Pneumocystis jirovecii is an airborne human-specific ascomycetous fungus responsible for Pneumocystis pneumonia (PCP) in immunocompromised patients, affecting >500,000 patients per year (www.gaffi.org). The understanding of its epidemiology is limited by the lack of standardised culture. Recent genotyping data suggests a limited genetic diversity of P. jirovecii. The objective of the study was to assess the diversity of P. jirovecii across European hospitals and analyse P. jirovecii diversity in respect to clinical data obtained from the patients. Genotyping was performed using six already validated short tandem repeat (STR) markers on 249 samples (median: 17 per centre interquartile range [11-20]) from PCP patients of 16 European centres. Mixtures of STR markers (i.e., ≥2 alleles for ≥1 locus) were detected in 67.6% (interquartile range [61.4; 76.5]) of the samples. Mixture was significantly associated with the underlying disease of the patient, with an increased proportion in HIV patients (78.3%) and a decreased proportion in renal transplant recipients (33.3%) (p<0.001). The distribution of the alleles was significantly different (p<0.001) according to the centres in three out of six markers. In analysable samples, 201 combinations were observed corresponding to 137 genotypes: 116 genotypes were country-specific; 12 in two; six in three; and two in four and one in five countries. Nine genotypes were recorded more than once in a given country. Genotype 123 (Gt123) was significantly associated with France (14/15, p<0.001) and Gt16 with Belgium (5/5, p<0.001). More specifically, Gt123 was observed mainly in France (14/15/16 patients) and in renal transplant patient (13/15). Our study showed the wide population diversity across Europe, with evidence of local clusters of patients harbouring a given genotype. These data suggest a specific association between genotype and underlying disease, with evidence of a different natural history of PCP in HIV patients and renal transplant recipients.

CIBER de Epidemiología y Salud Pública Instituto de Biomedicina de Sevilla Hospital Universitario Virgen del Rocío CSIC Universidad de Sevilla Spain

Department of Biology and Medical Parasitology Wroclaw Medical University Wroclaw Poland

Department of Clinical Sciences and Translational Medicine University of Rome Tor Vergata Italy

Department of Infectious Diseases Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department of Internal Medicine Hematology and Oncology University Hospital Brno Brno Czech Republic

Department of medical microbiology Radboud University Medical Centre Nijmegen The Netherlands

Department of Microbiology and Immunology Catholic University Leuven Leuven Belgium and National Reference Centre for Mycosis Department of Laboratory Medicine University Hospitals Leuven Leuven Belgium

Hospices Civils de Lyon Institut des Agents Infectieux Parasitologie Mycologie Hôpital de la Croix Rousse Integrative Physiology of the Brain Arousal Systems Centre de Recherche en Neurosciences de Lyon INSERM U1028 CNRS UMR 5292 Faculté de Médecine Université Claude Bernard Lyon 1 Lyon F 69000 France

Institut Pasteur CNRS Unité de Mycologie Moléculaire Centre National de Référence Mycoses Invasives et Antifongiques URA3012 Paris France

Institute for Medical Microbiology Immunology and Hygiene University Hospital Cologne Germany

Institute of Microbiology Lausanne University Hospital University of Lausanne Lausanne Switzerland

Instituto de Higiene e Medicina Tropical Universidade NOVA de Lisboa Lisboa Portugal

Laboratoire de Parasitologie Mycologie AP HP Groupe Hospitalier Saint Louis Lariboisière Fernand Widal Paris France

Parasitology and Mycology laboratory Nantes University Hospital Nantes France

Public Health Wales Microbiology Cardiff UHW Heath Park Cardiff UK

TB HIV and Opportunistic Diseases and Pathogens Global Health and Tropical Medicine Lisboa Portugal

Université Paris Diderot Sorbonne Paris Cité Paris France

University of Brest GEIHP EA 3142 Laboratory of Parasitology and Mycology Brest University Hospital Brest France

University of Picardy Jules Verne EA 4285 UMR 1 01 INERIS Department of Parasitology and Mycology Amiens University Hospital Amiens France

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$a Alanio, Alexandre $u Laboratoire de Parasitologie-Mycologie, AP-HP, Groupe Hospitalier Saint-Louis-Lariboisière-Fernand-Widal, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Institut Pasteur, CNRS, Unité de Mycologie Moléculaire, Centre National de Référence Mycoses Invasives et Antifongiques, URA3012, Paris, France. Electronic address: alexandre.alanio@aphp.fr.

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$a Diversity of Pneumocystis jirovecii Across Europe: A Multicentre Observational Study / $c A. Alanio, M. Gits-Muselli, N. Guigue, M. Desnos-Ollivier, EJ. Calderon, D. Di Cave, D. Dupont, A. Hamprecht, PM. Hauser, J. Helweg-Larsen, M. Kicia, K. Lagrou, M. Lengerova, O. Matos, WJG. Melchers, F. Morio, G. Nevez, A. Totet, LP. White, S. Bretagne,

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$a Pneumocystis jirovecii is an airborne human-specific ascomycetous fungus responsible for Pneumocystis pneumonia (PCP) in immunocompromised patients, affecting >500,000 patients per year (www.gaffi.org). The understanding of its epidemiology is limited by the lack of standardised culture. Recent genotyping data suggests a limited genetic diversity of P. jirovecii. The objective of the study was to assess the diversity of P. jirovecii across European hospitals and analyse P. jirovecii diversity in respect to clinical data obtained from the patients. Genotyping was performed using six already validated short tandem repeat (STR) markers on 249 samples (median: 17 per centre interquartile range [11-20]) from PCP patients of 16 European centres. Mixtures of STR markers (i.e., ≥2 alleles for ≥1 locus) were detected in 67.6% (interquartile range [61.4; 76.5]) of the samples. Mixture was significantly associated with the underlying disease of the patient, with an increased proportion in HIV patients (78.3%) and a decreased proportion in renal transplant recipients (33.3%) (p<0.001). The distribution of the alleles was significantly different (p<0.001) according to the centres in three out of six markers. In analysable samples, 201 combinations were observed corresponding to 137 genotypes: 116 genotypes were country-specific; 12 in two; six in three; and two in four and one in five countries. Nine genotypes were recorded more than once in a given country. Genotype 123 (Gt123) was significantly associated with France (14/15, p<0.001) and Gt16 with Belgium (5/5, p<0.001). More specifically, Gt123 was observed mainly in France (14/15/16 patients) and in renal transplant patient (13/15). Our study showed the wide population diversity across Europe, with evidence of local clusters of patients harbouring a given genotype. These data suggest a specific association between genotype and underlying disease, with evidence of a different natural history of PCP in HIV patients and renal transplant recipients.

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