , but sensitivity might be hampered by sampling errors , lack of expertise , or the impossibility to obtain representative material from severely ill patients . although sensitivity of polymerase chain reaction is highly dependent on the type of isolate ( culture vs. direct clinical ) , its impact lies in the reliable diagnostic differentiation between different fungal specimen . lipid formulation of amphotericin b at 35 mg / kg body weight per day , intravenously , for 12 weeks , followed by itraconazole at 200 mg 3 times daily for 3 days and then 200 mg twice daily for a total of 12 weeks p.o . , is the accepted gold - standard therapy for disseminated histoplasmosis . considering the severe illness of the patient , we decided for a prolongation of intravenous antifungal therapy up to 4 weeks . when clinical response was observed , antifungal therapy was replaced by oral itraconazole , and this treatment was continued for up to 1 year . as disease monitoring by the detection of the h. capsulatum antigen was impossible due to its exclusive availability in the usa , response to therapy was monitored on a clinical basis , showing a dramatic symptomatic improvement . disseminated histoplasmosis is an important differential diagnostic consideration in patients with systemic illness , especially when oropharyngeal and gastrointestinal lesions are dominating . the rising incidence of disseminated histoplasmosis in nonendemic areas emphasizes the need for a thorough examination of the patients travelling history . due to its heterogeneous clinical presentation , a close interaction between clinicians across the borders of their subdisciplines and between pathologists and microbiologists is mandatory for establishing the right diagnosis .
histoplasmosis is well characterized as an endemic fungal disease restricted to certain areas of the usa . in middle europe , 
 most patients present with acute pulmonary symptoms after travelling to endemic areas . here 
 , we want to illustrate the case of a 67-year - old man who presented with persistent oral ulcers , hoarseness , dysphagia , diarrhea , and weight loss to our department of otorhinolaryngology in december 2014 . 
 he was a retired construction worker and had a history of soil - disruptive activities in africa and middle and south america during employment . 
 a positron emission tomography - computed tomography scan revealed prominent hypermetabolic lesions in the cecum and the lung , pointing towards a malignant disease . surprisingly , histological examination of colonic and oral biopsies revealed abundant intracellular fungal elements , highly suspicious of histoplasma capsulatum . 
 diagnosis was finally confirmed by panfungal polymerase chain reaction . upon treatment with liposomal amphotericin followed by itraconazole 
 , the severely ill patient showed an impressive clinical response . 
 this case describes a disseminated manifestation of h. capsulatum years after the first exposure in an otherwise immunocompetent patient descending from a nonendemic area .