AUTHOR=Levy Emily R. , Yip Wai-Ki , Super Michael , Ferdinands Jill M. , Mistry Anushay J. , Newhams Margaret M. , Zhang Yu , Su Helen C. , McLaughlin Gwenn E. , Sapru Anil , Loftis Laura L. , Weiss Scott L. , Hall Mark W. , Cvijanovich Natalie , Schwarz Adam , Tarquinio Keiko M. , Mourani Peter M. ,  PALISI PICFLU Investigators , Randolph Adrienne G. 

TITLE=Evaluation of Mannose Binding Lectin Gene Variants in Pediatric Influenza Virus-Related Critical Illness

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01005

DOI=10.3389/fimmu.2019.01005

ISSN=1664-3224

ABSTRACT=<p><bold>Background:</bold> Mannose-binding lectin (MBL) is an innate immune protein with strong biologic plausibility for protecting against influenza virus-related sepsis and bacterial co-infection. In an autopsy cohort of 105 influenza-infected young people, carriage of the deleterious MBL gene <italic>MBL2</italic>_Gly54Asp(“B”) mutation was identified in 5 of 8 individuals that died from influenza-methicillin-resistant <italic>Staphylococcus aureus</italic> (MRSA) co-infection. We evaluated <italic>MBL2</italic> variants known to influence MBL levels with pediatric influenza-related critical illness susceptibility and/or severity including with bacterial co-infections.</p><p><bold>Methods:</bold> We enrolled children and adolescents with laboratory-confirmed influenza infection across 38 pediatric intensive care units from November 2008 to June 2016. We sequenced <italic>MBL2</italic> “low-producer” variants rs11003125(“H/L”), rs7096206(“Y/X”), rs1800450<sub>Gly54Asp</sub>(“B”), rs1800451<sub>Gly57Glu</sub>(“C”), rs5030737<sub>Arg52Cys</sub>(“D”) in patients and biologic parents. We measured serum levels and compared complement activity in low-producing homozygotes (“B/B,” “C/C”) to HYA/HYA controls. We used a population control of 1,142 healthy children and also analyzed family trios (PBAT/HBAT) to evaluate disease susceptibility, and nested case-control analyses to evaluate severity.</p><p><bold>Results:</bold> We genotyped 420 patients with confirmed influenza-related sepsis: 159 (38%) had acute lung injury (ALI), 165 (39%) septic shock, and 30 (7%) died. Although bacterial co-infection was diagnosed in 133 patients (32%), only MRSA co-infection (<italic>n</italic> = 33, 8% overall) was associated with death (<italic>p</italic> &lt; 0.0001), present in 11 of 30 children that died (37%). <italic>MBL2</italic> variants predicted serum levels and complement activation as expected. We found no association between influenza-related critical illness susceptibility and <italic>MBL2</italic> variants using family trios (633 biologic parents) or compared to population controls. <italic>MBL2</italic> variants were not associated with admission illness severity, septic shock, ALI, or bacterial co-infection diagnosis. Carriage of low-MBL producing <italic>MBL2</italic> variants was not a risk factor for mortality, but children that died did have higher carriage of one or more B alleles (OR 2.3; <italic>p</italic> = 0.007), including 7 of 11 with influenza MRSA-related death (vs. 2 of 22 survivors: OR 14.5, <italic>p</italic> = 0.0002).</p><p><bold>Conclusions:</bold><italic>MBL2</italic> variants that decrease MBL levels were not associated with susceptibility to pediatric influenza-related critical illness or with multiple measures of critical illness severity. We confirmed a prior report of higher B allele carriage in a relatively small number of young individuals with influenza-MRSA associated death.</p>