Abstract
BackgroundStudying cytokine/chemokine responses in severe influenza infections caused by different virus subtypes may improve understanding on pathogenesis.MethodsAdults hospitalized for laboratory-confirmed seasonal and pandemic 2009 A/H1N1 (pH1N1) influenza were studied. Plasma concentrations of 13 cytokines/chemokines were measured at presentation and then serially, using cytometric-bead-array with flow-cytometry and ELISA. PBMCs from influenza patients were studied for cytokine/chemokine expression using ex-vivo culture (Whole Blood Assay,±PHA/LPS stimulation). Clinical variables were prospectively recorded and analyzed.Results63 pH1N1 and 53 seasonal influenza patients were studied. pH1N1 patients were younger (mean±S.D. 42.8±19.2 vs 70.5±16.7 years), and fewer had comorbidities. Respiratory/cardiovascular complications were common in both groups (71.4% vs 81.1%), although severe pneumonia with hypoxemia (54.0% vs 28.3%) and ICU admissions (25.4% vs 1.9%) were more frequent with pH1N1. Hyperactivation of the proinflammatory cytokines IL-6, CXCL8/IL-8, CCL2/MCP-1 and sTNFR-1 was found in pH1N1 pneumonia (2–15 times normal) and in complicated seasonal influenza, but not in milder pH1N1 infections. The adaptive-immunity (Th1/Th17)-related CXCL10/IP-10, CXCL9/MIG and IL-17A however, were markedly suppressed in severe pH1N1 pneumonia (2–27 times lower than seasonal influenza; P−values<0.01). This pattern was further confirmed with serial measurements. Hypercytokinemia tended to be sustained in pH1N1 pneumonia, associated with a slower viral clearance [PCR-negativity: day 3–4, 55% vs 85%; day 6–7, 67% vs 100%]. Elevated proinflammatory cytokines, particularly IL-6, predicted ICU admission (adjusted OR 12.6, 95%CI 2.6–61.5, per log10unit increase; P = 0.002), and correlated with fever, tachypnoea, deoxygenation, and length-of-stay (Spearman's rho, P-values<0.01) in influenza infections. PBMCs in seasonal influenza patients were activated and expressed cytokines ex vivo (e.g. IL-6, CXCL8/IL-8, CCL2/MCP-1, CXCL10/IP-10, CXCL9/MIG); their ‘responsiveness’ to stimuli was shown to change dynamically during the illness course.ConclusionsA hyperactivated proinflammatory, but suppressed adaptive-immunity (Th1/Th17)-related cytokine response pattern was found in severe pH1N1 pneumonia, different from seasonal influenza. Cytokine/immune-dysregulation may be important in its pathogenesis.
Highlights
Seasonal influenza affects 5–10% of the world’s population annually, causing 3–5 million severe infections and 250,000– 500,000 deaths [1]
The diagnosis was established by immunofluorescence assay [7]; for pandemic A/H1N1 (pH1N1) influenza, the diagnosis was established by a specific RTPCR assay [8]; virus isolation was performed in parallel in all cases for confirmation
Gender distribution was not different. Both cohorts were hospitalized for severe, complicated influenza diseases: respiratory/cardiovascular complications 71.4% vs 81.1%, p = 0.224; oxygen desaturation 55.6% vs 49.1%, p = 0.485; radiographic evidence of pneumonia 57.1% vs 41.5%, p = 0.093
Summary
Seasonal influenza affects 5–10% of the world’s population annually, causing 3–5 million severe infections and 250,000– 500,000 deaths [1]. Severe progressive influenza diseases occur in patients who are of advanced age and have pre-existing, immunocompromising conditions. In early 2009, a novel influenza A/H1N1 virus (pH1N1) emerged and rapidly caused a pandemic [1,2,3,4]. The pH1N1 virus has continued to co-circulate with the seasonal influenza viruses in the community [1,3]. In contrast to seasonal influenza, young adults and previously healthy individuals may develop severe diseases [2,4,5,6]. Studying cytokine/chemokine responses in severe influenza infections caused by different virus subtypes may improve understanding on pathogenesis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
