Worcester Refugee Assistance Project: An Example of Strengths-Based, Community-Based, Culturally Sensitive Care.

Refugee populations are diverse and can present with a variety of unique and complex circumstances. The purpose of this article is to examine an organization that provides care to refugee youth, the ways in which this is accomplished, and a few of the challenges that have been faced. Specifically, the work of this organization will be examined using a Systems of Care philosophy to demonstrate how using these concepts can assist in providing sensitive, high-quality care.

RIG-I and TLR4 responses and adverse outcomes in pediatric influenza-related critical illness.

BACKGROUND: Decreased TNF-α production in whole blood after ex vivo LPS stimulation indicates suppression of the Toll-like receptor (TLR)4 pathway. This is associated with increased mortality in pediatric influenza critical illness. Whether antiviral immune signaling pathways are also suppressed in these patients is unclear. OBJECTIVES: We sought to evaluate suppression of the TLR4 and the antiviral retinoic acid-inducible gene-I (RIG-I) pathways with clinical outcomes in children with severe influenza infection. METHODS: In this 24-center, prospective, observational cohort study of children with confirmed influenza infection, blood was collected within 72 hours of intensive care unit admission. Ex vivo whole blood stimulations were performed with matched controls using the viral ligand polyinosinic-polycytidylic acid-low-molecular-weight/LyoVec and LPS to evaluate IFN-α and TNF-α production capacities (RIG-I and TLR4 pathways, respectively). RESULTS: Suppression of either IFN-α or TNF-α production capacity was associated with longer duration of mechanical ventilation and hospitalization, and increased organ dysfunction. Children with suppression of both RIG-I and TLR4 pathways (n = 33 of 103 [32%]) were more likely to have prolonged (≥7 days) multiple-organ dysfunction syndrome (30.3% vs 8.6%; P = .004) or prolonged hypoxemic respiratory failure (39.4% vs 11.4%; P = .001) compared with those with single- or no pathway suppression. CONCLUSIONS: Suppression of both RIG-I and TLR4 signaling pathways, essential for respective antiviral and antibacterial responses, is common in previously immunocompetent children with influenza-related critical illness and is associated with bacterial coinfection and adverse outcomes. Prospective testing of both pathways may aid in risk-stratification and in immune monitoring.

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

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"), rs1800450Gly54Asp("B"), rs1800451Gly57Glu("C"), rs5030737Arg52Cys("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 associated death.

Cytokine Profiles of Severe Influenza Virus-Related Complications in Children.

RATIONALE: Effective immunomodulatory therapies for children with life-threatening "cytokine storm" triggered by acute influenza infection are lacking. Understanding the immune profiles of children progressing to severe lung injury and/or septic shock could provide insight into pathogenesis. OBJECTIVES: To compare the endotracheal and serum cytokine profiles of children with influenza-related critical illness and to identify their associations with severe influenza-associated complications. METHODS: Children with influenza-related critical illness were enrolled across 32 hospitals in development (N = 171) and validation (N = 73) cohorts (December 2008 through May 2016). Concentrations of 42 cytokines were measured in serum and endotracheal samples and clustered into modules of covarying cytokines. Relative concentrations of cytokines and cytokine modules were tested for associations with acute lung injury (ALI), shock requiring vasopressors, and death/ECMO. MEASUREMENTS AND MAIN RESULTS: Modules of covarying cytokines were more significantly associated with disease severity than individual cytokines. In the development cohort, increased levels of a serum module containing IL6, IL8, IL10, IP10, GCSF, MCP1, and MIP1α [shock odds ratio (OR) = 3.37, family-wise error rate (FWER) p < 10-4], and decreased levels of a module containing EGF, FGF2, SCD40L, and PAI-1 (shock OR = 0.43, FWER p = 0.002), were both associated with ALI, shock, and death-ECMO independent of age and bacterial coinfection. Both of these associations were confirmed in the validation cohort. Endotracheal and serum cytokine associations differed markedly and were differentially associated with clinical outcomes. CONCLUSION: We identified strong positive and negative associations of cytokine modules with the most severe influenza-related complications in children, providing new insights into the pathogenesis of influenza-related critical illness in children. Effective therapies may need to target mediators of both inflammation and repair.