Host immunological response and factors associated with clinical outcome in patients with the novel influenza A H7N9 infection

Abstract

In March 2013, an influenza outbreak caused by the novel avian-origin H7N9 influenza A virus emerged in eastern China and had caused 43 fatalities by 31 July 2013, although the basis for disease pathogenesis still remains unclear. To assess the immunological and viral factors associated with disease severity, viral RNA and inflammatory cytokines were quantified for 18 H7N9 patients in Shanghai, China. Detailed clinical information was collected and clinical laboratory investigations were performed for all patients. H7N9 infection is characterized by high pharyngeal virus load and frequent detection of viral RNA in blood. High pharyngeal virus load persisted through the first 10 days of antiviral therapy in fatal cases. Genetic characterization of the H7N9 virus revealed an Arg292Lys mutation in the neuraminidase gene associated with oseltamivir-resistance. Pronounced lymphopenia and high chemokine and cytokine levels were observed in H7N9-infected patients, particularly in those where disease was fatal. Serum levels of interleukin-6 (IL-6), IL-8 and macrophage inflammatory protein-1β in our subjects also correlated positively with pharyngeal virus load. Lymphocyte counts <0.5 × 10(9) cells/L, and serum IL-6 >97 pg/mL, IL-8 >40 pg/mL and C-reactive protein >90 mg/L were identified as being connected with adverse clinical outcome through univariate logistic analysis. Significant survival differences were also observed between patients with serum C-reactive protein <90 mg/L or creatinine <90 μmol/L and those with higher levels. Our data demonstrated that high viral load, and the resulting intense inflammatory responses, played an important role in H7N9 pathogenesis. Though immunomodulatory treatment has potential benefits, the focus of clinical management should be on preventing the intense cytokine response by early diagnosis and effective antiviral treatment.

Enhanced natural killer-cell and T-cell responses to influenza A virus during pregnancy

“…Mice deficient in MIP-1α, another CC chemokine with similar functional properties to MIP-1β, have less influenza-induced pneumonitis despite delayed viral clearance (41). In humans, MIP-1β levels correlate with severity of influenza symptoms and viral replication, and rise with similar kinetics after influenza infection with other CC chemokines (42,43). In pregnant women, IFN-α and IFN-λ production are decreased compared with controls when PBMCs are cocultured with influenza (21,22).…”

A(H7N9) Virus Results in Early Induction of Proinflammatory Cytokine Responses in both Human Lung Epithelial and Endothelial Cells and Shows Increased Human Adaptation Compared with Avian H5N1 Virus

“…Similar to H5N1, A(H7N9) viruses are capable of efficient replication in human bronchus and lung tissues and are detected at high titers throughout the respiratory tracts of experimentally infected mammalian models (9)(10)(11)(12). Furthermore, hypercytokinemia has been reported among severe and fatal cases with both H5N1 and A(H7N9) viruses (13)(14)(15).…”

Cytokines and chemokines in mild/asymptomatic cases infected with avian influenza A (H7N9) virus

“…Earlier studies showed that IP-10, IL-6, IL-8, IL-10, MCP-1, MIG and MIP-1b were dramatically increased in severe H7N9 cases and H5N1 cases compared to controls (Peiris et al, 2004;de Jong et al, 2006;Chi et al, 2013;Zhou et al, 2013;Shen et al, 2014;Wang et al, 2014b;Wu et al, 2014). However, these cytokines in mild/asymptomatic H7N9 cases were similar to those in controls except that the level of IP-10 increased very slightly.…”

“…Previous studies with highly pathogenic avian influenza A (H5N1) virus as well as pandemic (H1N1) 2009 virus suggested that poor prognosis in humans with these viruses might be attributed to a cytokine storm or hypercytokinaemia in the host (Peiris et al, 2004;de Jong et al, 2006;To et al, 2010). Some studies with H7N9 virus also showed the presence of high levels of a series of cytokines and chemokines, such as IP-10, IL-6, IL-8, IL-10, MCP-1, MIG and MIP-1b, in human infections with severe disease with or without fatal outcomes (Chi et al, 2013;Zhou et al, 2013;Shen et al, 2014;Wang et al, 2014b;Wu et al, 2014). It should be noted that investigation on the profiles of cytokines and chemokines induced in mild/asymptomatic cases will aid in assessing their role in mild/asymptomatic versus severe/fatal outcomes of infection with H7N9 and the role of innate immunity and provides a new perspective on the evaluation of prognosis and the innovation of treatment.…”