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

Abstract

Background: 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 MBL2 _Gly54Asp(“B”) mutation was identified in 5 of 8 individuals that died from influenza-methicillin-resistant Staphylococcus aureus (MRSA) co-infection. We evaluated MBL2 variants known to influence MBL levels with pediatric influenza-related critical illness susceptibility and/or severity including with bacterial co-infections. Methods: We enrolled children and adolescents with laboratory-confirmed influenza infection across 38 pediatric intensive care units from November 2008 to June 2016. We sequenced MBL2 “low-producer” variants rs11003125(“H/L”), rs7096206(“Y/X”), rs1800450 Gly54Asp (“B”), rs1800451 Gly57Glu (“C”), rs5030737 Arg52Cys (“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. Results: 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 ( n = 33, 8% overall) was associated with death ( p < 0.0001), present in 11 of 30 children that died (37%). MBL2 variants predicted serum levels and complement activation as expected. We found no association between influenza-related critical illness susceptibility and MBL2 variants using family trios (633 biologic parents) or compared to population controls. MBL2 variants were not associated with admission illness severity, septic shock, ALI, or bacterial co-infection diagnosis. Carriage of low-MBL producing MBL2 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; p = 0.007), including 7 of 11 with influenza MRSA-related death (vs. 2 of 22 survivors: OR 14.5, p = 0.0002). Conclusions: MBL2 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 asso...

Pathobiology, Severity, and Risk Stratification of Pediatric Acute Respiratory Distress Syndrome: From the Second Pediatric Acute Lung Injury Consensus Conference

“…ARDS pathobiology is characterized by inflammation, loss of the alveolar epithelial, and lung vascular endothelial permeability barriers, dysregulated coagulation, and fibrosis. Recent advances related to individual and combinations of plasma biomarkers indicative of many of these aspects of PARDS pathobiology and studies aimed at identifying subphenotypes at greater risk of worse clinical outcome and/or response to therapy are described in the sections below (5, 22, 45, 49, 70, 96–139). Subphenotype identification offers enhanced prognostic ability beyond what bedside physiologic biomarkers and/or PARDS trigger (e.g., pneumonia, sepsis, trauma, etc.)…”

“…As a consequence, interpretation of genetic association studies for PARDS must be considered with this limitation in mind. In the last 10 years, studies have shown no association of specific variants in IL-1 receptor antagonist (116), IL-8 (119), caspase-12 (97), mannose-binding lectin (98), and interferon-induced transmembrane protein 3 (49) with PARDS. A study of children with pneumonia suggests that polymorphisms in the splicing factor CUGBP, Elav-like family member 2 that regulates splicing of cystic fibrosis transmembrane conductance regulator may be associated with increased risk for PARDS (100).…”

Mannose-Binding Lectin in Human Health and Disease

“…Studies have shown MBL’s protection also in vivo and it has been suggested that MBL deficiency may be a risk factor for influenza A virus infection (Chang et al 2010 ). Nevertheless, in a recent report where 420 patients with confirmed influenza-critical illness were studied, MBL deficiency was not found to be a risk factor for very severe influenza infection in children and adolescents (Levy et al 2019 ) (Table 1 ).…”

“…Children (<2 years) with MBL deficiency are in higher risk for PM Bautista-Rodriguez et al ( 2017 ) Bacterial infection Pneumonococcal infection MBL does not drive lectin pathway activation on the surface of S. pneumoniae Ali et al ( 2012 ) Respiratory Tract Infection Pneumonococcal disease Low MBL production could be associated with IPD in children <2 years Muñoz-Almagro et al ( 2014 ) Viral infection Influenza A viral infection In vivo studies on mice about protection of MBL from IAV infection. Suggesting MBL deficiency as a risk factor for IAV infection Chang et al ( 2010 ) Viral infection Influenza virus-related critical illness MBL deficiency is not a risk factor for severe influenza infection in children and young adults Levy et al ( 2019 ) Viral infection HIV There is an association between undetectable serum MBL concentrations and susceptibility to HIV infection. But the course of HIV infection does not seem to be influenced by the level of MBL Nielsen et al ( 1995 ) Viral infection HIV Homozygous carriers of MBL alleles are at increased risk of HIV infection Garred et al ( 1997 ) Autoimmune diseases Systemic lupus erythematosus Increased frequency of MBL allele (codon 54) in patients with SLE, but it represents a minor risk factor for this disease.…”

“…Study in Indian females Panda et al ( 2013 ) Autoimmune diseases Systemic lupus erythematosus A tendency of higher frequency of the B allele was observed in Spanish patients with SLE Losada López et al ( 2016 ) Autoimmune diseases CVD and SLE MBL variant alleles are associated with an increased risk of arterial thrombosis. Study in Danish patients with SLE Øhlenschlæger et al ( 2004 ) Autoimmune diseases CVD and SLE MBL deficiency is not determinant of CVD in SLE patients, independent of other risk factors Kieninger-Gräfitsch et al ( 2020 ) Virus infection Influenza MBL doesn’t increase susceptibility to severe influenza infection in pediatric patients Levy et al ( 2019 ) Bacterial infection Pulmonary tuberculosis MBL-2 gene polymorphisms may be involved in the pathogenesis of PTB (pulmonary tuberculosis) and serum may be a biomarker for the diagnosis of PTB Tong et al ( 2019 ) Autoimmune diseases RA MBL2 polymorphisms at codon 52, 54 and 57, as well as at promoter position −220, were not associated with increased risk to RA. (Meta-analysis) Epp Boschmann et al ( 2016 ) Neonatal sepsis MBL is protective toward the development of neonatal sepsis and low MBL levels at birth are associated with an increased risk of hospital-acquired sepsis in infants De Benedetti et al ( 2007 ) Neonatal sepsis Low MBL levels were not associated neither with gestational age or sepsis in infants Hartz et al ( 2018 ) Sepsis MBL2 exon polymorphisms with low serum levels of MBL increase the risk of sepsis infection and septic shock in pediatric patients Fidler et al ( 2004 ) Neonatal sepsis MBL levels below 400 ng/mL increase the chances of developing sepsis Dzwonek et al ( 2008 ) Neonatal sepsis No major impact on sepsis risk unless in infants between 32–36 gestational age Hartz et al ( ...…”