Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency

Hernandez, Nicholas; Melki, Isabelle; Jing, Huie; Habib, Tanwir; Huang, Susie S.Y.; Danielson, Jeffrey; Kula, Tomasz; Drutman, Scott; Belkaya, Serkan; Rattina, Vimel; Lorenzo-Diaz, Lazaro; Boulai, Anais; Rose, Yoann; Kitabayashi, Naoki; Rodero, Mathieu P.; Dumaine, Cecile; Blanche, Stéphane; Lebras, Marie-Noëlle; Leung, Man Chun; Mathew, Lisa Sara; Boisson, Bertrand; Zhang, Shen-Ying; Boisson-Dupuis, Stephanie; Giliani, Silvia; Chaussabel, Damien; Notarangelo, Luigi D.; Elledge, Stephen J.; Ciancanelli, Michael J.; Abel, Laurent; Zhang, Qian; Marr, Nico; Crow, Yanick J.; Su, Helen C.; Casanova, Jean-Laurent

Influenza virus is a common pathogen in children. It typically causes self-limiting respiratory disease, but can also cause severe illness with pneumonia and acute respiratory distress syndrome (ARDS; Short et al., 2014) . Virus strain differences can influence the frequency and severity of infections, as illustrated by seasonal epidemics and pandemics caused by new recombinant influenza viruses, but do not explain inter-individual variability in a given population infected by the same virus Morens, 2006, 2008 ; Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza et al., 2010) . Few human risk factors have been identified and consist mostly of acquired comorbidities, such as chronic pulmonary or cardiovascular disease and old age (Palese and Shaw, 2007; Shieh et al., 2010; Dawood et al., 2011) . Thus, the pathogenesis of life-threatening pulmonary influenza in individuals without preexisting cardiac or pulmonary disease remains largely unexplained, especially in children (Centers for Disease Control and Prevention, 2013) . Recently, we described autosomal recessive (AR), complete IRF7 deficiency as the first genetic etiology for life-threatening influenza ARDS in otherwise healthy humans . The lack of IRF7-dependent type I and type III IFN amplification by plasmacytoid dendritic cells (pDCs) or pulmonary epithelial cells, or both, probably underlies this patient's susceptibility to influenza. GATA2 haploinsufficiency is the only other known inborn error of immunity underlying severe influenza, albeit in patients with multiple infections.