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

Significantly, our IRF9-deficient patient was not hospitalized in the ICU following infection with RSV or HRV, both of which were confirmed by serology and VirScan, indicating that IRF9 deficiency may not result in an extensive susceptibility to pulmonary viral infections. This contrasts with an MDA5-deficient child who was prone to severe, recurrent rhinovirus infections (Lamborn et al., 2017) , and other MDA5-mutated children who were prone to RSV and other severe viral infections of the respiratory tract but not influenza (Asgari et al., 2017; Zaki et al., 2017) . Human MDA5 and IRF9 thus seem to control different sets of respiratory viruses in vivo. Interestingly, IRF7 deficiency may also result in a narrow infectious phenotype, as the only reported case in humans was uniquely susceptible to influenza infection at last follow-up, aged 9 yr, and without any prophylaxis other than annual influenza vaccination unpublished data) . IRF9 deficiency results in a slightly broader infectious phenotype, including infection with influenza virus and likely an MMR vaccine-strain virus. The phenotype might have been broader if the patient had not been started on IgG i.v. at 2.5 yr of age. However, IRF9 deficiency is clinically closer to IRF7 deficiency when compared with GATA2 deficiency. Indeed, all known patients with the latter defect suffered from many other severe infections, including mycobacterial infections, papilloma virus infections, blastomycosis, and repeated viral infections of the respiratory tract (Collin et al., 2015) . Severe influenza was the presenting feature in only one patient, who quickly thereafter displayed other phenotypes, infectious and otherwise (Sologuren et al., 2018) . This broad infectious phenotype is consistent with the broad immunological phenotype of GATA2 deficiency, which is not restricted to a lack of development of type I and III IFN-producing pDCs. With the reservations listed above, it is striking that both IRF7 and IRF9 deficiency underlie such a narrow range of se-vere infections, almost limited to severe influenza pneumonitis. Significantly, only single cases of IRF7 and IRF9 deficiency have been reported thus far; further studies are needed to more comprehensively define the viral susceptibility resulting from these deficiencies, to determine to what extent IRF7-and IRF9-dependent type I and III IFN immunity is redundant for protective immunity against viral infections, and to suggest what other factors may compensate for deficiencies in this pathway.