In late March 2013, three human cases of novel influenza A(H7N9) virus infection were reported by Chinese health authorities.[43] This was the first time A(H7N9) virus infection had been identified in humans and the first time a low-pathogenic avian influenza (LPAI) virus infection had caused critical illness with fatal outcomes in humans. As of June 2019, the current risk to the public’s health posed by Asian lineage A(H7N9) virus is low;[47] however, the pandemic potential of this virus is concerning. Influenza viruses constantly change and it is possible that this virus could evolve to gain the ability to spread easily and sustainably among people, triggering a widespread pandemic.[48][49][50][51]

Five distinct epidemic waves of Asian lineage A(H7N9) virus infections were observed in humans in China between 2013 and 2017.[2] Between October 2017 and June 2019, only a small number of sporadic human cases were reported in 2018 and the first half of 2019. Human infections with A(H7N9) virus generally have coincided or overlapped with annual outbreaks of seasonal influenza in China, with sporadic cases detected at other times of the year.[2][42][52]

Between 2013 and 2017 an increase in cases was reported annually, peaking in the fifth wave (2016 to 2017). From March 2013 to August 2017, 1557 cases of human infection with Asian lineage A(H7N9) virus were reported, with 759 reported during the fifth wave. From 2013 to 2017, 39% of the reported cases were fatal.[52] There has been a marked decline in reported cases since the end of the fifth wave, with only 4 cases reported between October 2017 and June 2019.[53] The decrease in reported cases is associated with decreased Asian lineage A(H7N9) virus detections in birds and the environment.[53] Closure of live bird markets in urban areas contributed to reducing human exposures to A(H7N9) virus and zoonotic transmission.[54][55] However, closure of live bird markets has also been reported to result in the spread of A(H7N9) virus among poultry to other areas.[56] It is likely that implementation of a bivalent H5-H7 poultry vaccination program in China has contributed to the sharp reduction in human infections with A(H7N9) viruses.[57][58]

The majority of Asian lineage A(H7N9) virus infections in humans have occurred in the eastern half of mainland China, although cases have also been reported by provinces in southwest and northwest China. Large case-series have shown all evaluated case-patients had histories of recent travel to affected provinces in mainland China.[2][42][59][60] Asian lineage A(H7N9) virus infections have been detected outside China, with one case reported by Malaysia in February 2014,[61] two cases reported by Canada in 2015,[62] and five cases reported by Taiwan between 2013 and 2017.[42] All of these cases were travel-associated and the infections were thought to have been acquired in mainland China.

Between February 2013 and June 2019, 616 of 1568 patients have died (case-fatality proportion 39%).[42] The proportion of fatalities has been similar for each of the epidemic waves. Severity-of-illness data from the second wave revealed that 218 of 219 patients who attended medical services required admission to the hospital and 191 of 218 (87.6%) hospitalized patients were reported to have severe respiratory complications or critical illness.[63] Estimates of symptomatic case-fatality risk suggest that Asian lineage LPAI A(H7N9) virus infection is more likely to cause death than seasonal influenza A(H1N1)pdm09 virus infection, but is less likely to cause death than highly pathogenic avian influenza (HPAI) A(H5N1) virus infection.[64]

In one large case-series, the mean age at presentation was 55.5 years (range 2-91 years) and infection had occurred more commonly in men than in women (male:female ratio 2:1). High frequencies of comorbidities have been observed in infected patients,[7] and the presence of at least one comorbidity has been identified as a risk factor for infection with Asian lineage LPAI A(H7N9) virus.[65] However, the risk of death is not greater among those with comorbidities than in those without underlying chronic conditions. From 2013 to 2017, the number of incident cases had shifted from predominantly older to middle-aged adults and from urban locations to semi-urban and rural areas; however, the severity of illness among hospitalized patients had not changed.[51]

Chickens appear to be most susceptible to Asian lineage LPAI A(H7N9) virus infection, but the virus has been detected in other poultry species including ducks and quail. Although pigs can be infected, exposure to pigs has not been implicated in the epidemiology of human infections with Asian lineage LPAI A(H7N9) virus.[66][67][68] Many infected patients reported contact with poultry or markets where live birds are sold and/or slaughtered. Genetic similarity has been demonstrated in Asian lineage LPAI A(H7N9) viruses isolated from patients and Asian lineage LPAI A(H7N9) viruses obtained from live chickens in epidemiologically linked markets.[5] Chickens and ducks account for most positive detections of Asian lineage A(H7N9) LPAI in studies of live poultry markets, but Asian lineage A(H7N9) LPAI virus RNA has also been detected in samples from quail and pigeons, as well as in environmental and water samples obtained from the same markets.[69] Songbirds and small terrestrial birds have been shown to be susceptible to infection with Asian lineage LPAI A(H7N9) virus, but their role in zoonotic transmission to humans is not known.[70] The prevalence of LPAI and HPAI Asian lineage A(H7N9) virus infections in migratory birds within China and elsewhere remains unclear. Asian lineage LPAI A(H7N9) virus was detected in a healthy tree sparrow in Shanghai, but the virus was not detected in over 2000 samples from other wild birds in Shanghai that were tested in the same study.[71] This suggests that monitoring of infection in nonpoultry birds is required and that infection in migratory birds or export of infected poultry could spread Asian lineage A(H7N9) viruses beyond China. The emergence of Asian lineage A(H7N9) viruses with high-pathogenicity properties reflects, by definition, increased pathogenicity in birds, but not necessarily in humans. Human infection with Asian lineage A(H7N9) virus after exposure to sick and dying birds may serve to increase awareness of the potential increased risk and lead to earlier health-seeking or diagnosis. No difference in disease severity has been seen among people with Asian lineage HPAI or LPAI A(H7N9) virus infection.[25][72]

Retrospective epidemiologic analyses suggest that at least 75% of confirmed Asian lineage LPAI A(H7N9) virus-infected case-patients had recent contact with domestic poultry.[73] An ecological study utilizing statistical modeling suggested that deliberate closures of poultry markets were effective in curtailing human outbreaks of Asian lineage LPAI A(H7N9) virus infections in several Chinese cities.[55] In contrast to HPAI A(H5N1), many Asian lineage LPAI A(H7N9) virus infections have occurred in urban areas and have not been associated with rearing or slaughtering "backyard" poultry. Asian lineage LPAI A(H7N9) virus infection does not cause sickness or death in poultry, leading to "silent" zoonotic transmission. By contrast, the recently emerged Asian lineage HPAI A(H7N9) virus does cause sickness and death in poultry, similar to HPAI A(H5N1) virus infection. The UN Food and Agriculture Organization reported that from October 2016 to June 2019, 290 samples from birds and the environment tested positive for A(H7N9) virus, with 44 (15%) identified as HPAI and the remainder identified as LPAI viruses.[53] It is not clear yet as to whether the HPAI virus will become the predominant circulating Asian lineage A(H7N9) virus in poultry in China, but if it becomes prevalent, then outbreaks in poultry should be easier to detect.

A study of 396 poultry workers from areas where Asian lineage LPAI A(H7N9) virus is known to circulate among poultry found that 25 of 396 (6%) workers had detectable antibodies (hemagglutinin inhibition titers ≥80) against A(H7N9) virus. By contrast, antibodies were not detected in over 1000 samples tested from the general population.[74] Other retrospective studies have reported lower seroprevalence of antibodies to A(H7N9) virus or low incidence and seroconversion among Chinese poultry workers.[75][76][77] An additional retrospective study did not find serologic evidence of A(H7N9) virus infection in poultry workers from eastern China prior to November 2012.[78] 

Experimental models of infection reveal that Asian lineage, avian-origin LPAI A(H7N9) virus can replicate in ferrets, mice, pigs, and nonhuman primates. Droplet transmission of Asian lineage LPAI A(H7N9) virus does occur in ferret models, but compared with A(H1N1)pdm09 virus, transmission in ferrets appears to be less effective. Despite epidemiologic investigations linking infections in humans to infections in chickens, Asian lineage LPAI A(H7N9) virus replicates poorly in chickens and could not be transmitted efficiently from infected chickens to naive chickens (or ferrets) in experimental models. Genetic analysis of Asian lineage LPAI A(H7N9) viruses revealed substitutions associated with mammalian adaptation, but it is likely that additional adaptations would be required to facilitate efficient human-to-human transmission.

Case-clusters of confirmed infection have been detected in China, but to date there is no evidence of sustained human-to-human transmission of Asian lineage A(H7N9) virus.[11][48][79] Fatal Asian lineage LPAI A(H7N9) virus infection in a healthcare worker has been reported, but a confirmed source of infection was not identified and there was no known contact with a confirmed case.[80] Nosocomial transmission, including patient-to-healthcare worker, and patient-to-patient, is possible with human infections with novel influenza A viruses, and has been reported for Asian lineage LPAI A(H7N9) viruses.[12][13][14] Therefore, specific infection prevention and control measures, including droplet and airborne precautions, should be implemented as soon as possible for any patient who is a suspected case of novel influenza A virus infection, including Asian lineage A(H7N9) virus, to prevent healthcare-associated transmission.

Other avian influenza A viruses (e.g., H5, H6, H7, H9, H10 viruses) have caused human illness ranging from mild (e.g., conjunctivitis, uncomplicated influenza-like illness) to fatal disease.[16][17][18][22][81][82][83][84][85][86][87]

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