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      Global Variability in Reported Mortality for Critical Illness during the 2009-10 Influenza A(H1N1) Pandemic: A Systematic Review and Meta-Regression to Guide Reporting of Outcomes during Disease Outbreaks

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          Abstract

          Purpose

          To determine how patient, healthcare system and study-specific factors influence reported mortality associated with critical illness during the 2009–2010 Influenza A (H1N1) pandemic.

          Methods

          Systematic review with meta-regression of studies reporting on mortality associated with critical illness during the 2009–2010 Influenza A (H1N1) pandemic.

          Data Sources

          Medline, Embase, LiLACs and African Index Medicus to June 2009-March 2016.

          Results

          226 studies from 50 countries met our inclusion criteria. Mortality associated with H1N1-related critical illness was 31% (95% CI 28–34). Reported mortality was highest in South Asia (61% [95% CI 50–71]) and Sub-Saharan Africa (53% [95% CI 29–75]), in comparison to Western Europe (25% [95% CI 22–30]), North America (25% [95% CI 22–27]) and Australia (15% [95% CI 13–18]) (P<0.0001). High income economies had significantly lower reported mortality compared to upper middle income economies and lower middle income economies respectively (P<0.0001). Mortality for the first wave was non-significantly higher than wave two (P = 0.66). There was substantial variability in reported mortality among the specific subgroups of patients: unselected critically ill adults (27% [95% CI 24–30]), acute respiratory distress syndrome (37% [95% CI 32–44]), acute kidney injury (44% [95% CI 26–64]), and critically ill pregnant patients (10% [95% CI 5–19]).

          Conclusion

          Reported mortality for outbreaks and pandemics may vary substantially depending upon selected patient characteristics, the number of patients described, and the region and economic status of the outbreak location. Outcomes from a relatively small number of patients from specific regions may lead to biased estimates of outcomes on a global scale.

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          Most cited references12

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          Newcastle-Ottawa Scale: comparing reviewers’ to authors’ assessments

          Background Lack of appropriate reporting of methodological details has previously been shown to distort risk of bias assessments in randomized controlled trials. The same might be true for observational studies. The goal of this study was to compare the Newcastle-Ottawa Scale (NOS) assessment for risk of bias between reviewers and authors of cohort studies included in a published systematic review on risk factors for severe outcomes in patients infected with influenza. Methods Cohort studies included in the systematic review and published between 2008–2011 were included. The corresponding or first authors completed a survey covering all NOS items. Results were compared with the NOS assessment applied by reviewers of the systematic review. Inter-rater reliability was calculated using kappa (K) statistics. Results Authors of 65/182 (36%) studies completed the survey. The overall NOS score was significantly higher (p < 0.001) in the reviewers’ assessment (median = 6; interquartile range [IQR] 6–6) compared with those by authors (median = 5, IQR 4–6). Inter-rater reliability by item ranged from slight (K = 0.15, 95% confidence interval [CI] = −0.19, 0.48) to poor (K = −0.06, 95% CI = −0.22, 0.10). Reliability for the overall score was poor (K = −0.004, 95% CI = −0.11, 0.11). Conclusions Differences in assessment and low agreement between reviewers and authors suggest the need to contact authors for information not published in studies when applying the NOS in systematic reviews.
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            Extracorporeal Membrane Oxygenation for 2009 Influenza A(H1N1) Acute Respiratory Distress Syndrome.

            The novel influenza A(H1N1) pandemic affected Australia and New Zealand during the 2009 southern hemisphere winter. It caused an epidemic of critical illness and some patients developed severe acute respiratory distress syndrome (ARDS) and were treated with extracorporeal membrane oxygenation (ECMO). To describe the characteristics of all patients with 2009 influenza A(H1N1)-associated ARDS treated with ECMO and to report incidence, resource utilization, and patient outcomes. An observational study of all patients (n = 68) with 2009 influenza A(H1N1)-associated ARDS treated with ECMO in 15 intensive care units (ICUs) in Australia and New Zealand between June 1 and August 31, 2009. Incidence, clinical features, degree of pulmonary dysfunction, technical characteristics, duration of ECMO, complications, and survival. Sixty-eight patients with severe influenza-associated ARDS were treated with ECMO, of whom 61 had either confirmed 2009 influenza A(H1N1) (n = 53) or influenza A not subtyped (n = 8), representing an incidence rate of 2.6 ECMO cases per million population. An additional 133 patients with influenza A received mechanical ventilation but no ECMO in the same ICUs. The 68 patients who received ECMO had a median (interquartile range [IQR]) age of 34.4 (26.6-43.1) years and 34 patients (50%) were men. Before ECMO, patients had severe respiratory failure despite advanced mechanical ventilatory support with a median (IQR) Pao(2)/fraction of inspired oxygen (Fio(2)) ratio of 56 (48-63), positive end-expiratory pressure of 18 (15-20) cm H(2)O, and an acute lung injury score of 3.8 (3.5-4.0). The median (IQR) duration of ECMO support was 10 (7-15) days. At the time of reporting, 48 of the 68 patients (71%; 95% confidence interval [CI], 60%-82%) had survived to ICU discharge, of whom 32 had survived to hospital discharge and 16 remained as hospital inpatients. Fourteen patients (21%; 95% CI, 11%-30%) had died and 6 remained in the ICU, 2 of whom were still receiving ECMO. During June to August 2009 in Australia and New Zealand, the ICUs at regional referral centers provided mechanical ventilation for many patients with 2009 influenza A(H1N1)-associated respiratory failure, one-third of whom received ECMO. These ECMO-treated patients were often young adults with severe hypoxemia and had a 21% mortality rate at the end of the study period.
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              Critically Ill patients with 2009 influenza A(H1N1) in Mexico.

              In March 2009, novel 2009 influenza A(H1N1) was first reported in the southwestern United States and Mexico. The population and health care system in Mexico City experienced the first and greatest early burden of critical illness. To describe baseline characteristics, treatment, and outcomes of consecutive critically ill patients in Mexico hospitals that treated the majority of such patients with confirmed, probable, or suspected 2009 influenza A(H1N1). Observational study of 58 critically ill patients with 2009 influenza A(H1N1) at 6 hospitals between March 24 and June 1, 2009. Demographic data, symptoms, comorbid conditions, illness progression, treatments, and clinical outcomes were collected using a piloted case report form. The primary outcome measure was mortality. Secondary outcomes included rate of 2009 influenza (A)H1N1-related critical illness and mechanical ventilation as well as intensive care unit (ICU) and hospital length of stay. Critical illness occurred in 58 of 899 patients (6.5%) admitted to the hospital with confirmed, probable, or suspected 2009 influenza (A)H1N1. Patients were young (median, 44.0 [range, 10-83] years); all presented with fever and all but 1 with respiratory symptoms. Few patients had comorbid respiratory disorders, but 21 (36%) were obese. Time from hospital to ICU admission was short (median, 1 day [interquartile range {IQR}, 0-3 days]), and all patients but 2 received mechanical ventilation for severe acute respiratory distress syndrome and refractory hypoxemia (median day 1 ratio of Pao(2) to fraction of inspired oxygen, 83 [IQR, 59-145] mm Hg). By 60 days, 24 patients had died (41.4%; 95% confidence interval, 28.9%-55.0%). Patients who died had greater initial severity of illness, worse hypoxemia, higher creatine kinase levels, higher creatinine levels, and ongoing organ dysfunction. After adjusting for a reduced opportunity of patients dying early to receive neuraminidase inhibitors, neuraminidase inhibitor treatment (vs no treatment) was associated with improved survival (odds ratio, 8.5; 95% confidence interval, 1.2-62.8). Critical illness from 2009 influenza A(H1N1) in Mexico occurred in young individuals, was associated with severe acute respiratory distress syndrome and shock, and had a high case-fatality rate.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                12 May 2016
                2016
                : 11
                : 5
                : e0155044
                Affiliations
                [1 ]Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
                [2 ]Department of Critical Care, Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, United States of America
                [3 ]Trauma, Emergency and Critical Care Program, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
                [4 ]Interdepartmental Division of Critical Care and Department of Medicine, University of Toronto, Toronto, Ontario, Canada
                University of Hong Kong, HONG KONG
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: AD RP GR RF. Analyzed the data: AD RP RF. Wrote the paper: AD RP GR RF.

                Author information
                http://orcid.org/0000-0003-4220-2359
                Article
                PONE-D-16-02902
                10.1371/journal.pone.0155044
                4865181
                27170999
                74351b78-8b20-4714-b7af-57b4aacf86ad
                © 2016 Duggal et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 January 2016
                : 22 April 2016
                Page count
                Figures: 4, Tables: 3, Pages: 14
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100004411, Heart and Stroke Foundation of Canada;
                Award Recipient :
                This work was supported by a personnel award from the Heart and Stroke Foundation, Ontario Provincial Office for Dr. Robert A. Fowler.
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