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Physicians, American Lung Association, Astra Zeneca, Bayer, William Beaumont Hospital, Boehringer Ingelheim, Center for Health Care Education, CME Incite, Forest, Foundation for Improving Patient Outcomes, France Foundation, GlaxoSmithKline, Inova Health System, Lovelace, MedEd, MedScape/WebMD, National Association for Continuing Education, Network for Continuing Medical Education, Nycomed/Takeda, Peer Voice, Projects in Knowledge, St Luke’s Hospital, St. Mary’s Hospital, the University of Illinois Chicago, University of Texas Southwestern, University of Virginia, and UpToDate. He has served on DSMBs for Biogen and Novartis. He has received royalties from Castle Connolly and Informa. 1

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Vestbo J, Hurd SS, Agustí AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013; 187: 347–65. Decramer ML, Chapman KR, Dahl R, et al, on behalf of the INVIGORATE investigators. Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study. Lancet Respir Med 2013; published online Aug 21. http://dx.doi.org/10.1016/ S22132600(13)70158-9. Vogelmeier C, Ramos-Barbon D, Jack D, et al. Indacaterol provides 24-hour bronchodilation in COPD: a placebo-controlled blinded comparison with tiotropium. Respir Res 2010; 11: 135.

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Donohue JF, Fogarty C, Lötvall J, et al. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit Care Med 2010; 182: 155–62. Buhl R, Dunn LJ, Disdier C, et al. Blinded 12-week comparison of once-daily indacaterol and tiotropium in COPD. Eur Respir J 2011; 38: 797–803. Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011; 364: 1093–103. Lin FJ, Lee TA, Wong PS, Pickard AS. Evaluation of changes in guidelines for medication management of stable chronic obstructive pulmonary disease. J Eval Clin Pract 2012; published online Aug 14. DOI: 10.1111/j.13652753.2012.01892.x. Rennard S, Thomashow B, Crapo J, et al. Introducing the COPD Foundation Guide for Diagnosis and Management of COPD, recommendations of the COPD Foundation. COPD 2013; 10: 378–89. Agusti A, Hurd S, Jones P, et al. Frequently asked questions (FAQs) about the GOLD 2011 assessment proposal of COPD. Eur Respir J 2013; published online May 3. doi:10.1183/09031936.00036513.

The first reports of human infection with avian influenza A H7N9 appeared 3 months ago, and since then there have been more than 130 confirmed cases with 43 fatalities.1 Until this outbreak, H7 subtype influenza virus infection in human beings was typically associated with mild respiratory illness or conjunctivitis. The atypical association of H7N9 virus infection with severe human respiratory illness and death clearly represents a new and pressing public health threat. The high incidence of pneumonia and acute respiratory distress syndrome among severe and fatal cases2 is similar to H5N1 virus infection and necessitates a greater understanding of the ability of this virus subtype to target the human respiratory tract. In The Lancet Respiratory Medicine, Michael C W Chan and colleagues3 report the cell tropism and induction of innate host responses of two H7N9 viruses in several in-vitro and ex-vivo cultures, representative of, or derived from, the upper and lower human respiratory tract. Compared with other avian influenza viruses, Chan and colleagues find a heightened ability for the H7N9 viruses to replicate in human bronchus and lung, with induction of proinflammatory cytokines and chemokines in respiratory cells playing a lesser part in the overall pathogenesis of this virus subtype. These analyses support several initial clinical and epidemiological findings2 and provide greater insight www.thelancet.com/respiratory Vol 1 September 2013

into the remarkable ability of this low pathogenic avian influenza virus to cause severe human disease. The findings of Chan and colleagues contribute to several areas of ongoing investigation. The two phylogenetically distinct H7N9 viruses examined, which differ in key aminoacids in the virus haemagglutinin known to modulate receptor binding,4 displayed comparable infectivity and tropism in this study, suggesting that these residues do not dramatically alter the pathogenicity of H7N9 disease; in-vivo studies in the ferret model corroborate this finding.5 While pneumonia and acute respiratory distress syndrome have been associated with severe human disease after both H5N1 and H7N9 virus infection, the observation that H7N9 viruses exhibit an enhanced ability to infect the bronchus and lung compared with H5N1 viruses offers an avenue for further investigation and potential therapeutic application against this virus subtype. Examination of the relative ability of H5N1 and H7N9 viruses to dysregulate host innate immune responses in human tissues, revealing that H7N9 viruses elicit a greater induction of proinflammatory cytokines and chemokines compared with 2009 pandemic H1N1 but not H5N1 virus, similarly provides guidance for treatment and control. Still, the study by Chan and colleagues raises as many questions regarding the pathogenicity of H7N9 viruses as it addresses. The unusual age distribution among

CDC/Science Photo Library

Tropism of H7N9 influenza viruses in the human respiratory tract

Published Online July 25, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70161-9 See Articles page 534

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H7N9 human cases remains unanswered; expansion of tropism and infectivity studies to include tissues collected from case patients representing a greater distribution of age and health statuses might shed light on this characteristic. Second, this study adds to growing evidence that Eurasian-lineage H7 influenza viruses, H7N9 viruses among them, are poor inducers of innate immune responses in human respiratory tissues.6 Understanding the ability of H7 viruses to evade host responses has implications for both the pathogenesis of human disease and the poor immunogenicity observed in clinical trials of H7 vaccine candidates.7 Third, the absence of conjunctivitis among human cases of H7N9 infection is in stark contrast with the previous association of this virus subtype with ocular disease. Extension of the tropism and host response studies conducted by Chan and colleagues to human conjunctival ex-vivo cultures, which have been shown by the investigators to support replication of many human and avian influenza viruses,8 could further our understanding of this virus property. The efficiency of H7N9 viruses to replicate in lower respiratory tract ex-vivo cultures reported by Chan and colleagues is in agreement with recent in-vivo studies that show high viral titres in the lungs of H7N9 virus-infected ferrets.5,9 These ferret studies also revealed efficient transmission of H7N9 virus to naive animals in the presence of direct contact, with reduced transmission detected by the airborne route. Interestingly, H5N1 viruses replicate to comparably high titres throughout the ferret respiratory tract and cause severe respiratory disease in human beings, but unlike H7N9 viruses, do not transmit efficiently to naive ferrets. This finding could be due, in part, to the lack of binding to α-2,6-linked sialic acid analogues among H5N1 viruses and diminished production of inflammatory mediators in the ferret nasal passages associated with sneezing and rhinorrhoea after infection with H5N1

viruses.10 Notably, H7N9 viruses isolated from human beings possess a greater affinity for α-2,6-linked sialic acid analogues compared with avian H7 and H5 subtype viruses, while maintaining robust binding to α-2,3-linked sialic acid analogues.4,11 The findings of Chan and colleagues support the need for future studies investigating the interplay between H7N9 virus tropism, receptor binding specificity, the magnitude of local innate immune responses, and transmissibility. *Jessica A Belser, Terrence M Tumpey Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA [email protected] We declare that we have no conflicts of interest. The findings and conclusions are those of the authors and do not necessarily reflect the views of the funding agency. 1

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WHO. Number of confirmed human cases of avian influenza A(H7N9) reported to WHO. http://www.who.int/influenza/human_animal_ interface/influenza_h7n9/Data_Reports/en/index.html (accessed July 9, 2013). Gao HN, Lu HZ, Cao B, et al. Clinical findings in 111 cases of influenza A (H7N9) virus infection. N Engl J Med 2013; 368: 2277–85. Chan MCW, Chan RWY, Chan LLY, et al. Tropism and innate host responses of a novel avian origin influenza A (H7N9) virus: an analysis of ex-vivo and in-vitro cultures of the human respiratory tract. Lancet Respir Med 2013; published online July 25. http://dx.doi.org/10.1016/S2213-2600(13)70138-3. Tharakaraman K, Jayaraman A, Raman R, et al. Glycan receptor binding of the influenza A virus H7N9 hemagglutinin. Cell 2013; 153: 1486–93. Belser JA, Gustin KM, Pearce MB, et al. Pathogenesis and transmission of avian influenza A(H7N9) virus in ferrets and mice. Nature 2013; published online July 10. http://dx/doi.org/10.1038/nature12391. Belser JA, Zeng H, Katz JM, Tumpey TM. Infection with highly pathogenic H7 influenza viruses results in an attenuated proinflammatory cytokine and chemokine response early after infection. J Infect Dis 2011; 203: 40–48. Couch RB, Patel SM, Wade-Bowers CL, Nino D. A randomized clinical trial of an inactivated avian influenza A (H7N7) vaccine. PLoS One 2012; 7: e49704. Chan MC, Chan RW, Yu WC, et al. Tropism and innate host responses of the 2009 pandemic H1N1 influenza virus in ex vivo and in vitro cultures of human conjunctiva and respiratory tract. Am J Pathol 2010; 176: 1828–40. Zhu H, Wang D, Kelvin DJ, et al. Infectivity, transmission, and pathology of human H7N9 influenza in ferrets and pigs. Science 2013; 341: 183–86. Maines TR, Belser JA, Gustin KM, et al. Local innate immune responses and influenza virus transmission and virulence in ferrets. J Infect Dis 2012; 205: 474–85. Xiong X, Martin SR, Haire LF, et al. Receptor binding by an H7N9 influenza virus from humans. Nature 2013; published online June 20. http://dx.doi. org/10.1038/nature12372.

COPD in never smokers: prognosis unveiled Published Online July 29, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70157-7 See Articles page 543

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We were told by our medical school professors that only smokers developed chronic obstructive pulmonary disease (COPD) as dogma. Many of us have perpetuated this myth by telling our housestaff and students that non-smokers never develop COPD in industrialised western nations such as the USA and the UK.1 However,

according to the international Burden of Lung Disease (BOLD) study2 and other large population-based studies, 5% of adults older than 40 years in these countries, who have never smoked, have significant and persistent airflow limitation. Based on these estimates, there are 7 million never smokers with COPD in the USA and www.thelancet.com/respiratory Vol 1 September 2013

Tropism of H7N9 influenza viruses in the human respiratory tract.

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