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Paragraph: In February 2013 , China detected the first human cases of H7N9 infection in severely ill patients with pneumonia. 3 As of May 22, 2014 , there have been 446 confirmed H7N9 cases in China resulting in 163 deaths. 4 The cases have occurred mainly during two waves (weeks [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] 2013 and week 40, 2013week 20, 2014) , 4 of which 85% had prior exposure to poultry or contaminated live poultry markets. The median time from poultry exposure to disease onset was 5 days, whereas the median time from illness onset to hospital admission, ARDS development, antiviral therapy and death was 5, 6Á8, 7 and 14 days, respectively. 5 Closure of live poultry markets has markedly reduced the risk of H7N9 infection. Across nine areas in the two most affected provinces in China, modelling analysis estimated that the effectiveness of market closure was 97% (95% CI: 89%, 100%). 6 A retrospective serological study of blood specimens taken in January-May and October-November in 2012 from 1544 subjects who worked in live poultry markets, farms, slaughter houses or kept backyard poultry revealed no evidence of H7N9 infection, 7 indicating widespread population susceptibility and lack of prior circulation of antigenically related viruses. Multiple family clusters have been reported, but no sustained human-to-human transmission, with studies demonstrating a very low detection of virus or specific antibody in close contacts (0Á34% and 0Á2% in the first and second waves, respectively) and healthcare workers of positive cases. 8 In both the first and the second waves, the majority of the patients hospitalised with H7N9 infection were older men (median age, 62 and 58 years, respectively with an overall male/female ratio of 2Á2:1) and the case fatality was similar (32% and 39%, respectively). Pre-existing medical conditions occurred in >60% of these cases. The prominent clinical features on admission were those of a severe influenza syndrome with fever, cough, fatigue and dyspnoea, while the most striking laboratory findings were marked lymphopenia and thrombocytopenia. Elevated cytokine levels have been observed in patients and such excessive cytokine responses may contribute to the clinical severity of H7N9 infection. 9 Originating from reassortment events involving at least three avian influenza viruses, H7N9 viruses with multiple genotypes continue to emerge on a more frequent basis in 2014. Many viruses isolated from humans contain the E627K amino acid substitution in the polymerase PB2 component, associated with mammalian adaptation, and the G186V and Q226L substitutions in the haemagglutinin (HA) that are associated with dual receptor binding to both a2,3 and a2,6-linked sialic acid receptors. 10 All H7N9 viruses from the outbreak to date are antigenically similar to the (original) candidate vaccine strain. Prototype inactivated whole particle H7N9 vaccines have been investigated in macaques and shown to induce good antibody responses that significantly reduced the number of days of virus shedding in experimentally infected animals. Treatment of H7N9-infected patients with neuraminidase inhibitors (NAIs), including intravenous (IV) peramivir or zanamivir, 11 appears to have been beneficial even when therapy was started late, although emergence of oseltamivir resistance has been associated with poor clinical outcomes. 12 All H7N9 viruses are amantadine-resistant due to the S31N substitution in the M2 ion channel protein, while viruses containing the R292K substitution in neuraminidase (NA), which confers resistance to both oseltamivir and peramivir (>1000-fold rise in IC 50 ) and reduced susceptibility to zanamivir and laninamivir (50-and 25-fold rises in IC 50 , respectively), have been reported in six cases. Two of these patients with severe H7N9 infection requiring extracorporeal membrane oxygenation (ECMO) also received systemic corticosteroid treatment leading to treatment failure and a poor clinical outcome. 12 The replication and transmission of H7N9 viruses containing the R292K NA mutation have been shown to be comparable to those of wild-type H7N9 viruses in guinea pigs, 13 and in ferrets following both contact and non-contact exposure. However, the wild-type virus did outgrow the R292K-resistant strain in some ferrets over the course of the infection. 14 Interestingly, the R292K variant appeared to be the dominant virus in ferret lung lobes, while in nasal turbinates, the wild-type virus was predominant. Therefore, it appears that the R292K mutation causes less fitness loss in H7N9 virus than in seasonal H3N2 viruses. 13

A new reassortant genotype of H5N1 containing the HA and NA genes from clade 1.1.2 and the internal genes from clade 2.3.2.1 emerged during 2013 and was associated with the highest number of cases (n = 26) and deaths (n = 14) in Cambodia. 15 Globally since 2003, there have been 650 confirmed H5N1 cases and 386 deaths reported in humans, 16 with most infections in the last 2 years being in children. Human-to-human transmission remains extremely rare based on virological and serological data from analysis of close contacts of confirmed cases in Cambodia, Thailand and Vietnam. 17 A study of household transmission patterns in Indonesia has shown that the overall household attack rate was 18Á3% and the secondary attack rate was 5Á5%, independent of household size. 18 Oseltamivir therapy appears to reduce mortality when administered within 8 days of H5N1 illness onset, although earlier treatment is more effective, highlighting the need for early patient diagnosis. 19 Early initiation of oseltamivir was particularly effective in reducing mortality in H5N1 patients without respiratory failure (odds ratio, 0Á17; P = 0Á04), whereas those requiring ventilatory support at the time of oseltamivir initiation were more likely to die. 20 A study of the risk factors for mortality related to H5N1 identified age, country, per capita government health expenditure and delay from symptom onset to hospitalisation as the key parameters, highlighting the importance of early diagnosis, treatment and supportive care. 21 High-dose systemic corticosteroids (SC) are associated with worse outcomes in H5N1 patients. 22 One human case of avian H5N6 was recently detected in China; the virus was a reassortant that contained seven genes from H5N1 and the NA gene from an H6N6 virus circulating in ducks. 23 China has also reported the detection of three human infections, two fatal, with avian H10N8 viruses that contain the internal genes from H9N2, as does H7N9. 24 Like the H7N9 virus, the H10N8 virus has low pathogenicity in poultry and is therefore difficult to detect in birds. Burden in target populations Pregnant women and infants have an increased risk of complications following influenza infection. Globally, significant numbers of pregnant women died during the 2009-2010 pandemic, but no maternal mortality occurred in Japan. 25 Through education campaigns directed at pregnant women and healthcare professionals, 67% of pregnant women were vaccinated against H1N1pdm09 resulting in an infection rate among pregnant women in Japan of 3Á5% compared to the overall infection rate in the population of 12%. 26 Of those pregnant women who were infected with H1N1pdm09 in Japan, 95% were treated with antivirals, and importantly, 88% of those were treated within 2 days of symptom onset. 25 In Mongolia, a prospective cohort study during 2013-2014 found that influenza-like illness (ILI) was detected in 17Á9% of pregnant women, of whom the majority tested positive for influenza A, with substantially lower influenza B and respiratory syncytial virus (RSV) infection. 27 During the same period, ILI was detected in 30Á9% of infants <6 months of age, with an even spread of influenza A, influenza B and RSV. 27 The influenza burden in children in a rural Indian community was found to be substantial with 11Á6% of ILI cases being caused by influenza A or B viruses. 28 These findings underscore the importance of maternal immunisation. 29 Transmission patterns Sequence analysis of influenza viruses isolated from students on a Singapore University Campus provided insights into the chain of transmission, showing that 62% of 32 viruses were highly similar, demonstrating that the majority of transmission was occurring on the university campus rather than from infections outside. 30 The effectiveness of surgical masks, hand hygiene and health education investigated in households in Hong Kong and Bangkok detected no significant difference in attack rate in cohorts using one of these interventions. 31 Further analysis of the data enabled some insights into the relative importance of aerosol, large droplet and contact transmission within the households. For influenza A infections, aerosol transmission appeared to be the most common route, whereas contact transmission caused the highest number of influenza B infections. 31 

Use and effectiveness Neuraminidase inhibitors are commonly used for the treatment of influenza in Japan, typically following a positive result from a point-of-care (POC) test. During the 2009-2010 pandemic, over 20 million POC test kits were shipped to hospitals and clinics in Japan to enable rapid diagnosis, and 89% of treated cases were administered NAIs within 48 hours of symptom onset. 32 In Japan during 2013, oseltamivir and laninamivir each represented 40% of NAIs used, while zanamivir (15%) and peramivir (5%) use was considerably less. NAI effectiveness has been assessed in numerous observational studies in Japan. Oseltamivir effectiveness is significantly reduced in patients with delayed treatment, and duration of fever and viral shedding is longer in treated patients with influenza B compared to influenza A virus infections. 33, 34 The reduced effectiveness against influenza B viruses was also observed in zanamivir 33, 35 and laninamivir 35 trials. To determine whether NAIs reduced mortality during the 2009-2010 pandemic, data were compiled on 29 234 patients hospitalised with confirmed A(H1N1)pdm09 infection. 36 Compared with no treatment, NAI treatment was associated with significantly reduced mortality, with early treatment also showing a reduced risk of mortality compared to late treatment. Although there was no significant clinical effect when comparing late treatment with no treatment in hospitalised patients, there was a significant benefit in treating patients who arrive late into intensive care units. 36 In a household prophylaxis study, inhaled laninamivir given for either 2 or 3 days reduced the illness rate within households to 3Á9% and 3Á7%, respectively, compared to 16Á9% in households given a placebo. 37 A ferret model of oseltamivir prophylaxis has shown that while morbidity was significantly reduced, the prophylaxis regimes did not prevent infection nor significantly reduce virus load. 38 Resistance Although all four NAIs are sialic acid analogues, they have subtle differences in chemical structure and binding properties. Consequently, resistance patterns vary across NAIs. The most commonly detected NA substitution causing NAI resistance in N1-containing influenza viruses is H275Y, which confers resistance to oseltamivir and peramivir, but not to zanamivir and laninamivir. This resistance mutation became fixed in seasonal H1N1 viruses circulating in 2008-2009. 39 A late 2013 cluster of H1N1pdm09 viruses containing the H275Y substitution was detected in 38 (39%) of 97 H1N1pdm09 viruses from community patients not receiving NAIs in Sapporo, Japan, 40 reminiscent of a similar cluster of oseltamivir-resistant H1N1pdm09 viruses in community patients in Australia in 2011. 41, 42 Importantly, both sets of viruses contained permissive NA mutations (V241I and N369K) that have been shown in ferret studies to offset the destabilising and negative effect of the H275Y NA mutation. 43 In hospitalised influenza patients being treated with intravenous zanamivir, next-generation sequencing has been utilised to identify minor resistant virus populations. A total of five NA substitutions were identified in different viruses, including E119K and E119D; however, all apart from E119D were present in such low proportions that they could not be detected by Sanger 'population' sequencing methods. 44 The effects of various mutations in catalytic and framework residues of influenza B NA were investigated using reverse genetics and a range of functional assays. Four substitutions (D198E, I222T, H274Y and N294S) conferred reduced susceptibility to oseltamivir, while three substitutions (E119A, D198Y and R371K) caused highly reduced inhibition by oseltamivir, zanamivir and peramivir. 45 Two of these variants (H274Y, E119A) had in vitro replication fitness comparable to the NAI-susceptible viruses. To date, these substitutions have only been detected on rare occasions in circulating influenza viruses. An intravenous formulation of zanamivir showed both virological and clinical effectiveness without safety concerns in patients hospitalised with influenza in Japan. 46 A range of new adamantane derivatives have good antiviral activity in vitro and in animal models against H1N1pdm09 and H3N2 viruses that contain the S31N M2 ion channel substitution that confers resistance to amantadine. 47 Favipiravir is a novel pyrazinamide molecule that inhibits replication of various RNA viruses, including influenza types A, B and C (including oseltamivir-resistant strains), and has recently been licensed in Japan for the control of novel or reemerging influenza viruses. Its triphosphate metabolite is an RNA polymerase inhibitor which disrupts virus genome replication; synergy with oseltamivir has been demonstrated in pre-clinical models. 48 A phase II study in the US has shown that a twice-daily regimen decreased the titre and time to cessation of virus shedding, and had a significant benefit in reducing clinical symptoms (NCT01068912; www.clinicaltrials.gov).

Question: When did China detect the first human case of H7N9 infection?
February 2013