Comment www.thelancet.com/respiratory Vol 1 December 2013 757 failure. 9 Unexpectedly, the haemagglutinin of this virus lacks the pathogenicity marker for poultry, and studies have confirmed that it causes few symptoms in poultry. 10 As a consequence, finding the source of this infection is not easy, and, so far, it remains unclear where the main reservoir resides, although contact with poultry in live bird markets is a recorded risk factor. For pandemic circulation, an essential additional feature is the ability to transmit efficiently from person to person. Research into the genetic factors governing transmissibility is under substantial debate, but work to enhance our ability to predict which viruses might lead to onward transmission is urgently needed. 3 At present, human beings are the sentinels for detection of the transmission potential, shifting the burden of doing the proper studies to public health systems across the world; a situation that is far from ideal. With the detection of a virus of subtype H6N1, the list of questions to address is a familiar one. Viruses with H6 subtype haemagglutinins are quite prevalent in wild birds and have often been identified in poultry, along with other influenza viruses, resulting in generation of an ever expanding diverse set of influenza viruses through genetic reassortment. 11–13 Furthermore, previous serological studies have identified increased concentrations of antibodies to H6 haemagglutinin in poultry workers, suggesting human beings are susceptible. 13–15 Therefore, the question again is what would it take for these viruses to evolve into a pandemic strain? And an overriding question is if it is time to review our approaches to influenza surveillance at the human–animal interface? We surely can do better than to have human beings as sentinels. Marion Koopmans Virology Division, Laboratory for Infectious Diseases Research, Diagnosis and Screening, Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, Netherlands, and Department of Viroscience, Erasmus MC, Rotterdam, Netherlands m.koopmans@erasmusmc.nl I declare that I have no conflicts of interest. 1 Wei S-H, Yang J-R, Wu H-S, et al. Human infection with avian influenza A H6N1 virus: an epidemiological analysis. Lancet Respir Med 2013; published online Nov 14. http://dx.doi.org/10.1016/S2213-2600(13)70221-2. 2 Beare AS, Webster RG. Replication of avian influenza viruses in humans. Arch Virol 1991; 119: 37–42. 3 Reperant LA, Kuiken T, Osterhaus AD. Adaptive pathways of zoonotic influenza viruses: from exposure to establishment in humans. Vaccine 2012; 30: 4419–34. 4 Kasowski EJ, Garten RJ, Bridges CB. Influenza pandemic epidemiologic and virologic diversity: reminding ourselves of the possibilities. Clin Infect Dis 2011; 52 (suppl 1): S44–49. 5 Vandegrift KJ, Sokolow SH, Daszak P, Kilpatrick AM. Ecology of avian influenza viruses in a changing world. Ann N Y Acad Sci 2010; 1195: 113–28. 6 Lvov DK, Shchelkanov MY, Prilipov AG, et al. Evolution of highly pathogenic avian influenza H5N1 virus in natural ecosystems of northern Eurasia (2005– 08). Avian Dis 2010; 54 (1 suppl): 483–95. 7 Stallknecht DE, Goekjian VH, Wilcox BR, Poulson RL, Brown JD. Avian influenza virus in aquatic habitats: what do we need to learn? Avian Dis 2010; 54 (1 suppl): 461–65. 8 World Organisation for Animal Health. Global strategy for avian influenza. http://www.oie.int/animal-health-in-the-world/web-portal-on-avian- influenza/global-strategy/ (accessed Oct 28, 2013). 9 Yu H, Cowling BJ, Feng L, et al. Human infection with avian influenza A H7N9 virus: an assessment of clinical severity. Lancet 2013; 382: 138–45. 10 Chen Y, Liang W, Yang S, et al. Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: clinical analysis and characterisation of viral genome. Lancet 2013; 381: 1916–25. 11 Shi W, Shi Y, Wu Y, Liu D, Gao GF. Origin and molecular characterization of the human-infecting H6N1 influenza virus in Taiwan. Protein Cell 2013; published online Oct 17. DOI:10.1007/s13238-013-3083-0. 12 Huang K, Bahl J, Fan XH, et al. Establishment of an H6N2 influenza virus lineage in domestic ducks in southern China. J Virol 2010; 84: 6978–86. 13 Pfeiffer DU, Otte MJ, Roland-Holst D, Inui K, Nguyen T, Zilberman D. Implications of global and regional patterns of highly pathogenic avian influenza virus H5N1 clades for risk management. Vet J 2011; 190: 309–16. 14 Kayali G, Ortiz EJ, Chorazy ML, Gray GC. Evidence of previous avian influenza infection among US turkey workers. Zoonoses Public Health 2010; 57: 265–72. 15 Wan XF. Lessons from emergence of A/goose/Guangdong/1996-like H5N1 highly pathogenic avian influenza viruses and recent influenza surveillance efforts in southern China. Zoonoses Public Health 2012; 59 (suppl 2): 32–42. The club cell and its protein, CC16: time to shine Club cell (formerly Clara cell) protein or CC16 (also known as CC10, club cell secretory protein, and uteroglobin) is a member of the secretoglobin family of small disulphide bridge dimeric proteins. It is secreted by non-ciliated epithelial club cells in the large and small airways and is the most abundant protein present in normal airway secretions. Several lines of evidence suggest that CC16 has an important role in lung defence in experimental animals. When compared with wild-type mice, mice genetically deficient in CC16 (CC16 –/– mice) have an increased oxidant stress response in conducting airways 1 and increased lung inflammation and airway reactivity after acute viral infection. 2 Furthermore, depletion of the club cell secretory protein population results in alveolar damage, oedema, and reduced lung repair. 3 Despite this evidence from animals, little interest has developed in exploration of the role of the club cell and its product, CC16 protein, in human beings. However, this should Published Online November 15, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70247-9 See Articles page 779