Serological Evidence of Human Infection With Avian Influenza A(H7N9) Virus: A Systematic Review and Meta-analysis

Abstract

Background: The extent of human infections with avian influenza A(H7N9) virus, including mild and asymptomatic infections, is uncertain.

Methods: We performed a systematic review and meta-analysis of serosurveys for avian influenza A(H7N9) virus infections in humans published during 2013-2020. Three seropositive definitions were assessed to estimate pooled seroprevalence, seroconversion rate, and seroincidence by types of exposures. We applied a scoring system to assess the quality of included studies.

Results: Of 31 included studies, pooled seroprevalence of A(H7N9) virus antibodies from all participants was 0.02%, with poultry workers, close contacts, and general populations having seroprevalence of 0.1%, 0.2%, and 0.02%, respectively, based on the World Health Organization (WHO)-recommended definition. Although most infections were asymptomatic, evidence of infection was highest in poultry workers (5% seroconversion, 19.1% seroincidence per 100 person-years). Use of different virus clades did not significantly affect seroprevalence estimates. Most serological studies were of low to moderate quality and did not follow standardized seroepidemiological protocols or WHO-recommended laboratory methods.

Conclusions: Human infections with avian influenza A(H7N9) virus have been uncommon, especially for general populations. Workers with occupational exposures to poultry and close contacts of A(H7N9) human cases had low risks of infection.

Keywords: erological evidence; influenza A (H7N9); influenza in humans.

Figure 1.

Flowchart of the selection of serological studies of A(H7N9) virus infection, 2013–2020. Abbreviation: WOS, web of Science.

Figure 2.

Epidemic curves of virologically confirmed avian influenza A(H7N9) virus infections in humans and animal reservoirs, and temporal distribution of 31 A(H7N9) virus serosurveys in humans by type of exposure, 2013–2020. A, Epidemic curve of virologically confirmed human infections with avian influenza A(H7N9) viruses across epidemics since 2013. B, Epidemic curve of A(H7N9) virus outbreaks in poultry and wild birds in mainland China. C, Temporal distribution of the implementation of 31 A(H7N9) virus serological studies in poultry workers, close contacts, mixed-exposures population, and general population. In (C), the color represents whether A(H7N9) virus infections in humans, poultry, or wild birds were occurring (red) or not occurring (white) before or during the implementation of each study. The number below the symbol was the reference number. Part of the serum samples of the general population in the No. 1 study was collected in 2009. Abbreviations: CC, close contacts; GP, general population; HPAI, highly pathogenic avian influenza; MP, mixed-exposures population; PW, poultry workers.

Figure 3.

Geographical distribution of virologically confirmed avian influenza A(H7N9) virus infections in human and animal reservoirs, and distribution of 31 A(H7N9) virus serosurveys in humans by types of exposure, 2013–2020. A, Geographical distribution of virologically confirmed human cases of A(H7N9) virus infection and outbreaks in domestic poultry and wild birds. B, Geographical distribution of 31 A(H7N9) virus serosurveys in humans by types of exposure. Abbreviation: HPAI, highly pathogenic avian influenza.

Figure 4.

Pooled estimates of seroprevalence of human infections with avian influenza A(H7N9) virus, using the World Health Organization (WHO)–recommended seropositive definition. The WHO-recommended seropositive definition refers to a hemagglutination inhibition (HAI) titer ≥160 tested by horse erythrocytes or an HAI titer of 20–80 tested by horse erythrocytes with a positive result using a second confirmatory assay (ie, microneutralization assay [neutralizing antibody titer ≥80] or Western blot assay). Abbreviation: CI, confidence interval.

Figure 5.

Estimated seroprevalence of human infection with avian influenza A(H7N9) virus, using 3 seropositive definitions (World Health Organization [WHO]–recommended, modified WHO-recommended, and nonstandardized seropositive definitions). The WHO-recommended seropositive definition refers to a hemagglutination inhibition (HAI) titer ≥160 tested by horse erythrocytes or an HAI titer of 20–80 tested by horse erythrocytes with a positive result using a second confirmatory assay (ie, microneutralization assay [MN] [neutralizing antibody titer ≥80] or Western blot assay [WB]). The modified WHO-recommended seropositive definition refers to an HAI titer ≥160 using erythrocytes from other species (eg, chickens, turkeys, and guinea pigs), or an HAI titer of 20–80 using other species’ erythrocytes and a positive result by a second confirmatory assay (ie, MN [neutralizing antibody titer ≥80] or WB). The nonstandardized seropositive definition refers to criteria other than the WHO-recommended or modified WHO-recommended criteria used in individual studies to define a seropositive result. A, Studies conducted after February 2013. B, Studies conducted before February 2013. C, All 31 studies. Abbreviations: ND, no data; WHO, World Health Organization.

Figure 6.

Comparison of seroconversion rate and seroincidence estimates for human infections with avian influenza A(H7N9) virus by types of exposure, using nonstandardized seropositive definition. Data are presented for seroconversion rate for human infections with A(H7N9) virus. The nonstandardized seropositive definition refers to criteria other than the World Health Organization (WHO)–recommended or modified WHO-recommended criteria used in individual studies to define a seropositive result. A, Seroincidence of human infections with A(H7N9) virus considering whether A(H7N9) virus outbreaks occurred in humans or poultry (B) or did not occur (C).