Journal of Fungi Review Histoplasmosis Diagnosed in Europe and Israel: A Case Report and Systematic Review of the Literature from 2005 to 2020 Spinello Antinori 1,2,* , Andrea Giacomelli 1,2 , Mario Corbellino 2, Alessandro Torre 2, Marco Schiuma 1,2 , Giacomo Casalini 1,2 , Carlo Parravicini 3, Laura Milazzo 2, Cristina Gervasoni 2 and Anna Lisa Ridolfo 2 1 Luigi Sacco Department of Biomedical and Clinical Sciences, Università di Milano, 20157 Milan, Italy; [email protected] (A.G.); [email protected] (M.S.); [email protected] (G.C.) 2 III Division of Infectious Diseases, ASST Fatebenefratelli Sacco, 20157 Milan, Italy; [email protected] (M.C.); [email protected] (A.T.); [email protected] (L.M.); [email protected] (C.G.); [email protected] (A.L.R.) 3 Pathology Unit, ASST Fatebenefratelli Sacco, 20157 Milan, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-0250319765; Fax: +39-0250319758 Abstract: Human histoplasmosis is a mycosis caused by two distinct varieties of a dimorphic fungus: Histoplasma capsulatum var. capsulatum and H. capsulatum var. duboisii. In Europe, it is usually imported by migrants and travellers, although there have been some autochthonous cases, especially in Italy; however, most European physicians are unfamiliar with its clinical and pathological picture, particularly among immunocompromised patients without HIV infection. This systematic review of all the cases of Citation: Antinori, S.; Giacomelli, A.; histoplasmosis reported in Europe and Israel between 2005 and 2020 identified 728 cases diagnosed in Corbellino, M.; Torre, A.; 17 European countries and Israel described in 133 articles. The vast majority were imported (mainly Schiuma, M.; Casalini, G.; from Central and South America), but there were also seven autochthonous cases (six in Europe and Parravicini, C.; Milazzo, L.; one in Israel). The patients were prevalently males (60.4%), and their ages ranged from 2 to 86 years. Gervasoni, C.; Ridolfo, A.L. The time between leaving an endemic region and the diagnosis of histoplasmosis varied from a few Histoplasmosis Diagnosed in Europe weeks to more than 40 years. Progressive disseminated histoplasmosis was the most frequent clinical and Israel: A Case Report and picture among people living with HIV infection (89.5%) or a different immunocompromising condition Systematic Review of the Literature from 2005 to 2020. J. Fungi 2021, 7, 481. (57.1%), but it was also recorded in 6.2% of immunocompetent patients. Twenty-eight cases were https://doi.org/10.3390/jof7060481 caused by Histoplasma duboisii. Immunocompromised patients without HIV infection had the worst outcomes, with a mortality rate of 32%. Academic Editors: Nathan C. Bahr and Mathieu Nacher Keywords: histoplasmosis; Histoplasma capsulatum; Histoplasma duboisii; HIV; immunocompromise; travellers; progressive disseminated histoplasmosis; diagnosis Received: 13 May 2021 Accepted: 10 June 2021 Published: 14 June 2021 1. Introduction Publisher’s Note: MDPI stays neutral Human histoplasmosis is a disease that is traditionally considered to be caused by two with regard to jurisdictional claims in varieties of the fungus Histoplasma capsulatum var. capsulatum (Hcc) and H. capsulatum var. published maps and institutional affil- duboisii (Hcd, also known as African histoplasmosis) [1,2]. Although the number of species iations. belonging to the Histoplasma genus is unknown, the findings of genome-wide population genetic and phylogenetic analyses suggest the existence of four species that are endemic in the Americas: Histoplasma capsulatum sensu stricto, H. mississippiense sp. nov (formerly known as NAm1), H. ohiense sp. nov (formerly known as NAm2), and H. suramericanum sp. Copyright: © 2021 by the authors. nov (formerly known as LAm A) [3]. A fifth lineage, the African clade (H. capsulatum var. Licensee MDPI, Basel, Switzerland. duboisii), is probably a separate species, but confirmation of its status will require further This article is an open access article analyses of more samples [3]. distributed under the terms and The disease is highly endemic in the USA and Latin America [4] but is probably more conditions of the Creative Commons widespread than previously thought [5,6]; a survey by the European Confederation of Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ Medical Mycology Working Group has described the cases diagnosed in Europe between 4.0/). January 1995 and December 1999 [7], and Antinori et al. have reviewed cases observed in J. Fungi 2021, 7, 481. https://doi.org/10.3390/jof7060481 https://www.mdpi.com/journal/jof J. Fungi 2021, 7, 481 2 of 22 patients living with HIV infection in Europe between 1984 and 2004 [8]. Other publications include a systematic review of cases of acute histoplasmosis in immunocompetent travellers worldwide [9] and a review of the worldwide cases of African histoplasmosis diagnosed between 1993 and 2019 [10]. The aim of this systematic review is to describe the imported and autochthonous cases of histoplasmosis diagnosed in Europe and Israel between 2005 and 2020 as well as a new case of progressive disseminated histoplasmosis in a Brazilian trans-sexual male living with HIV/AIDS. 2. Materials and Methods This systematic review was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement [11]. 2.1. Search Strategy The PubMed database was searched for articles published between January 2005 and December 2020 using combinations of key words: histoplasmosis (AND) Europe; Histoplasma capsulatum (AND) Europe; Histoplasma duboisii (AND) Europe; histoplasmosis, disseminated (AND) Europe; histoplasmosis, pulmonary (AND) Europe; histoplasmosis, extra-pulmonary (AND) Europe; histoplasmosis, autochthonous (AND) Europe; histo- plasmosis, imported (AND) Europe; histoplasmosis, HIV (AND) Europe; histoplasmosis, immunocompetent (AND) Europe; histoplasmosis, immunocompromised (AND) Europe; histoplasmosis, travellers (AND) Europe; histoplasmosis (AND) Albania; histoplasmosis (AND) Andorra; histoplasmosis (AND) Armenia; histoplasmosis (AND) Austria; histoplas- mosis (AND) Azerbaijan; histoplasmosis (AND) Belarus; histoplasmosis (AND) Belgium; histoplasmosis (AND) Bosnia (OR) Herzegovina; histoplasmosis (AND) Bulgaria; histo- plasmosis (AND) Croatia; histoplasmosis (AND) Cyprus; histoplasmosis (AND) Czech; histoplasmosis (AND) Denmark; histoplasmosis (AND) Estonia; histoplasmosis (AND) Finland; histoplasmosis (AND) France; histoplasmosis (AND) Georgia; histoplasmosis (AND) Germany; histoplasmosis (AND) Greece; histoplasmosis (AND) Hungary; histo- plasmosis (AND) Iceland; histoplasmosis (AND) Ireland; histoplasmosis (AND) Israel; histoplasmosis (AND) Italy; histoplasmosis (AND) Kazakhstan; histoplasmosis (AND) Kosovo; histoplasmosis (AND) Latvia; histoplasmosis (AND) Lichtenstein; histoplasmosis (AND) Lithuania; histoplasmosis (AND) Luxembourg; histoplasmosis (AND) Macedonia; histoplasmosis (AND) Malta; histoplasmosis (AND) Moldovia; histoplasmosis (AND) Montenegro; histoplasmosis (AND) Netherlands; histoplasmosis (AND) Norway; histo- plasmosis (AND) Poland; histoplasmosis (AND) Portugal; histoplasmosis (AND) Romania; histoplasmosis (AND) Russia; histoplasmosis (AND) Serbia; histoplasmosis (AND) Slo- vakia; histoplasmosis (AND) Slovenia; histoplasmosis (AND) Spain; histoplasmosis (AND) Sweden; histoplasmosis (AND) Switzerland; histoplasmosis (AND) Turkey; histoplasmosis (AND) Ukraine; and histoplasmosis (AND) United Kingdom. 2.2. Eligibility Criteria and Study Selection The populations considered were children and adults of any age and origin diagnosed with histoplasmosis in geographical Europe and Israel. All publications were considered regardless of their type (individual case reports, case series, observational studies, and reviews providing information regarding age, gender, nationality, travel history, affected organs, latency period, diagnosis, antifungal therapy, and outcome) or language (excluding Turkish, Finnish, Romanian, and Russian). The cases included travel-related, possible autochthonous, and veterinary cases diagnosed in the same geographical areas. The patients were divided into three categories based on their immune status: people living with HIV (PLWH); patients with other immunocompromising conditions (OIC: solid organ or stem cell transplant recipients; cancer patients; patients treated with im- munosuppressive drugs including corticosteroids, biological immunosuppressants, and J. Fungi 2021, 7, 481 3 of 22 non-biological, non-corticosteroidal drugs); and immunocompetent subjects (HIV-negative patients not meeting any of the OIC criteria). 2.3. Data Collection and Evidence Summary The following information was extracted from each article and entered into pilot-tested evidence tables: author, year, study design, language, country of diagnosis, country of exposure, latency period, number of cases, patients’ characteristics (age, gender, occupation, and affected organs), systemic antifungal therapy, and outcomes. 3. Results 3.1. Case Report A 27 year old trans-sexual male born in Brazil was admitted to our infectious dis- eases ward in April 2012 with a 2-month history of intermittent high fever, productive cough, dysphagia, and diarrhoea. He had been concomitantly diagnosed with human immunodeficiency virus-1 (HIV-1) infection and disseminated tuberculosis in February 2006, after which