Int Health 2015; 7: 73–75 doi:10.1093/inthealth/ihu083 Advance Access publication 23 November 2014
SHORT COMMUNICATION
Prognostic factors for mortality in patients hospitalized with influenza complications, in Taiwan Wan-Ting Huanga,*, Chih-Hsi Changa, Yu-Fen Hsua and Jen-Hsiang Chuanga,b a
Taiwan Centers for Disease Control, Ministry of Health and Welfare, Taipei, Taiwan; bInstitute of Biomedical Informatics & Institute of Public Health, National Yang-Ming University, Taipei, Taiwan *Corresponding author: Tel: +886 2 2395 9825 ext 3180; E-mail: [email protected]
Background: This study aims to assess factors associated with fatal hospitalized influenza with complications in Taiwan. Methods: We identified reports of complications and illness onset in patients hospitalized with influenza between week 26, 2009 and week 25, 2012 from the National Notifiable Disease Surveillance System. We used a multivariate logistic regression model to evaluate covariates that can be associated with in-hospital mortality. Results: Among 4735 patients (413 deaths), age ≥50 years (p,0.001), male (p¼0.014), comorbidities (p,0.001), and delayed oseltamivir treatment (p,0.001) increased the likelihood of in-hospital mortality. Conclusions: We recommend influenza vaccination and early antiviral treatment for at-risk populations. Keywords: Case fatality rate, Influenza, Mortality determinant, Surveillance, Taiwan
Introduction Mortality or case fatality measures influenza severity and guides principles for allocating resources and targeting interventions to populations at risk.1 Identifying factors associated with mortality is critical in preparing for a potential influenza pandemic or annual seasonal influenza epidemics.1,2 In this study, we assessed characteristics that can be associated with mortality in patients hospitalized with influenza complications in Taiwan.
We used x2 tests to identify covariates associated with mortality, including age group (,50 or ≥50 years), sex (male or female), presence of high-risk medical conditions (yes or no), having received ≥1 dose of influenza vaccine before illness onset (yes or no), initiation of oseltamivir treatment ≤48 hours after illness onset (yes or no), and influenza PCR result (H1N1, H3N2, or B virus). Variables that differed between the nonfatal and fatal cases at p,0.05 were evaluated in the multivariate logistic regression models by using backward elimination procesures, retaining variables that were associated at p,0.10.
Materials and methods Cases of hospitalized influenza with complications are nationally notifiable in Taiwan.2 A confirmed case is defined as influenza-like illness and evidence of pneumonia, neurologic symptoms, myopericarditis or invasive bacterial infections, with a positive influenza real-time reverse transcription PCR. We identified confirmed reports from the National Notifiable Disease Surveillance System (NNDSS) in patients who had onset of illness from week 26, 2009 through week 25, 2012. Data were obtained for onset of illness, influenza PCR result, demographics, preexisting medical conditions that confer increased risk for influenza complications (Supplementary Box 1), influenza vaccination status (from self-reports or paper records), oseltamivir treatment and in-hospital mortality.
Results Of 4735 patients (413 deaths [8.7%]) who had confirmed hospitalized influenza with complications, median age was 50 years (IQR 24–69 years), and median length from illness onset to hospital discharge or mortality was 8 days (IQR 5–14 days). In multivariate analyses (Table 1), 264/2472 (10.7%) males and 187/2053 (9.1%) females were vaccinated against influenza; age ≥50 years (OR 2.05), male (OR 1.31), presence of high-risk medical conditions (OR 3.38), and delay of oseltamivir treatment (OR 2.40) was independently associated with mortality. Specifically, male (OR 1.65) and absence of influenza vaccination before illness onset (OR 2.70) increased the likelihood of mortality among
# The Author 2014. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: [email protected].
73
Downloaded from http://inthealth.oxfordjournals.org/ at University of North Dakota on May 31, 2015
Received 18 June 2014; revised 7 October 2014; accepted 7 October 2014
W.-T. Huang et al.
Table 1. Factors associated with mortality for influenza hospitalized patients with complicationsa Factor
Non-fatal n¼4126
Univariate OR
p-value
Multivariate ORc
p-value
292 107
2.61 ref
,0.001
2.05 ref
,0.001
246 153
1.34 ref
0.007
1.31 ref
0.014
304 95
3.41 ref
,0.001
3.38d ref
39 360
1.06 ref
NS
NA ref
201 198
1.87 ref
,0.001
2.40d ref
178 107 114
0.90 0.88 ref
NS NS
NA NA ref
,0.001
,0.001
NA: not applicable; NS: not significant. Data excluded 210 cases (14 deaths) for which low viral loads prevented further subtypings. b Defined as having received ≥1 dose of influenza vaccine before illness onset. c Adjusted for variables that were associated at p,0.05 by univariate analysis. d The two variables were independently associated with mortality, regardless of influenza test result. a
patients with H1N1 (Supplementary Table 1), but not H3N2 or B virus infection.
Discussion Our analyses suggest that age ≥50 years, male, comorbidities, and delayed oseltamivir treatment are associated with fatal hospitalized influenza; new among these risk factors is male gender. Because disease progression to mortality from onset can be rapid,3,4 those at-risk groups should be vaccinated against influenza. Early antiviral treatment of hospitalized patients may reduce mortality associated with influenza. The findings that age and comorbid conditions significantly contributed to patient mortality in influenza hospitalizations were consistent with established data for the 2009 H1N1 pandemic and seasonal influenza.2,3,5 Published studies, including two nationwide reviews in Taiwan,4,6 did not identify male– female differences in risk of influenza-related respiratory failure or death. The observed male disadvantage in H1N1 mortality might be due to additional risk factors (tobacco use, obesity or coinfection), or differences in immune responses, health-seeking behaviors, and access to healthcare services. These biological and sociobehavior factors should also be considered when planning influenza prevention and control strategies.
74
The Taiwan government has provided antiviral medications free of charge to patients hospitalized with suspected or confirmed influenza. The results from this study support previous studies that have noted that initiation of oseltamivir treatment within 48 hours of symptom onset may prevent influenza-related death in these patients.7 Clinicians are recommended to start empirical antiviral therapy for any hospitalized patient with clinically compatible illness and should not delay initiation of treatment while awaiting collection of specimens or results from the laboratory. Our results suggest influenza virus subtype is an effect modifier of the association between influenza vaccination and mortality; persons who did not receive influenza vaccine before illness onset were more likely to die only if they were hospitalized for H1N1 complications. This observed difference in the vaccine benefit of mortality might reflect a higher proportion of young individuals in subjects with H1N1 infection, compared with other influenza viruses.2,6 This study has limitations. The NNDSS data were collected passively and not chart verified; data quality and patient treatment could vary. The small number of fatality limited statistical power for analysis on multiple strata or additional patient characteristics (e.g., pregnancy). The 2011–2012 seasonal epidemic was predominated by a vaccine-mistmatched B/Yamagata-lineage virus,
Downloaded from http://inthealth.oxfordjournals.org/ at University of North Dakota on May 31, 2015
Age group ≥50 years 2019 ,50 years 2107 Sex Male 2226 Female 1900 High-risk medical condition Yes 1886 No 2240 Vaccinatedb Yes 412 No 3714 Oseltamivir treatment ≤48 hours after illness onset No 1394 Yes 2732 Influenza PCR result H1N1 1882 H3N2 1167 B 1077
Fatal n¼399
International Health
but the analyses did not quantify the potential impact of variable vaccine effectiveness on the association between influenza vaccination and mortality. Based on three consecutive years of NNDSS data from 4735 influenza hospitalizations and 413 deaths, we recommend influenza vaccination for at-risk persons who are aged ≥50 years, male, and with high-risk medical conditions, and early antiviral treatment for hospitalized patients with clinically compatible illness.
Supplementary data
Authors’ disclaimer: Preliminary results of this work were presented at the 2013 Taiwan Joint Public Health Annual Meeting and Symposium, Taipei, Taiwan, 19–20 October 2013.
Ethical approval: The Institutional Review Board at Taiwan Centers for Disease Control determined that the study met the conditions that allow for an exempt from review (#102025).
References 1 World Health Organization. Pandemic Influenza Risk Management: WHO Interim Guidance. http://www.who.int/influenza/preparedness/ pandemic/influenza_risk_management/en/index.html [accessed 19 August 2014]. 2 Chuang JH, Huang AS, Huang WT et al. Nationwide surveillance of influenza during the pandemic (2009–10) and post-pandemic (2010– 11) periods in Taiwan. PLoS One 2012;7:e36120. 3 Louie JK, Acosta M, Winter K et al. Factors associated with death or hospitalization due to pandemic 2009 influenza A(H1N1) infection in California. JAMA 2009;302:1896–902. 4 Ho YC, Wang JL, Wang JT et al. Prognostic factors for fatal adult influenza pneumonia. J Infect 2009;58:439–45.
Authors’ contributions: WTH and JHC conceived and designed the study; WTH, CHC and YFH collected, analyzed and interpreted the data; WTH drafted the manuscript; WTH, CHC, YFH and JHC critically revised the manuscript for intellectual content. All authors read and approved the final manuscript. WTH is the guarantor of this paper.
5 Van Kerkhove MD, Vandemaele KAH, Shinde V et al. Risk factors for severe outcomes following 2009 influenza A (H1N1) infection: a global pooled analysis. PLoS Med 2011;8:e1001053.
Funding: This work was supported by Taiwan Centers for Disease Control [grant number DOH102-DC-2101]. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
7 Muthuri SG, Venkatesan S, Myles PR et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med 2014;2:395–404.
6 Chien YS, Su CP, Tsai HT et al. Predictors and outcomes of respiratory failure among hospitalized pneumonia patients with 2009 H1N1 influenza in Taiwan. J Infect 2010;60:168–74.
75
Downloaded from http://inthealth.oxfordjournals.org/ at University of North Dakota on May 31, 2015
Supplementary data are available at International Health Online (http://inthealth.oxfordjournals.org/).
Competing interests: None declared.
SHORT COMMUNICATION
Prognostic factors for mortality in patients hospitalized with influenza complications, in Taiwan Wan-Ting Huanga,*, Chih-Hsi Changa, Yu-Fen Hsua and Jen-Hsiang Chuanga,b a
Taiwan Centers for Disease Control, Ministry of Health and Welfare, Taipei, Taiwan; bInstitute of Biomedical Informatics & Institute of Public Health, National Yang-Ming University, Taipei, Taiwan *Corresponding author: Tel: +886 2 2395 9825 ext 3180; E-mail: [email protected]
Background: This study aims to assess factors associated with fatal hospitalized influenza with complications in Taiwan. Methods: We identified reports of complications and illness onset in patients hospitalized with influenza between week 26, 2009 and week 25, 2012 from the National Notifiable Disease Surveillance System. We used a multivariate logistic regression model to evaluate covariates that can be associated with in-hospital mortality. Results: Among 4735 patients (413 deaths), age ≥50 years (p,0.001), male (p¼0.014), comorbidities (p,0.001), and delayed oseltamivir treatment (p,0.001) increased the likelihood of in-hospital mortality. Conclusions: We recommend influenza vaccination and early antiviral treatment for at-risk populations. Keywords: Case fatality rate, Influenza, Mortality determinant, Surveillance, Taiwan
Introduction Mortality or case fatality measures influenza severity and guides principles for allocating resources and targeting interventions to populations at risk.1 Identifying factors associated with mortality is critical in preparing for a potential influenza pandemic or annual seasonal influenza epidemics.1,2 In this study, we assessed characteristics that can be associated with mortality in patients hospitalized with influenza complications in Taiwan.
We used x2 tests to identify covariates associated with mortality, including age group (,50 or ≥50 years), sex (male or female), presence of high-risk medical conditions (yes or no), having received ≥1 dose of influenza vaccine before illness onset (yes or no), initiation of oseltamivir treatment ≤48 hours after illness onset (yes or no), and influenza PCR result (H1N1, H3N2, or B virus). Variables that differed between the nonfatal and fatal cases at p,0.05 were evaluated in the multivariate logistic regression models by using backward elimination procesures, retaining variables that were associated at p,0.10.
Materials and methods Cases of hospitalized influenza with complications are nationally notifiable in Taiwan.2 A confirmed case is defined as influenza-like illness and evidence of pneumonia, neurologic symptoms, myopericarditis or invasive bacterial infections, with a positive influenza real-time reverse transcription PCR. We identified confirmed reports from the National Notifiable Disease Surveillance System (NNDSS) in patients who had onset of illness from week 26, 2009 through week 25, 2012. Data were obtained for onset of illness, influenza PCR result, demographics, preexisting medical conditions that confer increased risk for influenza complications (Supplementary Box 1), influenza vaccination status (from self-reports or paper records), oseltamivir treatment and in-hospital mortality.
Results Of 4735 patients (413 deaths [8.7%]) who had confirmed hospitalized influenza with complications, median age was 50 years (IQR 24–69 years), and median length from illness onset to hospital discharge or mortality was 8 days (IQR 5–14 days). In multivariate analyses (Table 1), 264/2472 (10.7%) males and 187/2053 (9.1%) females were vaccinated against influenza; age ≥50 years (OR 2.05), male (OR 1.31), presence of high-risk medical conditions (OR 3.38), and delay of oseltamivir treatment (OR 2.40) was independently associated with mortality. Specifically, male (OR 1.65) and absence of influenza vaccination before illness onset (OR 2.70) increased the likelihood of mortality among
# The Author 2014. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: [email protected].
73
Downloaded from http://inthealth.oxfordjournals.org/ at University of North Dakota on May 31, 2015
Received 18 June 2014; revised 7 October 2014; accepted 7 October 2014
W.-T. Huang et al.
Table 1. Factors associated with mortality for influenza hospitalized patients with complicationsa Factor
Non-fatal n¼4126
Univariate OR
p-value
Multivariate ORc
p-value
292 107
2.61 ref
,0.001
2.05 ref
,0.001
246 153
1.34 ref
0.007
1.31 ref
0.014
304 95
3.41 ref
,0.001
3.38d ref
39 360
1.06 ref
NS
NA ref
201 198
1.87 ref
,0.001
2.40d ref
178 107 114
0.90 0.88 ref
NS NS
NA NA ref
,0.001
,0.001
NA: not applicable; NS: not significant. Data excluded 210 cases (14 deaths) for which low viral loads prevented further subtypings. b Defined as having received ≥1 dose of influenza vaccine before illness onset. c Adjusted for variables that were associated at p,0.05 by univariate analysis. d The two variables were independently associated with mortality, regardless of influenza test result. a
patients with H1N1 (Supplementary Table 1), but not H3N2 or B virus infection.
Discussion Our analyses suggest that age ≥50 years, male, comorbidities, and delayed oseltamivir treatment are associated with fatal hospitalized influenza; new among these risk factors is male gender. Because disease progression to mortality from onset can be rapid,3,4 those at-risk groups should be vaccinated against influenza. Early antiviral treatment of hospitalized patients may reduce mortality associated with influenza. The findings that age and comorbid conditions significantly contributed to patient mortality in influenza hospitalizations were consistent with established data for the 2009 H1N1 pandemic and seasonal influenza.2,3,5 Published studies, including two nationwide reviews in Taiwan,4,6 did not identify male– female differences in risk of influenza-related respiratory failure or death. The observed male disadvantage in H1N1 mortality might be due to additional risk factors (tobacco use, obesity or coinfection), or differences in immune responses, health-seeking behaviors, and access to healthcare services. These biological and sociobehavior factors should also be considered when planning influenza prevention and control strategies.
74
The Taiwan government has provided antiviral medications free of charge to patients hospitalized with suspected or confirmed influenza. The results from this study support previous studies that have noted that initiation of oseltamivir treatment within 48 hours of symptom onset may prevent influenza-related death in these patients.7 Clinicians are recommended to start empirical antiviral therapy for any hospitalized patient with clinically compatible illness and should not delay initiation of treatment while awaiting collection of specimens or results from the laboratory. Our results suggest influenza virus subtype is an effect modifier of the association between influenza vaccination and mortality; persons who did not receive influenza vaccine before illness onset were more likely to die only if they were hospitalized for H1N1 complications. This observed difference in the vaccine benefit of mortality might reflect a higher proportion of young individuals in subjects with H1N1 infection, compared with other influenza viruses.2,6 This study has limitations. The NNDSS data were collected passively and not chart verified; data quality and patient treatment could vary. The small number of fatality limited statistical power for analysis on multiple strata or additional patient characteristics (e.g., pregnancy). The 2011–2012 seasonal epidemic was predominated by a vaccine-mistmatched B/Yamagata-lineage virus,
Downloaded from http://inthealth.oxfordjournals.org/ at University of North Dakota on May 31, 2015
Age group ≥50 years 2019 ,50 years 2107 Sex Male 2226 Female 1900 High-risk medical condition Yes 1886 No 2240 Vaccinatedb Yes 412 No 3714 Oseltamivir treatment ≤48 hours after illness onset No 1394 Yes 2732 Influenza PCR result H1N1 1882 H3N2 1167 B 1077
Fatal n¼399
International Health
but the analyses did not quantify the potential impact of variable vaccine effectiveness on the association between influenza vaccination and mortality. Based on three consecutive years of NNDSS data from 4735 influenza hospitalizations and 413 deaths, we recommend influenza vaccination for at-risk persons who are aged ≥50 years, male, and with high-risk medical conditions, and early antiviral treatment for hospitalized patients with clinically compatible illness.
Supplementary data
Authors’ disclaimer: Preliminary results of this work were presented at the 2013 Taiwan Joint Public Health Annual Meeting and Symposium, Taipei, Taiwan, 19–20 October 2013.
Ethical approval: The Institutional Review Board at Taiwan Centers for Disease Control determined that the study met the conditions that allow for an exempt from review (#102025).
References 1 World Health Organization. Pandemic Influenza Risk Management: WHO Interim Guidance. http://www.who.int/influenza/preparedness/ pandemic/influenza_risk_management/en/index.html [accessed 19 August 2014]. 2 Chuang JH, Huang AS, Huang WT et al. Nationwide surveillance of influenza during the pandemic (2009–10) and post-pandemic (2010– 11) periods in Taiwan. PLoS One 2012;7:e36120. 3 Louie JK, Acosta M, Winter K et al. Factors associated with death or hospitalization due to pandemic 2009 influenza A(H1N1) infection in California. JAMA 2009;302:1896–902. 4 Ho YC, Wang JL, Wang JT et al. Prognostic factors for fatal adult influenza pneumonia. J Infect 2009;58:439–45.
Authors’ contributions: WTH and JHC conceived and designed the study; WTH, CHC and YFH collected, analyzed and interpreted the data; WTH drafted the manuscript; WTH, CHC, YFH and JHC critically revised the manuscript for intellectual content. All authors read and approved the final manuscript. WTH is the guarantor of this paper.
5 Van Kerkhove MD, Vandemaele KAH, Shinde V et al. Risk factors for severe outcomes following 2009 influenza A (H1N1) infection: a global pooled analysis. PLoS Med 2011;8:e1001053.
Funding: This work was supported by Taiwan Centers for Disease Control [grant number DOH102-DC-2101]. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
7 Muthuri SG, Venkatesan S, Myles PR et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data. Lancet Respir Med 2014;2:395–404.
6 Chien YS, Su CP, Tsai HT et al. Predictors and outcomes of respiratory failure among hospitalized pneumonia patients with 2009 H1N1 influenza in Taiwan. J Infect 2010;60:168–74.
75
Downloaded from http://inthealth.oxfordjournals.org/ at University of North Dakota on May 31, 2015
Supplementary data are available at International Health Online (http://inthealth.oxfordjournals.org/).
Competing interests: None declared.
