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Meta-Analysis
. 2020 Dec 2;18(1):377.
doi: 10.1186/s12916-020-01836-y.

Serological evidence of human infections with highly pathogenic avian influenza A(H5N1) virus: a systematic review and meta-analysis

Xinhua Chen  1 , Wei Wang  1 , Yan Wang  1 , Shengjie Lai  1   2 , Juan Yang  1 , Benjamin J Cowling  3 , Peter W Horby  4 , Timothy M Uyeki  5 , Hongjie Yu  6
Affiliations
Meta-Analysis

Serological evidence of human infections with highly pathogenic avian influenza A(H5N1) virus: a systematic review and meta-analysis

Xinhua Chen et al. BMC Med. .

Abstract

Background: Highly pathogenic avian influenza A(H5N1) virus poses a global public health threat given severe and fatal zoonotic infections since 1997 and ongoing A(H5N1) virus circulation among poultry in several countries. A comprehensive assessment of the seroprevalence of A(H5N1) virus antibodies remains a gap and limits understanding of the true risk of A(H5N1) virus infection.

Methods: We conducted a systematic review and meta-analysis of published serosurveys to assess the risk of subclinical and clinically mild A(H5N1) virus infections. We assessed A(H5N1) virus antibody titers and changes in titers among populations with variable exposures to different A(H5N1) viruses.

Results: Across studies using the World Health Organization-recommended seropositive definition, the point estimates of the seroprevalence of A(H5N1) virus-specific antibodies were higher in poultry-exposed populations (range 0-0.6%) and persons exposed to both human A(H5N1) cases and infected birds (range 0.4-1.8%) than in close contacts of A(H5N1) cases or the general population (none to very low frequencies). Seroprevalence was higher in persons exposed to A(H5N1) clade 0 virus (1.9%, range 0.7-3.2%) than in participants exposed to other clades of A(H5N1) virus (range 0-0.5%) (p < 0.05). Seroprevalence was higher in poultry-exposed populations (range 0-1.9%) if such studies utilized antigenically similar A(H5N1) virus antigens in assays to A(H5N1) viruses circulating among poultry.

Conclusions: These low seroprevalences suggest that subclinical and clinically mild human A(H5N1) virus infections are uncommon. Standardized serological survey and laboratory methods are needed to fully understand the extent and risk of human A(H5N1) virus infections.

Keywords: Influenza A(H5N1); Influenza in humans; Serological evidence.

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Conflict of interest statement

H.Y. has received research funding from Sanofi Pasteur, and Shanghai Roche Pharmaceutical Company; none of this research funding is related to avian influenza viruses. BJC has received honoraria from Roche and Sanofi Pasteur. X.C., W.W., Y.W., S.L., J.Y., B.J.C., P.W.H., and T.M.U. declare no competing interests.

Figures

Fig. 1
Fig. 1
Flowchart of the selection of A(H5N1) serological studies, 1997–2020
Fig. 2
Fig. 2
Epidemic curves of highly pathogenic avian influenza A(H5N1) virus infections in humans and animal reservoirs by country and temporal distribution of sixty-six A(H5N1) serosurveys in human by type of exposure, 1997–2020. a Epidemic curve of lab-confirmed human infections with highly pathogenic avian influenza A(H5N1) viruses. b Epidemic curve of lab-confirmed A(H5N1) outbreaks in poultry and wild birds. c Temporal distribution of the implementation of sixty-six A(H5N1) serological studies in poultry workers (PW), poultry cullers (PC), other occupationally exposed populations (OP), poultry-exposed residents (ER), exposed healthcare workers (HCW), household contacts (HC), social contacts (SC), other close contacts (OC), persons with both poultry and human exposures (MP), suspected mixed exposure population (SP), and general population (GP). In panel c, the color represents whether A(H5N1) virus infection occurred in humans, poultry, or wild birds occurred (red) or not (white) before or during the implementation of each study. The number below each symbol is the study reference number. The symbols in red color refer to A(H5N1) outbreaks that occurred in one of three species (i.e., humans, domestic poultry, or wild birds), while the human+chicken symbols together refer to A(H5N1) outbreaks that occurred in both humans and domestic poultry. Note that three multi-year cohort studies were classified as independent studies in panel c
Fig. 3
Fig. 3
Geographical distribution of highly pathogenic avian influenza A(H5N1) virus infections in human and animal reservoirs by country and distribution of sixty-six A(H5N1) virus antibody serosurveys in humans by type of exposure, 1997–2020. a The geographical distribution of laboratory-confirmed human cases of highly pathogenic avian influenza A(H5N1) virus infection. b The geographical distribution of A(H5N1) outbreaks in domestic poultry and wild birds. c–e The geographical distribution of 66 A(H5N1) serosurveys in humans by type of exposure. Note that one human A(H5N1) case reported in Canada was in a returned traveler from China
Fig. 4
Fig. 4
Seroprevalence of antibodies to highly pathogenic avian influenza A(H5N1) virus estimated through random effects models, using standard antibody titers for seropositivity recommended by the World Health Organization. The World Health Organization (WHO) recommendations refer to a neutralizing (NT) antibody titer ≥ 1:80 with a positive result using a 2nd assay method, i.e., hemagglutination inhibition (HAI) assay (HAI antibody titer ≥ 1:160), enzyme-linked immunosorbent assay, or western blot assay
Fig. 5
Fig. 5
Seroprevalence of antibodies to avian influenza A (H5N1) virus estimated through random effects models by type of exposure and virus clade, using three antibody titer thresholds (World Health Organization recommended, modified World Health Organization recommended, and non-standardized antibody titer thresholds to define a seropositive result). World Health Organization (WHO) recommendations refer to a neutralizing (NT) antibody titer ≥ 1:80 with a positive result using a 2nd assay method, i.e., hemagglutination inhibition test (HAI) (HAI antibody titer ≥ 1:160), enzyme-linked immunosorbent assay, or western blot assay. The modified WHO definition of a seropositive result refers to an NT antibody titer ≥ 1:80 with a positive result using a 2nd confirmatory assay (i.e., HAI antibody titer ≥ 1:40, ELISA, or western blot assay). The non-standardized seropositive definition refers to criteria used to define a seropositive result other than the WHO or modified WHO definitions. Data are presented if A(H5N1) virus-specific antibodies were detected. a A(H5N1) virus antibody seroprevalence by type of exposure. b Changes in A(H5N1) virus antibody seroprevalence by type of exposure after excluding studies related to A(H5N1) outbreaks in Hong Kong in 1997. c A(H5N1) virus antibody seroprevalence by virus clade
Fig. 6
Fig. 6
Comparison of seroconversion rate and seroincidence for human infection with highly pathogenic avian influenza A(H5N1) virus estimated through random effects models by type of exposure, using a non-standardized antibody titer threshold. The non-standardized antibody titer threshold refers to criteria to define seropositive results in each study rather than the World Health Organization-recommended or modified World Health Organization-recommended criteria [i.e., a neutralizing (NT) antibody titer ≥ 1:80 with a positive result confirmed by a 2nd assay (i.e., HAI antibody titer ≥ 1:40, ELISA or western blot assay)]. Data are presented for seroconversion rate for human infection with A(H5N1) virus (a), and seroincidence of human infection with A(H5N1) virus considering whether A(H5N1) outbreaks in humans or animal reservoirs occurred (b) or not (c). The red color in panel a represents the estimates of the pooled seroconversion rate are based on all thirteen studies excluding reports related to A(H5N1) outbreaks in Hong Kong in 1997
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