Asymptomatic, Mild, and Severe Influenza A(H7N9) Virus Infection in Humans, Guangzhou, China

Chen, Zongqiu; Liu, Hui; Lu, Jianyun; Luo, Lei; Li, Kuibiao; Liu, Yuanyuan; Lau, Eric H. Y.; Di, Biao; Yang, Zhicong; Xiao, Xue

doi:10.3201/eid2009.140424

Cited by 30 publications

(27 citation statements)

References 9 publications

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“…The lack of clinical symptoms in our study may be related to the intrabronchial inoculation used by us, which is in contrast to the combined inoculation route in other animal studies (28) or the intranasal application used in most human studies. However, also in humans infected with pathogenic influenza virus, clinical manifestations may vary from asymptomatic to severe pneumonia (34). We previously reported that although the intrabronchial inoculation does result in lung pathology and virus production in the trachea and fever, virus replication in the nasal cavity is low, and sneezing, nasal discharge, or coughing are almost never seen (29), limiting dissemination of the virus to the upper respiratory tract.…”

Section: Discussionmentioning

confidence: 99%

Correlation between Virus Replication and Antibody Responses in Macaques following Infection with Pandemic Influenza A Virus

Koopman

Mooij

Dekking

et al. 2016

J Virol

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Influenza virus infection of nonhuman primates is a well-established animal model for studying pathogenesis and for evaluating prophylactic and therapeutic intervention strategies. However, usually a standard dose is used for the infection, and there is no information on the relation between challenge dose and virus replication or the induction of immune responses. Such information is also very scarce for humans and largely confined to evaluation of attenuated virus strains. Here, we have compared the effect of a commonly used dose (4 ؋ 10 6 50% tissue culture infective doses) versus a 100-fold-higher dose, administered by intrabronchial installation, to two groups of 6 cynomolgus macaques. Animals infected with the high virus dose showed more fever and had higher peak levels of gamma interferon in the blood. However, virus replication in the trachea was not significantly different between the groups, although in 2 out of 6 animals from the high-dose group it was present at higher levels and for a longer duration. The virus-specific antibody response was not significantly different between the groups. However, antibody enzyme-linked immunosorbent assay, virus neutralization, and hemagglutination inhibition antibody titers correlated with cumulative virus production in the trachea. In conclusion, using influenza virus infection in cynomolgus macaques as a model, we demonstrated a relationship between the level of virus production upon infection and induction of functional antibody responses against the virus. IMPORTANCEThere is only very limited information on the effect of virus inoculation dose on the level of virus production and the induction of adaptive immune responses in humans or nonhuman primates. We found only a marginal and variable effect of virus dose on virus production in the trachea but a significant effect on body temperature. The induction of functional antibody responses, including virus neutralization titer, hemagglutination inhibition titer, and antibody-dependent cell-mediated cytotoxicity, correlated with the level of virus replication measured in the trachea. The study reveals a relationship between virus production and functional antibody formation, which could be relevant in defining appropriate criteria for new influenza virus vaccine candidates.

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Section: Discussionmentioning

confidence: 99%

Correlation between Virus Replication and Antibody Responses in Macaques following Infection with Pandemic Influenza A Virus

Koopman

Mooij

Dekking

et al. 2016

J Virol

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“…Timing of collection of residual sera from 5340 patients in Guangzhou in two phases (black lines), and the detection of severe cases of infection with influenza A(H7N9) virus in Guangzhou (gray bars) described in a separate study [8]…”

Section: Resultsmentioning

confidence: 99%

“…2) indicates that the most credible estimate of the overall age-standardized cumulative incidence of H7N9 infections between December 2013 and April 2014 was 0.50 % (95 % credibility interval, CrI: 0.06, 1.51 %), corresponding to 64,000 (95 % CrI: 7300, 190,000) infections in Guangzhou (Table 2). Using this as the denominator, and the 16 severe cases and 11 deaths as the numerators respectively [8], we estimated that the risk of a severe illness following infection was 5.2 (95 % CrI: 0.72, 23) per 10,000 infections while the risk of death following infection was 3.6 (95 % CrI: 0.47, 15) per 10,000 infections. Alternative assumptions about the waning in antibody titers after infection led to broadly similar estimates (Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…In this study we estimated that 64,000 (95 % credibility interval: 7300, 190,000) humans were infected with influenza A(H7N9) virus in Guangzhou between January 2014 and April 2014, which far exceeds the 20 laboratory-confirmed infections [8]. It was previously estimated that the number of cases of symptomatic H7N9 virus infections could be around 500–1000 times the number of laboratory-confirmed cases [3, 10], and this is consistent with our estimates of the numbers of infections albeit with considerable uncertainty.…”

Section: Discussionmentioning

confidence: 99%

“…In a previously published study [8], 16 severe cases of H7N9 were identified through routine surveillance of pneumonia of unknown etiology from January 2014 to March 2014. No severe cases of H7N9 were reported in Guangzhou from October 2014 to December 2014.…”

Section: Methodsmentioning

confidence: 99%

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Population seroprevalence of antibody to influenza A(H7N9) virus, Guangzhou, China

et al. 2016

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BackgroundSince the identification in early 2013 of severe disease caused by influenza A(H7N9) virus infection, there have been few attempts to characterize the full severity profile of human infections. Our objective was to estimate the number and severity of H7N9 infections in Guangzhou, using a serological study.MethodsWe collected residual sera from patients of all ages admitted to a hospital in the city of Guangzhou in southern China in 2013 and 2014. We screened the sera using a haemagglutination inhibition assay against a pseudovirus containing the H7 and N9 of A/Anhui/1/2013(H7N9), and samples with a screening titer ≥10 were further tested by standard hemagglutination-inhibition and virus neutralization assays for influenza A(H7N9). We used a statistical model to interpret the information on antibody titers in the residual sera, assuming that the residual sera provided a representative picture of A(H7N9) infections in the general population, accounting for potential cross-reactions.ResultsWe collected a total of 5360 residual sera from December 2013 to April 2014 and from October 2014 to December 2014, and found two specimens that tested positive for H7N9 antibody at haemagglutination inhibition titer ≥40 and a neutralization titer ≥40. Based on this, we estimated that 64,000 (95 % credibility interval: 7300, 190,000) human infections with influenza A(H7N9) virus occurred in Guangzhou in early 2014, with an infection-fatality risk of 3.6 deaths (95 % credibility interval: 0.47, 15) per 10,000 infections.ConclusionsOur study suggested that the number of influenza A(H7N9) virus infections in Guangzhou substantially exceeded the number of laboratory-confirmed cases there, albeit with considerable imprecision. Our study was limited by the small number of positive specimens identified, and larger serologic studies would be valuable. Our analytic framework would be useful if larger serologic studies are done.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-016-1983-3) contains supplementary material, which is available to authorized users.

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Age‐Dependent Pathogenesis of Influenza A Virus H7N9 Mediated Through PB1‐F2‐Induced Mitochondrial DNA Release and Activation of cGAS‐STING‐NF‐κB Signaling

Cheung,

Yuen,

Tang

et al. 2024

Journal of Medical Virology

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Exactly why human infection of avian influenza A virus H7N9 causes more severe disease in the elderly remains elusive. In this study, we found that H7N9 PB1‐F2 is a pathogenic factor in 15–18‐month‐old BALB/C mice (aged mice) but not in 6–8‐week‐old young adult mice (young mice). Recombinant influenza A virus with H7N9 PB1‐F2‐knockout was less pathogenic in aged mice as indicated with delayed weight loss. In contrast, survival of young mice infected with this virus was diminished. Furthermore, tissue damage, inflammation, proinflammatory cytokine and 2′3′‐cGAMP production in the lung were less pronounced in infected aged mice despite no change in viral titer. cGAS is known to produce 2′3′‐cGAMP to boost proinflammatory cytokine expression through STING‐NF‐κB signaling. We found that H7N9 PB1‐F2 promoted interferon β (IFNβ) and chemokine gene expression in cultured cells through the mitochondrial DNA‐cGAS‐STING‐NF‐κB pathway. H7N9 PB1‐F2 formed protein aggregate and caused mitochondrial cristae collapse, complex V‐dependent electron transport dysfunction, reverse electron transfer‐dependent oxidized mitochondrial DNA release to the cytoplasm and activation of cGAS‐STING‐NF‐κB signaling. PB1‐F2 N57 truncation, which is frequently observed in human circulating strains, mitigated H7N9 PB1‐F2‐mediated mitochondrial dysfunction and cGAS activation. In addition, we found that PB1‐F2 of pathogenic avian influenza viruses triggered more robust cGAS activation than their human‐adapted descendants. Our findings provide one explanation to age‐dependent pathogenesis of H7N9 infection.

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Asymptomatic, Mild, and Severe Influenza A(H7N9) Virus Infection in Humans, Guangzhou, China

Cited by 30 publications

References 9 publications

Correlation between Virus Replication and Antibody Responses in Macaques following Infection with Pandemic Influenza A Virus

Correlation between Virus Replication and Antibody Responses in Macaques following Infection with Pandemic Influenza A Virus

Population seroprevalence of antibody to influenza A(H7N9) virus, Guangzhou, China

Age‐Dependent Pathogenesis of Influenza A Virus H7N9 Mediated Through PB1‐F2‐Induced Mitochondrial DNA Release and Activation of cGAS‐STING‐NF‐κB Signaling

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