Viral Clearance and Inflammatory Response Patterns in Adults Hospitalized for Pandemic 2009 Influenza A(H1N1) Virus Pneumonia

Lee, Nelson; Chan, Paul Kay Sheung; Wong, Chun Kwok; Wong, Kam-Fai; Choi, Kin Wing; Joynt, Gavin M.; Lam, Paul; Chan, Michael; Wong, Billy; Lui, Grace; Sin, Winnie W. Y.; Wong, Ricky W.K.; Lam, Wai Yip; Yeung, Albert T.; Leung, Ting‐Fan; So, H.; Yu, Alex W.; Sung, Joseph J.Y.; Hui, David S.

doi:10.3851/imp1722

Cited by 116 publications

(160 citation statements)

References 39 publications

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“…This early proinflammatory burst of cytokines is reminiscent of the hypercytokinemia observed in some animal models of severe infection and humans infected with A (H5N1) viruses (9,12,22). Previous studies focusing exclusively on hospitalized patients with influenza infection found positive associations between serum IL-6, IL-8, MCP-1, and IP-10 levels and clinical severity (10,11,13,23), whereas others showed no differences, possibly because of the restricted nature of their cohorts (24)(25)(26)(27). The association shown here was independent of existing immunity as determined by protective neutralization antibody titer.…”

Section: Discussionmentioning

confidence: 99%

Mucosal Immune Responses Predict Clinical Outcomes during Influenza Infection Independently of Age and Viral Load

Oshansky¹,

Gartland

Wong

et al. 2014

Am J Respir Crit Care Med

156

196

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Rationale: Children are an at-risk population for developing complications following influenza infection, but immunologic correlates of disease severity are not understood. We hypothesized that innate cellular immune responses at the site of infection would correlate with disease outcome.Objectives: To test the immunologic basis of severe illness during natural influenza virus infection of children and adults at the site of infection.Methods: An observational cohort study with longitudinal sampling of peripheral and mucosal sites in 84 naturally influenza-infected individuals, including infants. Cellular responses, viral loads, and cytokines were quantified from nasal lavages and blood, and correlated to clinical severity. Measurements and Main Results:We show for the first time that although viral loads in children and adults were similar, innate responses in the airways were stronger in children and varied considerably between plasma and site of infection. Adjusting for age and viral load, an innate immune profile characterized by increased nasal lavage monocyte chemotactic protein-3, IFN-a2, and plasma IL-10 levels at enrollment predicted progression to severe disease. Increased plasma IL-10, monocyte chemotactic protein-3, and IL-6 levels predicted hospitalization. This inflammatory cytokine production correlated significantly with monocyte localization from the blood to the site of infection, with conventional monocytes positively correlating with inflammation. Increased frequencies of CD14 lo monocytes were in the airways of participants with lower inflammatory cytokine levels.Conclusions: An innate profile was identified that correlated with disease progression independent of viral dynamics and age. The airways and blood displayed dramatically different immune profiles emphasizing the importance of cellular migration and localized immune phenotypes.

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Section: Discussionmentioning

confidence: 99%

Mucosal Immune Responses Predict Clinical Outcomes during Influenza Infection Independently of Age and Viral Load

Oshansky¹,

Gartland

Wong

et al. 2014

Am J Respir Crit Care Med

156

196

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“…The observation that the sensitivity of RIDTs tended to be lower in cases with pneumonia has serious clinical implications and should warrant further study. There are increasing reports of false-negative test results for upper respiratory samples in influenza patients who developed pneumonia (21), even with the use of PCR assays. Because of a relatively low level of viral shedding in the upper respiratory tract, obtaining a lower respiratory tract sample (e.g., sputum, tracheal aspirate, or bronchoalveolar lavage specimens) for testing is generally advisable (5,22).…”

Section: Discussionmentioning

confidence: 99%

Clinical and Virologic Factors Associated with Reduced Sensitivity of Rapid Influenza Diagnostic Tests in Hospitalized Elderly Patients and Young Children

et al. 2014

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Rapid influenza diagnostic tests (RIDTs) are commonly used by clinicians to guide patient management. Data on sensitivities among hospitalized patients are limited. Here, we evaluated the clinical and virologic factors affecting the sensitivities of 2 commercially available RIDTs (BinaxNOW Influenza A&B and QuickVue Influenza A؉B) on nasopharyngeal aspirate (NPA) specimens collected from elderly patients and young children hospitalized for influenza. Influenza cases and age-matched negative controls were prospectively enrolled during the 2011-2012 influenza season in Hong Kong. NPA specimens were collected at presentation before antiviral treatment. Real-time reverse transcription-PCR (RT-PCR) results were used as references for the sensitivity analyses. One hundred patients (57 influenza cases and 43 controls) were studied. Both RIDTs had 100% specificities. The sensitivities of the BinaxNOW Influenza A&B and QuickVue Influenza A؉B tests were 70% and 82%, respectively. For both tests, the sensitivities were lower in cases with presentation times beyond 2 days of illness onset than for those within this time (50 to 71% versus 85 to 91%, respectively). There were trends toward lower sensitivities for influenza B than for influenza A (66 to 81% versus 76 to 84%, respectively), among young children than among the elderly patients (63 to 78% versus 80 to 88%, respectively), and among cases with pneumonia than those without pneumonia (75% versus 82 to 94%, respectively). The sensitivities of the RIDTs decreased with reduced NPA viral RNA levels (5.6 to 15.0% reduction per 1-log decrease), which declined progressively after illness onset (Spearman's rho, ؊0.47 [P < 0.05] and ؊0.66 [P < 0.001] for influenza A and B, respectively). Collectively, late presentation, a low NPA viral load, and probably lower respiratory manifestation are factors associated with reduced sensitivities of RIDTs for diagnosing influenza in hospitalized patients. A negative RIDT result should be interpreted with caution.

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“…CXCL16 is produced by several cell types including dendritic cells (21), lymphocytes (56), vascular smooth muscle cells (52), bone marrow stromal cells (40), tumor cells (35,36), and cardiac tissue (58). SR-PSOX/CXCL16 expression in endothelial cells is upregulated by proinflammatory cytokines, such as TNF-␣ or IFN-␥ (1,25), known mediators of inflammation and ischemia (46,50).…”

Section: Discussionmentioning

confidence: 99%

Sphingomyelinase-induced adhesion of eryptotic erythrocytes to endothelial cells

Abed

Towhid

Mia

et al. 2012

American Journal of Physiology-Cell Physiology

141

101

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Eryptosis, the suicidal erythrocyte death, leads to cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the cell surface. Eryptotic erythrocytes adhere to the vascular wall by binding of phosphatidylserine to the CXC chemokine ligand 16 (CXCL16). Stimulators of eryptosis include increased cytosolic Ca 2ϩ activity, energy depletion, and activation of ceramide-producing sphingomyelinase. The present study explored whether sphingomyelinase triggers erythrocyte adhesion to endothelial cells. To this end, human erythrocytes were exposed for 6 h to bacterial sphingomyelinase (1-10 mU/ml) and phosphatidylserine exposure was estimated from fluorescent annexin-V-binding, cell volume from forward scatter in FACS-analysis, erythrocyte adhesion to human umbilical vein endothelial cells (HUVEC) from trapping of labeled erythrocytes in a flow chamber under flow conditions at arterial shear rates, and CXCL16 protein abundance utilizing Western blotting and FACS analysis of fluorescent antibody binding. As a result, sphingomyelinase (Ն1 mU/ml) triggered cell shrinkage, phosphatidylserine exposure and erythrocyte adhesion to HUVEC, effects blunted by Ca 2ϩ removal. Adhesion was significantly blunted by phosphatidylserine-coating annexin-V (5 l/ml), following addition of neutralizing antibodies against endothelial CXCL16 (4 g/ml) and following silencing of the CXCL16 gene with small interfering RNA. Pretreatment of HUVEC with sphingomyelinase upregulated CXCL16 protein abundance. Six hours pretreatment of HUVEC with sphingomyelinase (10 mU/ml) or C6-ceramide (50 M) augmented erythrocyte adhesion following a 30-min treatment with Ca 2ϩ ionophore ionomycin (1 M) or following energy depletion by 48-h glucose removal. Thus exposure to sphingomyelinase or C6-ceramide triggers eryptosis followed by phosphatidylserine-and CXCL16-sensitive adhesion of eryptotic erythrocytes to HUVEC.

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Viral Clearance and Inflammatory Response Patterns in Adults Hospitalized for Pandemic 2009 Influenza A(H1N1) Virus Pneumonia

Abstract: In severe 2009 H1N1 pneumonia, viral clearance is slow with treatment, particularly in the lower respiratory tract. A more sustained antiviral regime appears warranted.

Cited by 116 publications

References 39 publications

Mucosal Immune Responses Predict Clinical Outcomes during Influenza Infection Independently of Age and Viral Load

Mucosal Immune Responses Predict Clinical Outcomes during Influenza Infection Independently of Age and Viral Load

Clinical and Virologic Factors Associated with Reduced Sensitivity of Rapid Influenza Diagnostic Tests in Hospitalized Elderly Patients and Young Children

Sphingomyelinase-induced adhesion of eryptotic erythrocytes to endothelial cells

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