Prevention and treatment of respiratory viral infections: Presentations on antivirals, traditional therapies and host-directed interventions at the 5th ISIRV Antiviral Group conference

Antiviral Research

Volumn 149, Issue , 2018, Pages 118-142

  McKimm Breschkin, Jennifer L ^a   Jiang, Shibo ^b,c   Hui, David S ^d   Beigel, John H ^e   Govorkova, Elena A ^f   Lee, Nelson ^g  

^a UNIVERSITY OF MELBOURNE   (Australia)

^b FUDAN UNIVERSITY   (China)

^c NEW YORK BLOOD CENTER   (United States)

^d CHINESE UNIVERSITY OF HONG KONG   (Hong Kong)

^e NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES   (United States)

^f ST JUDE CHILDREN S RESEARCH HOSPITAL   (United States)

^g UNIVERSITY OF ALBERTA   (Canada)

Author keywords

Antivirals; Influenza; Isirv AVG; RSV; Vaccines

Indexed keywords

ABSENT IN MELANOMA 2 PROTEIN; AK 0529; ALS 008112; ANTIVIRUS AGENT; ARBIDOL; DANIRIXIN; DEAD BOX PROTEIN; DEAD BOX RNA HELICASE 19B; ESTERASE INHIBITOR; FAVIPIRAVIR; HOST FACTOR; INFLAMMASOME; JNJ 6362387; MACROLIDE; MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY MHAA45449A; MONOCLONAL ANTIBODY VIS410; NITAZOXANIDE; OSELTAMIVIR; PERAMIVIR; PIMODIVIR; PRESATOVIR; PROBIOTIC AGENT; RO 7; S 033188; SIALIDASE INHIBITOR; UMIFENOVIR; UNCLASSIFIED DRUG; UNINDEXED DRUG; VIRUS FUSION INHIBITOR; VIRUS LIKE PARTICLE VACCINE; VIRUS VACCINE; ZANAMIVIR;

ADENOVIRIDAE; ADENOVIRUS TYPE 80; ADULT RESPIRATORY DISTRESS SYNDROME; ANTIBODY RESPONSE; ANTIBODY SPECIFICITY; ANTIVIRAL RESISTANCE; ANTIVIRAL THERAPY; AUSTRALIA; BACTERIUM; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELLULAR IMMUNITY; CHINA; CHINESE MEDICINE; CLAP SCORE; CLINICAL FEATURE; CLINICAL OUTCOME; CLINICAL RESEARCH; COMBINATION DRUG THERAPY; COMMUNITY ACQUIRED PNEUMONIA; CONFERENCE PAPER; CONTACT EXAMINATION; CROSS RESISTANCE; DISEASE COURSE; DISEASE SEVERITY; DISEASE SEVERITY ASSESSMENT; DRUG EFFICACY; DRUG TARGETING; ENTEROVIRUS D68; EPIDEMIC; FATALITY; FEASIBILITY STUDY; GRAFT RECIPIENT; HEALTH CARE PERSONNEL; HOSPITAL INFECTION; HOSPITAL PATIENT; HUMAN; HUMAN METAPNEUMOVIRUS; HUMAN RESPIRATORY SYNCYTIAL VIRUS; HUMORAL IMMUNITY; IMMUNE RESPONSE; IN VITRO STUDY; IN VIVO STUDY; INCIDENCE; INFECTION CONTROL; INFECTION PREVENTION; INFLUENZA; INFLUENZA A (H1N1); INFLUENZA A (H7N9); INFLUENZA A VIRUS (H1N1); INFLUENZA A VIRUS (H3N2); INFLUENZA A VIRUS (H7N9); INTERVENTION STUDY; JAPAN; MADAGASCAR; META ANALYSIS (TOPIC); METAPNEUMOVIRUS; MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS; MOLECULAR DIAGNOSIS; MONOTHERAPY; MULTICENTER STUDY (TOPIC); MUTAGENESIS; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHILIPPINES; PRACTICE GUIDELINE; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REGULATORY T LYMPHOCYTE; SARS CORONAVIRUS; SEASONAL INFLUENZA; SEVERE ACUTE RESPIRATORY SYNDROME; SINGLE DRUG DOSE; STANDARD; SYSTEMS BIOLOGY; TRADITIONAL MEDICINE; VACCINATION; VIET NAM; VIRAL RESPIRATORY TRACT INFECTION; VIROLOGY; VIRUS DETECTION; VIRUS DIAGNOSIS; VIRUS GENOME; VIRUS PATHOGENESIS; VIRUS PNEUMONIA; VIRUS TRANSMISSION; VIRUS VIRULENCE; WORLD HEALTH ORGANIZATION; RESPIRATORY TRACT INFECTION;

HUMANS; RESPIRATORY TRACT INFECTIONS;

EID: 85035785809     PISSN: 01663542     EISSN: 18729096     Source Type: Journal    
DOI: 10.1016/j.antiviral.2017.11.013     Document Type: Conference Paper

References (178)

1. Acosta, P.L., Caballero, M.T., Polack, F.P., Brief history and characterization of enhanced respiratory syncytial virus disease. Clin. Vaccine Immunol. 23 (2015), 189–195.
2. Agrawal, A.S., Ying, T., Tao, X., Garron, T., Algaissi, A., Wang, Y., Wang, L., Peng, B.H., Jiang, S., Dimitrov, D.S., Tseng, C.T., Passive transfer of A germline-like neutralizing human monoclonal antibody protects transgenic mice against lethal Middle East respiratory syndrome coronavirus infection. Sci. Rep., 6, 2016, 31629.
3. AVWG, W., Summary Table of Neuraminidase Amino Acid Substitutions Associated with Reduced Inhibition by Neuraminidase Inhibitors (NAI). 2016, WHO GISRS antiviral susceptibility expert working group (AVWG) http://www.who.int/influenza/gisrs_laboratory/antiviral_susceptibility/avwg2014_nai_substitution_table.pdf?ua=1. (Accessed 13 September 2017)
4. Baranovich, T., Jones, J.C., Russier, M., Vogel, P., Szretter, K.J., Sloan, S.E., Seiler, P., Trevejo, J.M., Webby, R.J., Govorkova, E.A., The hemagglutinin stem-binding monoclonal antibody VIS410 controls influenza virus-induced acute respiratory distress syndrome. Antimicrob. Agents Chemother. 60 (2016), 2118–2131.
5. Baudon, E., Peyre, M., Peiris, M., Cowling, B.J., Epidemiological features of influenza circulation in swine populations: a systematic review and meta-analysis. PLoS One, 12, 2017, e0179044.
6. Beyer, W.E., Nauta, J.J., Palache, A.M., Giezeman, K.M., Osterhaus, A.D., Immunogenicity and safety of inactivated influenza vaccines in primed populations: a systematic literature review and meta-analysis. Vaccine 29 (2011), 5785–5792.
7. Biggs, H.M., McNeal, M., Nix, W.A., Kercsmar, C., Curns, A.T., Connelly, B., Rice, M., Chern, S.W., Prill, M.M., Back, N., Oberste, M.S., Gerber, S.I., Staat, M.A., Enterovirus D68 infection among children with medically attended acute respiratory illness, Cincinnati, Ohio, July-October 2014. Clin. Infect. Dis. 65 (2017), 315–323.
8. Brandt, C., Pavlovic, V., Radbruch, A., Worm, M., Baumgrass, R., Low-dose cyclosporine A therapy increases the regulatory T cell population in patients with atopic dermatitis. Allergy 64 (2009), 1588–1596.
9. Busch-Petersen, J., Carpenter, D.C., Burman, M., Foley, J., Hunsberger, G.E., Kilian, D.J., Salmon, M., Mayer, R.J., Yonchuk, J.G., Tal-Singer, R., Danirixin: a reversible and selective antagonist of the CXC chemokine receptor 2. J. Pharmacol. Exp. Ther. 362 (2017), 338–346.
10. Byrn, R.A., Jones, S.M., Bennett, H.B., Bral, C., Clark, M.P., Jacobs, M.D., Kwong, A.D., Ledeboer, M.W., Leeman, J.R., McNeil, C.F., Murcko, M.A., Nezami, A., Perola, E., Rijnbrand, R., Saxena, K., Tsai, A.W., Zhou, Y., Charifson, P.S., Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit. Antimicrob. Agents Chemother. 59 (2015), 1569–1582.
11. Cannon, M.J., Openshaw, P.J., Askonas, B.A., Cytotoxic T cells clear virus but augment lung pathology in mice infected with respiratory syncytial virus. J. Exp. Med. 168 (1988), 1163–1168.
12. Cao, B., Gao, H., Zhou, B., Deng, X., Hu, C., Deng, C., Lu, H., Li, Y., Gan, J., Liu, J., Li, H., Zhang, Y., Yang, Y., Fang, Q., Shen, Y., Gu, Q., Zhou, X., Zhao, W., Pu, Z., Chen, L., Sun, B., Liu, X., Hamilton, C.D., Li, L., Adjuvant corticosteroid treatment in adults with influenza a (H7N9) viral pneumonia. Crit. Care Med. 44 (2016), e318–e328.
13. Carrat, F., Vergu, E., Ferguson, N.M., Lemaitre, M., Cauchemez, S., Leach, S., Valleron, A.J., Time lines of infection and disease in human influenza: a review of volunteer challenge studies. Am. J. Epidemiol. 167 (2008), 775–785.
14. Casscells, S.W., Granger, E., Kress, A.M., Linton, A., Madjid, M., Cottrell, L., Use of oseltamivir after influenza infection is associated with reduced incidence of recurrent adverse cardiovascular outcomes among military health system beneficiaries with prior cardiovascular diseases. Circ. Cardiovasc. Qual. Outcomes 2 (2009), 108–115.
15. Castilow, E.M., Olson, M.R., Varga, S.M., Understanding respiratory syncytial virus (RSV) vaccine-enhanced disease. Immunol. Res. 39 (2007), 225–239.
16. Channappanavar, R., Lu, L., Xia, S., Du, L., Meyerholz, D.K., Perlman, S., Jiang, S., Protective effect of intranasal regimens containing peptidic Middle East respiratory syndrome coronavirus fusion inhibitor against MERS-CoV infection. J. Infect. Dis. 212 (2015), 1894–1903.
17. Channappanavar, R., Perlman, S., Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin. Immunopathol. 39 (2017), 529–539.
18. Charles, P.G., Wolfe, R., Whitby, M., Fine, M.J., Fuller, A.J., Stirling, R., Wright, A.A., Ramirez, J.A., Christiansen, K.J., Waterer, G.W., Pierce, R.J., Armstrong, J.G., Korman, T.M., Holmes, P., Obrosky, D.S., Peyrani, P., Johnson, B., Hooy, M., Grayson, M.L., SMART-COP: a tool for predicting the need for intensive respiratory or vasopressor support in community-acquired pneumonia. Clin. Infect. Dis. 47 (2008), 375–384.
19. Chen, H., Liu, S., Liu, J., Chai, C., Mao, H., Yu, Z., Tang, Y., Zhu, G., Chen, H.X., Zhu, C., Shao, H., Tan, S., Wang, Q., Bi, Y., Zou, Z., Liu, G., Jin, T., Jiang, C., Gao, G.F., Peiris, M., Yu, H., Chen, E., Nosocomial Co-Transmission of avian influenza A(H7N9) and A(H1N1)pdm09 viruses between 2 patients with hematologic disorders. Emerg. Infect. Dis. 22 (2016), 598–607.
20. Chen, J.X., Xue, H.J., Ye, W.C., Fang, B.H., Liu, Y.H., Yuan, S.H., Yu, P., Wang, Y.Q., Activity of andrographolide and its derivatives against influenza virus in vivo and in vitro. Biol. Pharm. Bull. 32 (2009), 1385–1391.
21. Chen, W., Lim, C.E., Kang, H.J., Liu, J., Chinese herbal medicines for the treatment of type A H1N1 influenza: a systematic review of randomized controlled trials. PLoS One, 6, 2011, e28093.
22. Choe, P.G., Perera, R., Park, W.B., Song, K.H., Bang, J.H., Kim, E.S., Kim, H.B., Ko, L.W.R., Park, S.W., Kim, N.J., Lau, E.H.Y., Poon, L.L.M., Peiris, M., Oh, M.D., MERS-CoV antibody responses 1 Year after symptom onset, South Korea, 2015. Emerg. Infect. Dis. 23 (2017), 1079–1084.
23. Chor, J.S., Pada, S.K., Stephenson, I., Goggins, W.B., Tambyah, P.A., Medina, M., Lee, N., Leung, T.F., Ngai, K.L., Law, S.K., Rainer, T.H., Griffiths, S., Chan, P.K., Differences in the compliance with hospital infection control practices during the 2009 influenza H1N1 pandemic in three countries. J. Hosp. Infect. 81 (2012), 98–103.
24. Clark, T.W., Ewings, S., Medina, M.J., Batham, S., Curran, M.D., Parmar, S., Nicholson, K.G., Viral load is strongly associated with length of stay in adults hospitalised with viral acute respiratory illness. J. Infect. 73 (2016), 598–606.
25. Cockrell, A.S., Yount, B.L., Scobey, T., Jensen, K., Douglas, M., Beall, A., Tang, X.C., Marasco, W.A., Heise, M.T., Baric, R.S., A mouse model for MERS coronavirus-induced acute respiratory distress syndrome. Nat. Microbiol., 2, 2016, 16226.
26. Cole, S.L., Dunning, J., Kok, W.L., Benam, K.H., Benlahrech, A., Repapi, E., Martinez, F.O., Drumright, L., Powell, T.J., Bennett, M., Elderfield, R., Thomas, C., Dong, T., McCauley, J., Liew, F.Y., Taylor, S., Zambon, M., Barclay, W., Cerundolo, V., Openshaw, P.J., McMichael, A.J., Ho, L.P., M1-like monocytes are a major immunological determinant of severity in previously healthy adults with life-threatening influenza. JCI Insight, 2, 2017, e91868.
27. de Jong, M.D., Ison, M.G., Monto, A.S., Metev, H., Clark, C., O'Neil, B., Elder, J., McCullough, A., Collis, P., Sheridan, W.P., Evaluation of intravenous peramivir for treatment of influenza in hospitalized patients. Clin. Infect. Dis. 59 (2014), e172–e185.
28. Deng, R., Lee, A.P., Maia, M., Lim, J.J., Burgess, T., Horn, P., Derby, M.A., Newton, E., Tavel, J.A., Hanley, W.D., Pharmacokinetics of MHAA4549A, an anti-influenza a monoclonal antibody, in healthy subjects challenged with influenza a virus in a phase IIa randomized trial. Clin. Pharmacokinet., 2017, 10.1007/s40262-017-0564-y.
29. DeVincenzo, J.P., McClure, M.W., Symons, J.A., Fathi, H., Westland, C., Chanda, S., Lambkin-Williams, R., Smith, P., Zhang, Q., Beigelman, L., Blatt, L.M., Fry, J., Activity of oral ALS-008176 in a respiratory syncytial virus challenge study. N. Engl. J. Med. 373 (2015), 2048–2058.
30. DeVincenzo, J.P., Whitley, R.J., Mackman, R.L., Scaglioni-Weinlich, C., Harrison, L., Farrell, E., McBride, S., Lambkin-Williams, R., Jordan, R., Xin, Y., Ramanathan, S., O'Riordan, T., Lewis, S.A., Li, X., Toback, S.L., Lin, S.L., Chien, J.W., Oral GS-5806 activity in a respiratory syncytial virus challenge study. N. Engl. J. Med. 371 (2014), 711–722.
31. Ding, Y., Zeng, L., Li, R., Chen, Q., Zhou, B., Chen, Q., Cheng, P.L., Yutao, W., Zheng, J., Yang, Z., Zhang, F., The Chinese prescription lianhuaqingwen capsule exerts anti-influenza activity through the inhibition of viral propagation and impacts immune function. BMC Complement. Altern. Med., 17, 2017, 130.
32. Diot, C., Fournier, G., Dos Santos, M., Magnus, J., Komarova, A., van der Werf, S., Munier, S., Naffakh, N., Influenza a virus polymerase recruits the RNA helicase DDX19 to promote the nuclear export of viral mRNAs. Sci. Rep., 6, 2016, 33763.
33. Du, L., He, Y., Zhou, Y., Liu, S., Zheng, B.J., Jiang, S., The spike protein of SARS-CoV–a target for vaccine and therapeutic development. Nat. Rev. Microbiol. 7 (2009), 226–236.
34. Du, L., Kou, Z., Ma, C., Tao, X., Wang, L., Zhao, G., Chen, Y., Yu, F., Tseng, C.T., Zhou, Y., Jiang, S., A truncated receptor-binding domain of MERS-CoV spike protein potently inhibits MERS-CoV infection and induces strong neutralizing antibody responses: implication for developing therapeutics and vaccines. PLoS One, 8, 2013, e81587.
35. Du, L., Tai, W., Yang, Y., Zhao, G., Zhu, Q., Sun, S., Liu, C., Tao, X., Tseng, C.K., Perlman, S., Jiang, S., Zhou, Y., Li, F., Introduction of neutralizing immunogenicity index to the rational design of MERS coronavirus subunit vaccines. Nat. Commun., 7, 2016, 13473.
36. Du, L., Zhao, G., Kou, Z., Ma, C., Sun, S., Poon, V.K., Lu, L., Wang, L., Debnath, A.K., Zheng, B.J., Zhou, Y., Jiang, S., Identification of a receptor-binding domain in the S protein of the novel human coronavirus Middle East respiratory syndrome coronavirus as an essential target for vaccine development. J. Virol. 87 (2013), 9939–9942.
37. Du, L., Zhao, G., Yang, Y., Qiu, H., Wang, L., Kou, Z., Tao, X., Yu, H., Sun, S., Tseng, C.T., Jiang, S., Li, F., Zhou, Y., A conformation-dependent neutralizing monoclonal antibody specifically targeting receptor-binding domain in Middle East respiratory syndrome coronavirus spike protein. J. Virol. 88 (2014), 7045–7053.
38. Dye, J.M., Wu, H., Hooper, J.W., Khurana, S., Kuehne, A.I., Coyle, E.M., Ortiz, R.A., Fuentes, S., Herbert, A.S., Golding, H., Bakken, R.A., Brannan, J.M., Kwilas, S.A., Sullivan, E.J., Luke, T.C., Smith, G., Glenn, G., Li, W., Ye, L., Yang, C., Compans, R.W., Tripp, R.A., Jiao, J.A., Production of potent fully human polyclonal antibodies against Ebola Zaire virus in transchromosomal cattle. Sci. Rep., 6, 2016, 24897.
39. Edwards, K.M., Zhu, Y., Griffin, M.R., Weinberg, G.A., Hall, C.B., Szilagyi, P.G., Staat, M.A., Iwane, M., Prill, M.M., Williams, J.V., Burden of human metapneumovirus infection in young children. N. Engl. J. Med. 368 (2013), 633–643.
40. Elnifro, E.M., Cooper, R.J., Dady, I., Hany, S., Mughal, Z.M., Klapper, P.E., Three nonfatal cases of neonatal adenovirus infection. J. Clin. Microbiol. 43 (2005), 5814–5815.
41. Fang, C.F., Ma, M.J., Zhan, B.D., Lai, S.M., Hu, Y., Yang, X.X., Li, J., Cao, G.P., Zhou, J.J., Zhang, J.M., Wang, S.Q., Hu, X.L., Li, Y.J., Wang, X.X., Cheng, W., Yao, H.W., Li, X.L., Yi, H.M., Xu, W.D., Jiang, J.F., Gray, G.C., Fang, L.Q., Chen, E.F., Cao, W.C., Nosocomial transmission of avian influenza A (H7N9) virus in China: epidemiological investigation. BMJ, 351, 2015 h5765.
42. FDA-CDER, Guidance for Industry Influenza: Developing Drugs for Treatment and/or Prophylaxis. 2011, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM091219.pdf. (Accessed 28 August 2017)
43. Feng, L., Li, Z., Zhao, S., Nair, H., Lai, S., Xu, W., Li, M., Wu, J., Ren, L., Liu, W., Yuan, Z., Chen, Y., Wang, X., Zhao, Z., Zhang, H., Li, F., Ye, X., Li, S., Feikin, D., Yu, H., Yang, W., Viral etiologies of hospitalized acute lower respiratory infection patients in China, 2009-2013. PLoS One, 9, 2014, e99419.
44. Feng, L., Shay, D.K., Jiang, Y., Zhou, H., Chen, X., Zheng, Y., Jiang, L., Zhang, Q., Lin, H., Wang, S., Ying, Y., Xu, Y., Wang, N., Feng, Z., Viboud, C., Yang, W., Yu, H., Influenza-associated mortality in temperate and subtropical Chinese cities, 2003-2008. Bull. World Health Organ., 90, 2012 279–288b.
45. Fine, M.J., Hanusa, B.H., Lave, J.R., Singer, D.E., Stone, R.A., Weissfeld, L.A., Coley, C.M., Marrie, T.J., Kapoor, W.N., Comparison of a disease-specific and a generic severity of illness measure for patients with community-acquired pneumonia. J. Gen. Intern. Med. 10 (1995), 359–368.
46. Fraaij, P.L., Schutten, M., Javouhey, E., Burleigh, L., Outlaw, R., Kumar, D., Boucher, C.A., Viral shedding and susceptibility to oseltamivir in hospitalized immunocompromised patients with influenza in the Influenza Resistance Information Study (IRIS). Antivir. Ther. 20 (2015), 633–642.
47. Fu, Y., Gaelings, L., Soderholm, S., Belanov, S., Nandania, J., Nyman, T.A., Matikainen, S., Anders, S., Velagapudi, V., Kainov, D.E., JNJ872 inhibits influenza A virus replication without altering cellular antiviral responses. Antivir. Res. 133 (2016), 23–31.
48. Furuta, Y., Gowen, B.B., Takahashi, K., Shiraki, K., Smee, D.F., Barnard, D.L., Favipiravir (T-705), a novel viral RNA polymerase inhibitor. Antivir. Res. 100 (2013), 446–454.
49. Gambaryan, A.S., Robertson, J.S., Matrosovich, M.N., Effects of egg-adaptation on the receptor-binding properties of human influenza A and B viruses. Virology 258 (1999), 232–239.
50. Gao, R., Cao, B., Hu, Y., Feng, Z., Wang, D., Hu, W., Chen, J., Jie, Z., Qiu, H., Xu, K., Xu, X., Lu, H., Zhu, W., Gao, Z., Xiang, N., Shen, Y., He, Z., Gu, Y., Zhang, Z., Yang, Y., Zhao, X., Zhou, L., Li, X., Zou, S., Zhang, Y., Li, X., Yang, L., Guo, J., Dong, J., Li, Q., Dong, L., Zhu, Y., Bai, T., Wang, S., Hao, P., Yang, W., Zhang, Y., Han, J., Yu, H., Li, D., Gao, G.F., Wu, G., Wang, Y., Yuan, Z., Shu, Y., Human infection with a novel avian-origin influenza A (H7N9) virus. N. Engl. J. Med. 368 (2013), 1888–1897.
51. Ge, X.Y., Li, J.L., Yang, X.L., Chmura, A.A., Zhu, G., Epstein, J.H., Mazet, J.K., Hu, B., Zhang, W., Peng, C., Zhang, Y.J., Luo, C.M., Tan, B., Wang, N., Zhu, Y., Crameri, G., Zhang, S.Y., Wang, L.F., Daszak, P., Shi, Z.L., Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature 503 (2013), 535–538.
52. Goodwin, K., Viboud, C., Simonsen, L., Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine 24 (2006), 1159–1169.
53. Graham, B.S., Vaccine development for respiratory syncytial virus. Curr. Opin. Virol. 23 (2017), 107–112.
54. Gubareva, L.V., Fallows, E., Mishin, V.P., Hodges, E., Brooks, A., Barnes, J., Fry, A.M., Kramp, W., Shively, R., Wentworth, D.E., Weidemaier, K., Jacobson, R., Monitoring influenza virus susceptibility to oseltamivir using a new rapid assay, iART. Euro Surveill., 22(18), 2017.
55. Guo, L., Zhang, X., Ren, L., Yu, X., Chen, L., Zhou, H., Gao, X., Teng, Z., Li, J., Hu, J., Wu, C., Xiao, X., Zhu, Y., Wang, Q., Pang, X., Jin, Q., Wu, F., Wang, J., Human antibody responses to avian influenza A(H7N9) virus, 2013. Emerg. Infect. Dis. 20 (2014), 192–200.
56. Gupta, P., Kamath, A.V., Park, S., Chiu, H., Lutman, J., Maia, M., Tan, M.W., Xu, M., Swem, L., Deng, R., Preclinical pharmacokinetics of MHAA4549A, a human monoclonal antibody to influenza A virus, and the prediction of its efficacious clinical dose for the treatment of patients hospitalized with influenza A. MAbs 8 (2016), 991–997.
57. Haffizulla, J., Hartman, A., Hoppers, M., Resnick, H., Samudrala, S., Ginocchio, C., Bardin, M., Rossignol, J.F., Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Lancet Infect. Dis. 14 (2014), 609–618.
58. Hao, Q., Dong, B.R., Wu, T., Probiotics for preventing acute upper respiratory tract infections. Cochrane Database Syst. Rev., 2015, 10.1002/14651858.CD006895.pub3 Cd006895.
59. He, Y., Lu, H., Siddiqui, P., Zhou, Y., Jiang, S., Receptor-binding domain of severe acute respiratory syndrome coronavirus spike protein contains multiple conformation-dependent epitopes that induce highly potent neutralizing antibodies. J. Immunol. 174 (2005), 4908–4915.
60. Hemida, M.G., Alnaeem, A., Chu, D.K., Perera, R.A., Chan, S.M., Almathen, F., Yau, E., Ng, B.C., Webby, R.J., Poon, L.L., Peiris, M., Longitudinal study of Middle East Respiratory Syndrome coronavirus infection in dromedary camel herds in Saudi Arabia, 2014-2015. Emerg. Microbes Infect., 6, 2017, e56.
61. Hu, Y., Lu, S., Song, Z., Wang, W., Hao, P., Li, J., Zhang, X., Yen, H.L., Shi, B., Li, T., Guan, W., Xu, L., Liu, Y., Wang, S., Zhang, X., Tian, D., Zhu, Z., He, J., Huang, K., Chen, H., Zheng, L., Li, X., Ping, J., Kang, B., Xi, X., Zha, L., Li, Y., Zhang, Z., Peiris, M., Yuan, Z., Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance. Lancet 381 (2013), 2273–2279.
62. Hung, I.F.N., To, K.K.W., Chan, J.F.W., Cheng, V.C.C., Liu, K.S.H., Tam, A., Chan, T.C., Zhang, A.J., Li, P., Wong, T.L., Zhang, R., Cheung, M.K.S., Leung, W., Lau, J.Y.N., Fok, M., Chen, H., Chan, K.H., Yuen, K.Y., Efficacy of clarithromycin-naproxen-oseltamivir combination in the treatment of patients hospitalized for influenza A(H3N2) infection: an open-label randomized, controlled, phase IIb/III trial. Chest 151 (2017), 1069–1080.
63. Hurt, A.C., Hardie, K., Wilson, N.J., Deng, Y.M., Osbourn, M., Leang, S.K., Lee, R.T., Iannello, P., Gehrig, N., Shaw, R., Wark, P., Caldwell, N., Givney, R.C., Xue, L., Maurer-Stroh, S., Dwyer, D.E., Wang, B., Smith, D.W., Levy, A., Booy, R., Dixit, R., Merritt, T., Kelso, A., Dalton, C., Durrheim, D., Barr, I.G., Characteristics of a widespread community cluster of H275Y oseltamivir-resistant A(H1N1)pdm09 influenza in Australia. J. Infect. Dis. 206 (2012), 148–157.
64. Ison, M.G., de Jong, M.D., Gilligan, K.J., Higgs, E.S., Pavia, A.T., Pierson, J., Hayden, F.G., End points for testing influenza antiviral treatments for patients at high risk of severe and life-threatening disease. J. Infect. Dis. 201 (2010), 1654–1662.
65. Jiang, S., Lin, K., Strick, N., Neurath, A.R., HIV-1 inhibition by a peptide. Nature, 365, 1993, 113.
66. Jones, J.C., Marathe, B.M., Vogel, P., Gasser, R., Najera, I., Govorkova, E.A., The PA endonuclease inhibitor RO-7 protects mice from lethal challenge with influenza A or B viruses. Antimicrob. Agents Chemother., 61(5), 2017.
67. Kadam, R.U., Wilson, I.A., Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol. Proc. Natl. Acad. Sci. U. S. A. 114 (2017), 206–214.
68. Kanekiyo, M., Wei, C.J., Yassine, H.M., McTamney, P.M., Boyington, J.C., Whittle, J.R., Rao, S.S., Kong, W.P., Wang, L., Nabel, G.J., Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies. Nature 499 (2013), 102–106.
69. Kang, C.K., Song, K.H., Choe, P.G., Park, W.B., Bang, J.H., Kim, E.S., Park, S.W., Kim, H.B., Kim, N.J., Cho, S.I., Lee, J.K., Oh, M.D., Clinical and epidemiologic characteristics of spreaders of middle east respiratory syndrome coronavirus during the 2015 outbreak in Korea. J. Korean Med. Sci. 32 (2017), 744–749.
70. Kanoh, S., Rubin, B.K., Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin. Microbiol. Rev. 23 (2010), 590–615.
71. Ke, C., Mok, C.K.P., Zhu, W., Zhou, H., He, J., Guan, W., Wu, J., Song, W., Wang, D., Liu, J., Lin, Q., Chu, D.K.W., Yang, L., Zhong, N., Yang, Z., Shu, Y., Peiris, J.S.M., Human infection with highly pathogenic avian influenza A(H7N9) virus, China. Emerg. Infect. Dis. 23 (2017), 1332–1340.
72. King, J., Zhou, J., Katzen, J., Gao, Y., Houk, J., Willis, M., Tegeris, J., Ison, M., Evaluation of a novel ordinal scale endpoint in hospitalized patients with severe influenza illness. Open Forum Infect. Dis., 3, 2016 638–638.
73. Kirchdoerfer, R.N., Cottrell, C.A., Wang, N., Pallesen, J., Yassine, H.M., Turner, H.L., Corbett, K.S., Graham, B.S., McLellan, J.S., Ward, A.B., Pre-fusion structure of a human coronavirus spike protein. Nature 531 (2016), 118–121.
74. Kumar, D., Michaels, M.G., Morris, M.I., Green, M., Avery, R.K., Liu, C., Danziger-Isakov, L., Stosor, V., Estabrook, M., Gantt, S., Marr, K.A., Martin, S., Silveira, F.P., Razonable, R.R., Allen, U.D., Levi, M.E., Lyon, G.M., Bell, L.E., Huprikar, S., Patel, G., Gregg, K.S., Pursell, K., Helmersen, D., Julian, K.G., Shiley, K., Bono, B., Dharnidharka, V.R., Alavi, G., Kalpoe, J.S., Shoham, S., Reid, G.E., Humar, A., Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study. Lancet Infect. Dis. 10 (2010), 521–526.
75. Lafond, K.E., Nair, H., Rasooly, M.H., Valente, F., Booy, R., Rahman, M., Kitsutani, P., Yu, H., Guzman, G., Coulibaly, D., Armero, J., Jima, D., Howie, S.R., Ampofo, W., Mena, R., Chadha, M., Sampurno, O.D., Emukule, G.O., Nurmatov, Z., Corwin, A., Heraud, J.M., Noyola, D.E., Cojocaru, R., Nymadawa, P., Barakat, A., Adedeji, A., von Horoch, M., Olveda, R., Nyatanyi, T., Venter, M., Mmbaga, V., Chittaganpitch, M., Nguyen, T.H., Theo, A., Whaley, M., Azziz-Baumgartner, E., Bresee, J., Campbell, H., Widdowson, M.A., Global role and burden of influenza in pediatric respiratory hospitalizations, 1982-2012: a systematic analysis. PLoS Med., 13, 2016, e1001977.
76. Lee, N., Leo, Y.S., Cao, B., Chan, P.K., Kyaw, W.M., Uyeki, T.M., Tam, W.W., Cheung, C.S., Yung, I.M., Li, H., Gu, L., Liu, Y., Liu, Z., Qu, J., Hui, D.S., Neuraminidase inhibitors, superinfection and corticosteroids affect survival of influenza patients. Eur. Respir. J. 45 (2015), 1642–1652.
77. Lee, N., Lui, G.C., Wong, K.T., Li, T.C., Tse, E.C., Chan, J.Y., Yu, J., Wong, S.S., Choi, K.W., Wong, R.Y., Ngai, K.L., Hui, D.S., Chan, P.K., High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections. Clin. Infect. Dis. 57 (2013), 1069–1077.
78. Lee, N., Wong, C.K., Chan, M.C.W., Yeung, E.S.L., Tam, W.W.S., Tsang, O.T.Y., Choi, K.W., Chan, P.K.S., Kwok, A., Lui, G.C.Y., Leung, W.S., Yung, I.M.H., Wong, R.Y.K., Cheung, C.S.K., Hui, D.S.C., Anti-inflammatory effects of adjunctive macrolide treatment in adults hospitalized with influenza: A randomized controlled trial. Antivir. Res. 144 (2017), 48–56.
79. Leneva, I.A., Burtseva, E.I., Yatsyshina, S.B., Fedyakina, I.T., Kirillova, E.S., Selkova, E.P., Osipova, E., Maleev, V.V., Virus susceptibility and clinical effectiveness of anti-influenza drugs during the 2010-2011 influenza season in Russia. Int. J. Infect. Dis. 43 (2016), 77–84.
80. Leneva, I.A., Russell, R.J., Boriskin, Y.S., Hay, A.J., Characteristics of arbidol-resistant mutants of influenza virus: implications for the mechanism of anti-influenza action of arbidol. Antivir. Res. 81 (2009), 132–140.
81. Li, C., Zhou, X., Zhong, Y., Li, C., Dong, A., He, Z., Zhang, S., Wang, B., A recombinant G protein plus cyclosporine A-based respiratory syncytial virus vaccine elicits humoral and regulatory T cell responses against infection without vaccine-enhanced disease. J. Immunol. 196 (2016), 1721–1731.
82. Li, J., Yang, X., Huang, L., Anti-influenza virus activity and constituents. Characterization of paeonia delavayi extracts. Molecules, 21(9), 2016.
83. Li, Q., Zhou, L., Zhou, M., Chen, Z., Li, F., Wu, H., Xiang, N., Chen, E., Tang, F., Wang, D., Meng, L., Hong, Z., Tu, W., Cao, Y., Li, L., Ding, F., Liu, B., Wang, M., Xie, R., Gao, R., Li, X., Bai, T., Zou, S., He, J., Hu, J., Xu, Y., Chai, C., Wang, S., Gao, Y., Jin, L., Zhang, Y., Luo, H., Yu, H., He, J., Li, Q., Wang, X., Gao, L., Pang, X., Liu, G., Yan, Y., Yuan, H., Shu, Y., Yang, W., Wang, Y., Wu, F., Uyeki, T.M., Feng, Z., Epidemiology of human infections with avian influenza A(H7N9) virus in China. N. Engl. J. Med. 370 (2014), 520–532.
84. Li, T.C., Chan, M.C., Lee, N., Clinical implications of antiviral resistance in influenza. Viruses 7 (2015), 4929–4944.
85. Liang, B., Surman, S., Amaro-Carambot, E., Kabatova, B., Mackow, N., Lingemann, M., Yang, L., McLellan, J.S., Graham, B.S., Kwong, P.D., Schaap-Nutt, A., Collins, P.L., Munir, S., Enhanced neutralizing antibody response induced by respiratory syncytial virus prefusion F protein expressed by a vaccine candidate. J. Virol. 89 (2015), 9499–9510.
86. Lim, J.J., Deng, R., Derby, M.A., Larouche, R., Horn, P., Anderson, M., Maia, M., Carrier, S., Pelletier, I., Burgess, T., Kulkarni, P., Newton, E., Tavel, J.A., Two phase 1, randomized, double-blind, placebo-controlled, single-ascending-dose studies to investigate the safety, tolerability, and pharmacokinetics of an anti-influenza A virus monoclonal antibody, MHAA4549A, in healthy volunteers. Antimicrob. Agents Chemother. 60 (2016), 5437–5444.
87. Lim, W.S., van der Eerden, M.M., Laing, R., Boersma, W.G., Karalus, N., Town, G.I., Lewis, S.A., Macfarlane, J.T., Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 58 (2003), 377–382.
88. Lin, T.J., Yeh, C.F., Wang, K.C., Chiang, L.C., Tsai, J.J., Chang, J.S., Water extract of Pueraria lobata Ohwi has anti-viral activity against human respiratory syncytial virus in human respiratory tract cell lines. Kaohsiung J. Med. Sci. 29 (2013), 651–657.
89. Liu, L., Nachbagauer, R., Zhu, L., Huang, Y., Xie, X., Jin, S., Zhang, A., Wan, Y., Hirsh, A., Tian, D., Shi, X., Dong, Z., Yuan, S., Hu, Y., Krammer, F., Zhang, X., Xu, J., Induction of broadly cross-reactive stalk-specific antibody responses to influenza group 1 and group 2 hemagglutinins by natural H7N9 virus infection in humans. J. Infect. Dis. 215 (2017), 518–528.
90. Liu, Q., Zhou, Y.H., Yang, Z.Q., The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell. Mol. Immunol. 13 (2016), 3–10.
91. Liu, S., Xiao, G., Chen, Y., He, Y., Niu, J., Escalante, C.R., Xiong, H., Farmar, J., Debnath, A.K., Tien, P., Jiang, S., Interaction between heptad repeat 1 and 2 regions in spike protein of SARS-associated coronavirus: implications for virus fusogenic mechanism and identification of fusion inhibitors. Lancet 363 (2004), 938–947.
92. Lu, L., Liu, Q., Zhu, Y., Chan, K.H., Qin, L., Li, Y., Wang, Q., Chan, J.F., Du, L., Yu, F., Ma, C., Ye, S., Yuen, K.Y., Zhang, R., Jiang, S., Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor. Nat. Commun., 5, 2014, 3067.
93. Ma, L.L., Ge, M., Wang, H.Q., Yin, J.Q., Jiang, J.D., Li, Y.H., Antiviral Activities of Several Oral Traditional Chinese Medicines against Influenza Viruses. Evid. Based Complement. Altern. Med., 2015, 2015, 367250.
94. Mair-Jenkins, J., Saavedra-Campos, M., Baillie, J.K., Cleary, P., Khaw, F.M., Lim, W.S., Makki, S., Rooney, K.D., Nguyen-Van-Tam, J.S., Beck, C.R., The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J. Infect. Dis. 211 (2015), 80–90.
95. Mao, X., Wu, J., Lau, E.H.Y., Cheng, K.L., Zhong, Z., Song, Y., Ji, X., Zou, L., Ke, C., Peiris, J.S.M., Wang, H., Yen, H.L., Monitoring avian influenza viruses from chicken carcasses sold at markets, China, 2016. Emerg. Infect. Dis., 23, 2017.
96. Marjuki, H., Mishin, V.P., Chai, N., Tan, M.W., Newton, E.M., Tegeris, J., Erlandson, K., Willis, M., Jones, J., Davis, T., Stevens, J., Gubareva, L.V., Human monoclonal antibody 81.39a effectively neutralizes emerging influenza A viruses of group 1 and 2 hemagglutinins. J. Virol. 90 (2016), 10446–10458.
97. Marjuki, H., Mishin, V.P., Chesnokov, A.P., De La Cruz, J.A., Davis, C.T., Villanueva, J.M., Fry, A.M., Gubareva, L.V., Neuraminidase mutations conferring resistance to oseltamivir in influenza A(H7N9) viruses. J. Virol. 89 (2015), 5419–5426.
98. Marty, F.M., Man, C.Y., van der Horst, C., Francois, B., Garot, D., Manez, R., Thamlikitkul, V., Lorente, J.A., Alvarez-Lerma, F., Brealey, D., Zhao, H.H., Weller, S., Yates, P.J., Peppercorn, A.F., Safety and pharmacokinetics of intravenous zanamivir treatment in hospitalized adults with influenza: an open-label, multicenter, single-arm, phase II study. J. Infect. Dis. 209 (2014), 542–550.
99. Marty, F.M., Vidal-Puigserver, J., Clark, C., Gupta, S.K., Merino, E., Garot, D., Chapman, M.J., Jacobs, F., Rodriguez-Noriega, E., Husa, P., Shortino, D., Watson, H.A., Yates, P.J., Peppercorn, A.F., Intravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase 3 trial. Lancet Respir. Med. 5 (2017), 135–146.
100. McBride, J.M., Lim, J.J., Burgess, T., Deng, R., Derby, M.A., Maia, M., Horn, P., Siddiqui, O., Sheinson, D., Chen-Harris, H., Newton, E.M., Fillos, D., Nazzal, D., Rosenberger, C.M., Ohlson, M.B., Lambkin-Williams, R., Fathi, H., Harris, J.M., Tavel, J.A., Phase 2 randomized trial of the safety and efficacy of MHAA4549A, a broadly neutralizing monoclonal antibody, in a human influenza A virus challenge model. Antimicrob. Agents Chemother., 61(11), 2017.
101. McKimm-Breschkin, J.L., Fry, A.M., Meeting report: 4th ISIRV antiviral group conference: Novel antiviral therapies for influenza and other respiratory viruses. Antivir. Res. 129 (2016), 21–38.
102. McLellan, J.S., Chen, M., Joyce, M.G., Sastry, M., Stewart-Jones, G.B., Yang, Y., Zhang, B., Chen, L., Srivatsan, S., Zheng, A., Zhou, T., Graepel, K.W., Kumar, A., Moin, S., Boyington, J.C., Chuang, G.Y., Soto, C., Baxa, U., Bakker, A.Q., Spits, H., Beaumont, T., Zheng, Z., Xia, N., Ko, S.Y., Todd, J.P., Rao, S., Graham, B.S., Kwong, P.D., Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus. Science 342 (2013), 592–598.
103. McMorrow, M.L., Wemakoy, E.O., Tshilobo, J.K., Emukule, G.O., Mott, J.A., Njuguna, H., Waiboci, L., Heraud, J.M., Rajatonirina, S., Razanajatovo, N.H., Chilombe, M., Everett, D., Heyderman, R.S., Barakat, A., Nyatanyi, T., Rukelibuga, J., Cohen, A.L., Cohen, C., Tempia, S., Thomas, J., Venter, M., Mwakapeje, E., Mponela, M., Lutwama, J., Duque, J., Lafond, K., Nzussouo, N.T., Williams, T., Widdowson, M.A., Severe acute respiratory illness deaths in Sub-Saharan Africa and the role of influenza: a case series from 8 countries. J. Infect. Dis. 212 (2015), 853–860.
104. Meijer, W.J., Linn, F.H., Wensing, A.M., Leavis, H.L., van Riel, D., GeurtsvanKessel, C.H., Wattjes, M.P., Murk, J.L., Acute influenza virus-associated encephalitis and encephalopathy in adults: a challenging diagnosis. JMM Case Rep., 3, 2016, e005076.
105. Memoli, M.J., Czajkowski, L., Reed, S., Athota, R., Bristol, T., Proudfoot, K., Fargis, S., Stein, M., Dunfee, R.L., Shaw, P.A., Davey, R.T., Taubenberger, J.K., Validation of the wild-type influenza A human challenge model H1N1pdMIST: an A(H1N1)pdm09 dose-finding investigational new drug study. Clin. Infect. Dis. 60 (2015), 693–702.
106. Menachery, V.D., Yount, B.L. Jr., Debbink, K., Agnihothram, S., Gralinski, L.E., Plante, J.A., Graham, R.L., Scobey, T., Ge, X.Y., Donaldson, E.F., Randell, S.H., Lanzavecchia, A., Marasco, W.A., Shi, Z.L., Baric, R.S., A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence. Nat. Med. 21 (2015), 1508–1513.
107. Myles, P.R., Semple, M.G., Lim, W.S., Openshaw, P.J., Gadd, E.M., Read, R.C., Taylor, B.L., Brett, S.J., McMenamin, J., Enstone, J.E., Armstrong, C., Bannister, B., Nicholson, K.G., Nguyen-Van-Tam, J.S., Predictors of clinical outcome in a national hospitalised cohort across both waves of the influenza A/H1N1 pandemic 2009-2010 in the UK. Thorax 67 (2012), 709–717.
108. Oberste, M.S., Maher, K., Schnurr, D., Flemister, M.R., Lovchik, J.C., Peters, H., Sessions, W., Kirk, C., Chatterjee, N., Fuller, S., Hanauer, J.M., Pallansch, M.A., Enterovirus 68 is associated with respiratory illness and shares biological features with both the enteroviruses and the rhinoviruses. J. Gen. Virol. 85 (2004), 2577–2584.
109. Oh, M.D., Park, W.B., Choe, P.G., Choi, S.J., Kim, J.I., Chae, J., Park, S.S., Kim, E.C., Oh, H.S., Kim, E.J., Nam, E.Y., Na, S.H., Kim, D.K., Lee, S.M., Song, K.H., Bang, J.H., Kim, E.S., Kim, H.B., Park, S.W., Kim, N.J., Viral load kinetics of MERS coronavirus infection. N. Engl. J. Med. 375 (2016), 1303–1305.
110. Osborne, R.H., Norquist, J.M., Elsworth, G.R., Busija, L., Mehta, V., Herring, T., Gupta, S.B., Development and validation of the Influenza Intensity and Impact Questionnaire (FluiiQ). Value Health 14 (2011), 687–699.
111. Paddock, C.D., Liu, L., Denison, A.M., Bartlett, J.H., Holman, R.C., Deleon-Carnes, M., Emery, S.L., Drew, C.P., Shieh, W.J., Uyeki, T.M., Zaki, S.R., Myocardial injury and bacterial pneumonia contribute to the pathogenesis of fatal influenza B virus infection. J. Infect. Dis. 205 (2012), 895–905.
112. Park, S.W., Perera, R.A., Choe, P.G., Lau, E.H., Choi, S.J., Chun, J.Y., Oh, H.S., Song, K.H., Bang, J.H., Kim, E.S., Kim, H.B., Park, W.B., Kim, N.J., Poon, L.L., Peiris, M., Oh, M.D., Comparison of serological assays in human Middle East respiratory syndrome (MERS)-coronavirus infection. Euro Surveill., 20(41), 2015.
113. Park, W.B., Perera, R.A., Choe, P.G., Lau, E.H., Choi, S.J., Chun, J.Y., Oh, H.S., Song, K.H., Bang, J.H., Kim, E.S., Kim, H.B., Park, S.W., Kim, N.J., Man Poon, L.L., Peiris, M., Oh, M.D., Kinetics of serologic responses to MERS coronavirus infection in humans, South Korea. Emerg. Infect. Dis. 21 (2015), 2186–2189.
114. Peiris, J.S., Cowling, B.J., Wu, J.T., Feng, L., Guan, Y., Yu, H., Leung, G.M., Interventions to reduce zoonotic and pandemic risks from avian influenza in Asia. Lancet Infect. Dis. 16 (2016), 252–258.
115. Perron, M., Stray, K., Kinkade, A., Theodore, D., Lee, G., Eisenberg, E., Sangi, M., Gilbert, B.E., Jordan, R., Piedra, P.A., Toms, G.L., Mackman, R., Cihlar, T., GS-5806 inhibits a broad range of respiratory syncytial virus clinical isolates by blocking the virus-cell fusion process. Antimicrob. Agents Chemother. 60 (2015), 1264–1273.
116. Piacentini, S., La Frazia, S., Rossignol, J.F., Santoro, G., Antiviral activity of nitazoxanide against paramyxoviridae infection: effect on the fusion (F) protein. XVIII International Symposium on Respiratory Viral Infections, 2016, The Macrae Foundation, Lisbon, Portugal.
117. Powers, J.H., Guerrero, M.L., Leidy, N.K., Fairchok, M.P., Rosenberg, A., Hernandez, A., Stringer, S., Schofield, C., Rodriguez-Zulueta, P., Kim, K., Danaher, P.J., Ortega-Gallegos, H., Bacci, E.D., Stepp, N., Galindo-Fraga, A., St Clair, K., Rajnik, M., McDonough, E.A., Ridore, M., Arnold, J.C., Millar, E.V., Ruiz-Palacios, G.M., Development of the Flu-PRO: a patient-reported outcome (PRO) instrument to evaluate symptoms of influenza. BMC Infect. Dis., 16, 2016, 1.
118. Qu, J.M., Cao, B., Guidelines for the diagnosis and treatment of adult community acquired pneumonia in China (2016 Edition). Zhonghua Jie He He Hu Xi Za Zhi 39 (2016), 241–242.
119. Reynolds, J., Ark Biosciences' Anti-respiratory Syncytial Virus Drug AK0529 Successfully Completes Phase 1 Study: Results Presented at International Conference, 2015 2017 http://www.fiercepharma.com/pharma-asia/ark-biosciences-anti-respiratory-syncytial-virus-drug-ak0529-successfully-completes. (Accessed 28 July 2017)
120. Roche, H.-L., Influenza Resistance Information Study (IRIS). 2016 https://clinicaltrials.gov/ct2/show/NCT00884117. (Accessed 16 August 2017)
121. Rodrigo, C., Leonardi-Bee, J., Nguyen-Van-Tam, J., Lim, W.S., Corticosteroids as adjunctive therapy in the treatment of influenza. Cochrane Database Syst. Rev., 3, 2016 Cd010406.
122. Rossignol, J.F., Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antivir. Res. 110 (2014), 94–103.
123. Russell, E., Ison, M.G., Parainfluenza virus in the hospitalized adult. Clin. Infect. Dis. 65 (2017), 1570–1576.
124. Schieble, J.H., Fox, V.L., Lennette, E.H., A probable new human picornavirus associated with respiratory diseases. Am. J. Epidemiol. 85 (1967), 297–310.
125. Sellers, S.A., Hagan, R.S., Hayden, F.G., Fischer, W.A. 2nd, The hidden burden of influenza: A review of the extra-pulmonary complications of influenza infection. Influenza Other Respir. Viruses 11 (2017), 372–393.
126. Seong, M.W., Kim, S.Y., Corman, V.M., Kim, T.S., Cho, S.I., Kim, M.J., Lee, S.J., Lee, J.S., Seo, S.H., Ahn, J.S., Yu, B.S., Park, N., Oh, M.D., Park, W.B., Lee, J.Y., Kim, G., Joh, J.S., Jeong, I., Kim, E.C., Drosten, C., Park, S.S., Microevolution of outbreak-associated middle east respiratory syndrome coronavirus, South Korea, 2015. Emerg. Infect. Dis. 22 (2016), 327–330.
127. Shakya, A., Bhat, H.R., Ghosh, S.K., Update on nitazoxanide: a multifunctional chemotherapeutic agent. Curr. Drug Discov. Technol., 2017, 10.2174/1570163814666170727130003.
128. Sheahan, T.P., Sims, A.C., Graham, R.L., Menachery, V.D., Gralinski, L.E., Case, J.B., Leist, S.R., Pyrc, K., Feng, J.Y., Trantcheva, I., Bannister, R., Park, Y., Babusis, D., Clarke, M.O., Mackman, R.L., Spahn, J.E., Palmiotti, C.A., Siegel, D., Ray, A.S., Cihlar, T., Jordan, R., Denison, M.R., Baric, R.S., Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci. Transl. Med., 9, 2017.
129. Shi, H., Ren, K., Lv, B., Zhang, W., Zhao, Y., Tan, R.X., Li, E., Baicalin from Scutellaria baicalensis blocks respiratory syncytial virus (RSV) infection and reduces inflammatory cell infiltration and lung injury in mice. Sci. Rep., 6, 2016, 35851.
130. Shi, T., McAllister, D.A., O'Brien, K.L., Simoes, E.A.F., Madhi, S.A., Gessner, B.D., Polack, F.P., Balsells, E., Acacio, S., Aguayo, C., Alassani, I., Ali, A., Antonio, M., Awasthi, S., Awori, J.O., Azziz-Baumgartner, E., Baggett, H.C., Baillie, V.L., Balmaseda, A., Barahona, A., Basnet, S., Bassat, Q., Basualdo, W., Bigogo, G., Bont, L., Breiman, R.F., Brooks, W.A., Broor, S., Bruce, N., Bruden, D., Buchy, P., Campbell, S., Carosone-Link, P., Chadha, M., Chipeta, J., Chou, M., Clara, W., Cohen, C., de Cuellar, E., Dang, D.A., Dash-Yandag, B., Deloria-Knoll, M., Dherani, M., Eap, T., Ebruke, B.E., Echavarria, M., de Freitas Lazaro Emediato, C.C., Fasce, R.A., Feikin, D.R., Feng, L., Gentile, A., Gordon, A., Goswami, D., Goyet, S., Groome, M., Halasa, N., Hirve, S., Homaira, N., Howie, S.R.C., Jara, J., Jroundi, I., Kartasasmita, C.B., Khuri-Bulos, N., Kotloff, K.L., Krishnan, A., Libster, R., Lopez, O., Lucero, M.G., Lucion, F., Lupisan, S.P., Marcone, D.N., McCracken, J.P., Mejia, M., Moisi, J.C., Montgomery, J.M., Moore, D.P., Moraleda, C., Moyes, J., Munywoki, P., Mutyara, K., Nicol, M.P., Nokes, D.J., Nymadawa, P., da Costa Oliveira, M.T., Oshitani, H., Pandey, N., Paranhos-Baccala, G., Phillips, L.N., Picot, V.S., Rahman, M., Rakoto-Andrianarivelo, M., Rasmussen, Z.A., Rath, B.A., Robinson, A., Romero, C., Russomando, G., Salimi, V., Sawatwong, P., Scheltema, N., Schweiger, B., Scott, J.A.G., Seidenberg, P., Shen, K., Singleton, R., Sotomayor, V., Strand, T.A., Sutanto, A., Sylla, M., Tapia, M.D., Thamthitiwat, S., Thomas, E.D., Tokarz, R., Turner, C., Venter, M., Waicharoen, S., Wang, J., Watthanaworawit, W., Yoshida, L.M., Yu, H., Zar, H.J., Campbell, H., Nair, H., Network, R.S.V.G.E., Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet 390 (2017), 946–958.
131. Smith, J.G., Wiethoff, C.M., Stewart, P.L., Nemerow, G.R., Adenovirus. Curr. Top. Microbiol. Immunol. 343 (2010), 195–224.
132. Stachulski, A.V., Swift, K., Cooper, M., Reynolds, S., Norton, D., Slonecker, S.D., Rossignol, J.F., Synthesis and pre-clinical studies of new amino-acid ester thiazolide prodrugs. Eur. J. Med. Chem. 126 (2017), 154–159.
133. Su, S., Gu, M., Liu, D., Cui, J., Gao, G.F., Zhou, J., Liu, X., Epidemiology, evolution, and pathogenesis of H7N9 influenza viruses in five epidemic waves since 2013 in China. Trends Microbiol. 25 (2017), 713–728.
134. Suarez, N.M., Bunsow, E., Falsey, A.R., Walsh, E.E., Mejias, A., Ramilo, O., Superiority of transcriptional profiling over procalcitonin for distinguishing bacterial from viral lower respiratory tract infections in hospitalized adults. J. Infect. Dis. 212 (2015), 213–222.
135. Takashita, E., Ejima, M., Itoh, R., Miura, M., Ohnishi, A., Nishimura, H., Odagiri, T., Tashiro, M., A community cluster of influenza A(H1N1)pdm09 virus exhibiting cross-resistance to oseltamivir and peramivir in Japan, November to December 2013. Euro Surveill., 19(1), 2014.
136. Takashita, E., Kiso, M., Fujisaki, S., Yokoyama, M., Nakamura, K., Shirakura, M., Sato, H., Odagiri, T., Kawaoka, Y., Tashiro, M., Characterization of a large cluster of influenza A(H1N1)pdm09 viruses cross-resistant to oseltamivir and peramivir during the 2013-2014 influenza season in Japan. Antimicrob. Agents Chemother. 59 (2015), 2607–2617.
137. Tao, X., Garron, T., Agrawal, A.S., Algaissi, A., Peng, B.H., Wakamiya, M., Chan, T.S., Lu, L., Du, L., Jiang, S., Couch, R.B., Tseng, C.T., Characterization and demonstration of the value of a lethal mouse model of middle east respiratory syndrome coronavirus infection and disease. J. Virol. 90 (2015), 57–67.
138. Tharakaraman, K., Subramanian, V., Viswanathan, K., Sloan, S., Yen, H.L., Barnard, D.L., Leung, Y.H., Szretter, K.J., Koch, T.J., Delaney, J.C., Babcock, G.J., Wogan, G.N., Sasisekharan, R., Shriver, Z., A broadly neutralizing human monoclonal antibody is effective against H7N9. Proc. Natl. Acad. Sci. U. S. A. 112 (2015), 10890–10895.
139. Thwaites, R.S., Ito, K., Chingono, J.M.S., Coates, M., Jarvis, H.C., Tunstall, T., Anderson-Dring, L., Cass, L., Rapeport, G., Openshaw, P.J., Nadel, S., Hansel, T.T., Nasosorption as a minimally invasive sampling procedure: mucosal viral load and inflammation in primary RSV bronchiolitis. J. Infect. Dis. 215 (2017), 1240–1244.
140. Tokarz, R., Firth, C., Madhi, S.A., Howie, S.R., Wu, W., Sall, A.A., Haq, S., Briese, T., Lipkin, W.I., Worldwide emergence of multiple clades of enterovirus 68. J. Gen. Virol. 93 (2012), 1952–1958.
141. Tomas, J., Macario, M.C., Gaspar, E., Santana, I., Severe post-influenza (H1N1) encephalitis involving pulvinar nuclei in an adult patient. BMJ Case Rep., 2015, 2015.
142. Torres, A., Lee, N., Cilloniz, C., Vila, J., Van der Eerden, M., Laboratory diagnosis of pneumonia in the molecular age. Eur. Respir. J. 48 (2016), 1764–1778.
143. Treanor, J.J., Hayden, F.G., Vrooman, P.S., Barbarash, R., Bettis, R., Riff, D., Singh, S., Kinnersley, N., Ward, P., Mills, R.G., Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group. JAMA 283 (2000), 1016–1024.
144. Trock, S.C., Burke, S.A., Cox, N.J., Development of framework for assessing influenza virus pandemic risk. Emerg. Infect. Dis. 21 (2015), 1372–1378.
145. Turner, R.B., Woodfolk, J.A., Borish, L., Steinke, J.W., Patrie, J.T., Muehling, L.M., Lahtinen, S., Lehtinen, M.J., Effect of probiotic on innate inflammatory response and viral shedding in experimental rhinovirus infection - a randomised controlled trial. Benef. Microbes 8 (2017), 207–215.
146. Uehara, T., Toru, I., Keiko, K., Kawaguchi, K., Sato, C., Ishida, T., Hirotsu, N., Watanabe, A., S-033188, a Small Molecule Inhibitor of Cap-dependent Endonuclease of Influenza A and B Virus, Leads to Rapid and Profound Viral Load Reduction, Options for the Control of Influenza IX. 2016, ISIRV, Chicago, USA., 78.
147. Waghmare, A., Englund, J.A., Boeckh, M., How I treat respiratory viral infections in the setting of intensive chemotherapy or hematopoietic cell transplantation. Blood 127 (2016), 2682–2692.
148. Waghmare, A., Wagner, T., Andrews, R., Smith, S., Kuypers, J., Boeckh, M., Moss, R., Englund, J.A., Successful treatment of parainfluenza virus respiratory tract infection with DAS181 in 4 immunocompromised children. J. Pediatr. Infect. Dis. Soc. 4 (2015), 114–118.
149. Wang, C., Cao, B., Liu, Q.Q., Zou, Z.Q., Liang, Z.A., Gu, L., Dong, J.P., Liang, L.R., Li, X.W., Hu, K., He, X.S., Sun, Y.H., An, Y., Yang, T., Cao, Z.X., Guo, Y.M., Wen, X.M., Wang, Y.G., Liu, Y.L., Jiang, L.D., Oseltamivir compared with the Chinese traditional therapy maxingshigan-yinqiaosan in the treatment of H1N1 influenza: a randomized trial. Ann. Intern. Med. 155 (2011), 217–225.
150. Wang, C.H., Chung, F.T., Lin, S.M., Huang, S.Y., Chou, C.L., Lee, K.Y., Lin, T.Y., Kuo, H.P., Adjuvant treatment with a mammalian target of rapamycin inhibitor, sirolimus, and steroids improves outcomes in patients with severe H1N1 pneumonia and acute respiratory failure. Crit. Care Med. 42 (2014), 313–321.
151. Wang, D., Yang, L., Zhu, W., Zhang, Y., Zou, S., Bo, H., Gao, R., Dong, J., Huang, W., Guo, J., Li, Z., Zhao, X., Li, X., Xin, L., Zhou, J., Chen, T., Dong, L., Wei, H., Li, X., Liu, L., Tang, J., Lan, Y., Yang, J., Shu, Y., Two outbreak sources of influenza A (H7N9) viruses have been established in China. J. Virol. 90 (2016), 5561–5573.
152. Wang, L., Shi, W., Joyce, M.G., Modjarrad, K., Zhang, Y., Leung, K., Lees, C.R., Zhou, T., Yassine, H.M., Kanekiyo, M., Yang, Z.Y., Chen, X., Becker, M.M., Freeman, M., Vogel, L., Johnson, J.C., Olinger, G., Todd, J.P., Bagci, U., Solomon, J., Mollura, D.J., Hensley, L., Jahrling, P., Denison, M.R., Rao, S.S., Subbarao, K., Kwong, P.D., Mascola, J.R., Kong, W.P., Graham, B.S., Evaluation of candidate vaccine approaches for MERS-CoV. Nat. Commun., 6, 2015, 7712.
153. Wang, P., Song, Y., Liu, Z., Wang, H., Zheng, W., Liu, S., Feng, Z., Zhai, J., Yao, C., Ren, M., Bai, C., Shang, H., Xuebijing injection in the treatment of severe pneumonia: study protocol for a randomized controlled trial. Trials, 17, 2016, 142.
154. Wang, W., Song, Z., Guan, W., Liu, Y., Zhang, X., Xu, L., Li, J., Yuan, Z., Hu, Y., PCR for detection of oseltamivir resistance mutation in influenza A(H7N9) virus. Emerg. Infect. Dis. 20 (2014), 847–849.
155. Wang, Y., Zhou, B., Lu, J., Chen, Q., Ti, H., Huang, W., Li, J., Yang, Z., Jiang, Z., Wang, X., Inhibition of influenza virus via a sesquiterpene fraction isolated from Laggera pterodonta by targeting the NF-kappaB and p38 pathways. BMC Complement. Altern. Med., 17, 2017, 25.
156. West, N.P., Horn, P.L., Pyne, D.B., Gebski, V.J., Lahtinen, S.J., Fricker, P.A., Cripps, A.W., Probiotic supplementation for respiratory and gastrointestinal illness symptoms in healthy physically active individuals. Clin. Nutr. 33 (2014), 581–587.
157. WHO, Meetings of the WHO working group on surveillance of influenza antiviral susceptibility - Geneva, November 2011 and June 2012. Wkly. Epidemiol. Rec. 87 (2012), 369–374.
158. WHO, WHO public health research agenda for influenza. Biannual Progress Review and Report 2010–2011, 2013 http://www.who.int/influenza/resources/research/RA_Progress_Report_short.pdf?ua=1. (Accessed 28 August 2017)
159. WHO, Infection Prevention and Control of Epidemic-and Pandemic Prone Acute Respiratory Infections in Health Care WHO Guidelines. 2014 http://www.who.int/csr/bioriskreduction/infection_control/publication/en/. (Accessed 1 August 2017)
160. WHO, WHO public health research agenda for influenza. http://www.who.int/influenza/resources/research/about/en/, 2017. (Accessed 28 August 2017)
161. Wollacott, A.M., Boni, M.F., Szretter, K.J., Sloan, S.E., Yousofshahi, M., Viswanathan, K., Bedard, S., Hay, C.A., Smith, P.F., Shriver, Z., Trevejo, J.M., Safety and upper respiratory pharmacokinetics of the hemagglutinin stalk-binding antibody VIS410 support treatment and prophylaxis based on population modeling of seasonal influenza A outbreaks. EBioMedicine 5 (2016), 147–155.
162. Wong, D.D., Choy, K.T., Chan, R.W., Sia, S.F., Chiu, H.P., Cheung, P.P., Chan, M.C., Peiris, J.S., Yen, H.L., Comparable fitness and transmissibility between oseltamivir-resistant pandemic 2009 and seasonal H1N1 influenza viruses with the H275Y neuraminidase mutation. J. Virol. 86 (2012), 10558–10570.
163. Yang, J., Jit, M., Leung, K.S., Zheng, Y.M., Feng, L.Z., Wang, L.P., Lau, E.H., Wu, J.T., Yu, H.J., The economic burden of influenza-associated outpatient visits and hospitalizations in China: a retrospective survey. Infect. Dis. Poverty, 4, 2015, 44.
164. Yassine, H.M., Boyington, J.C., McTamney, P.M., Wei, C.J., Kanekiyo, M., Kong, W.P., Gallagher, J.R., Wang, L., Zhang, Y., Joyce, M.G., Lingwood, D., Moin, S.M., Andersen, H., Okuno, Y., Rao, S.S., Harris, A.K., Kwong, P.D., Mascola, J.R., Nabel, G.J., Graham, B.S., Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection. Nat. Med. 21 (2015), 1065–1070.
165. Yates, P.J., Raimonde, D.S., Zhao, H.H., Man, C.Y., Steel, H.M., Mehta, N., Peppercorn, A.F., Phenotypic and genotypic analysis of influenza viruses isolated from adult subjects during a phase II study of intravenous zanamivir in hospitalised subjects. Antivir. Res. 134 (2016), 144–152.
166. Ying, T., Du, L., Ju, T.W., Prabakaran, P., Lau, C.C., Lu, L., Liu, Q., Wang, L., Feng, Y., Wang, Y., Zheng, B.J., Yuen, K.Y., Jiang, S., Dimitrov, D.S., Exceptionally potent neutralization of Middle East respiratory syndrome coronavirus by human monoclonal antibodies. J. Virol. 88 (2014), 7796–7805.
167. Ying, T., Prabakaran, P., Du, L., Shi, W., Feng, Y., Wang, Y., Wang, L., Li, W., Jiang, S., Dimitrov, D.S., Zhou, T., Junctional and allele-specific residues are critical for MERS-CoV neutralization by an exceptionally potent germline-like antibody. Nat. Commun., 6, 2015, 8223.
168. Yu, H., Alonso, W.J., Feng, L., Tan, Y., Shu, Y., Yang, W., Viboud, C., Characterization of regional influenza seasonality patterns in China and implications for vaccination strategies: spatio-temporal modeling of surveillance data. PLoS Med., 10, 2013, e1001552.
169. Yu, H., Huang, J., Huai, Y., Guan, X., Klena, J., Liu, S., Peng, Y., Yang, H., Luo, J., Zheng, J., Chen, M., Peng, Z., Xiang, N., Huo, X., Xiao, L., Jiang, H., Chen, H., Zhang, Y., Xing, X., Xu, Z., Feng, Z., Zhan, F., Yang, W., Uyeki, T.M., Wang, Y., Varma, J.K., The substantial hospitalization burden of influenza in central China: surveillance for severe, acute respiratory infection, and influenza viruses, 2010-2012. Influenza Other Respir. Viruses 8 (2014), 53–65.
170. Yu, H., Wu, J.T., Cowling, B.J., Liao, Q., Fang, V.J., Zhou, S., Wu, P., Zhou, H., Lau, E.H., Guo, D., Ni, M.Y., Peng, Z., Feng, L., Jiang, H., Luo, H., Li, Q., Feng, Z., Wang, Y., Yang, W., Leung, G.M., Effect of closure of live poultry markets on poultry-to-person transmission of avian influenza A H7N9 virus: an ecological study. Lancet 383 (2014), 541–548.
171. Yuan, J., Lau, E.H., Li, K., Leung, Y.H., Yang, Z., Xie, C., Liu, Y., Liu, Y., Ma, X., Liu, J., Li, X., Chen, K., Luo, L., Di, B., Cowling, B.J., Tang, X., Leung, G.M., Wang, M., Peiris, M., Effect of live poultry market closure on avian influenza A(H7N9) virus activity in Guangzhou, China, 2014. Emerg. Infect. Dis. 21 (2015), 1784–1793.
172. Yuan, L., Zhang, C., Sun, H., Liu, Q., Huang, J., Sheng, L., Lin, B., Wang, J., Chen, L., The semi-synthesis of novel andrographolide analogues and anti-influenza virus activity evaluation of their derivatives. Bioorg. Med. Chem. Lett. 26 (2016), 769–773.
173. Zhang, H., Luo, J., Alcorn, J.F., Chen, K., Fan, S., Pilewski, J., Liu, A., Chen, W., Kolls, J.K., Wang, J., AIM2 inflammasome is critical for influenza-induced lung injury and mortality. J. Immunol. 198 (2017), 4383–4393.
174. Zhao, Y., Zhang, Y.H., Denney, L., Young, D., Powell, T.J., Peng, Y.C., Li, N., Yan, H.P., Wang, D.Y., Shu, Y.L., Kendrick, Y., McMichael, A.J., Ho, L.P., Dong, T., High levels of virus-specific CD4+ T cells predict severe pandemic influenza A virus infection. Am. J. Respir. Crit. Care Med. 186 (2012), 1292–1297.
175. Zhou, J., Wu, J., Zeng, X., Huang, G., Zou, L., Song, Y., Gopinath, D., Zhang, X., Kang, M., Lin, J., Cowling, B.J., Lindsley, W.G., Ke, C., Peiris, J.S., Yen, H.L., Isolation of H5N6, H7N9 and H9N2 avian influenza A viruses from air sampled at live poultry markets in China, 2014 and 2015. Euro Surveill., 21(35), 2016.
176. Zhou, L., Ren, R., Yang, L., Bao, C., Wu, J., Wang, D., Li, C., Xiang, N., Wang, Y., Li, D., Sui, H., Shu, Y., Feng, Z., Li, Q., Ni, D., Sudden increase in human infection with avian influenza A(H7N9) virus in China, September-December 2016. West. Pac Surveill. Response J. 8 (2017), 6–14.
177. Zhou, L., Tan, Y., Kang, M., Liu, F., Ren, R., Wang, Y., Chen, T., Yang, Y., Li, C., Wu, J., Zhang, H., Li, D., Greene, C.M., Zhou, S., Iuliano, A.D., Havers, F., Ni, D., Wang, D., Feng, Z., Uyeki, T.M., Li, Q., Preliminary epidemiology of human infections with highly pathogenic avian influenza A(H7N9) Virus, China, 2017. Emerg. Infect. Dis. 23 (2017), 1355–1359.
178. Zhu, W., Zhou, J., Li, Z., Yang, L., Li, X., Huang, W., Zou, S., Chen, W., Wei, H., Tang, J., Liu, L., Dong, J., Wang, D., Shu, Y., Biological characterisation of the emerged highly pathogenic avian influenza (HPAI) A(H7N9) viruses in humans, in mainland China, 2016 to 2017. Euro Surveill., 22(19), 2017.