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The numerous global outbreaks and continuous reassortments of highly pathogenic avian influenza (HPAI) A(H5N6/H5N8) clade 2.3.4.4 viruses in birds pose a major risk to the public health. We investigated the tropism and innate host responses of 5 recent HPAI A(H5N6/H5N8) avian isolates of clades 2.3.4.4b, e, and h in human airway organoids and primary human alveolar epithelial cells. The HPAI A(H5N6/H5N8) avian isolates replicated productively but with lower competence than the influenza A(H1N1)pdm09, HPAI A(H5N1), and HPAI A(H5N6) isolates from humans in both or either models. They showed differential cellular tropism in human airway organoids; some infected all 4 major epithelial cell types: ciliated cells, club cells, goblet cells, and basal cells. Our results suggest zoonotic potential but low transmissibility of the HPAI A(H5N6/H5N8) avian isolates among humans. These viruses induced low levels of proinflammatory cytokines/chemokines, which are unlikely to contribute to the pathogenesis of severe disease. [ABSTRACT FROM AUTHOR]

Background: While patterns of incidence of clinical influenza have been well described, much uncertainty remains over patterns of incidence of infection. The 2009 pandemic provided both the motivation and opportunity to investigate patterns of mild and asymptomatic infection using serological techniques. However, to date, only broad epidemiological patterns have been defined, based on largely cross-sectional study designs with convenience sampling frameworks.Methods and Findings: We conducted a paired serological survey of a cohort of households in Hong Kong, recruited using random digit dialing, and gathered data on severe confirmed cases from the public hospital system (>90% inpatient days). Paired sera were obtained from 770 individuals, aged 3 to 103, along with detailed individual-level and household-level risk factors for infection. Also, we extrapolated beyond the period of our study using time series of severe cases and we simulated alternate study designs using epidemiological parameters obtained from our data. Rates of infection during the period of our study decreased substantially with age: for 3-19 years, the attack rate was 39% (31%-49%); 20-39 years, 8.9% (5.3%-14.7%); 40-59 years, 5.3% (3.5%-8.0%); and 60 years or older, 0.77% (0.18%-4.2%). We estimated parameters for a parsimonious model of infection in which a linear age term and the presence of a child in the household were used to predict the log odds of infection. Patterns of symptom reporting suggested that children experienced symptoms more often than adults. The overall rate of confirmed pandemic (H1N1) 2009 influenza (H1N1pdm) deaths was 7.6 (6.2-9.5) per 100,000 infections. However, there was substantial and progressive increase in deaths per 100,000 infections with increasing age from 0.66 (0.65-0.86) for 3-19 years up to 220 (50-4,000) for 60 years and older. Extrapolating beyond the period of our study using rates of severe disease, we estimated that 56% (43%-69%) of 3-19 year olds and 16% (13%-18%) of people overall were infected by the pandemic strain up to the end of January 2010. Using simulation, we found that, during 2009, larger cohorts with shorter follow-up times could have rapidly provided similar data to those presented here.Conclusions: Should H1N1pdm evolve to be more infectious in older adults, average rates of severe disease per infection could be higher in future waves: measuring such changes in severity requires studies similar to that described here. The benefit of effective vaccination against H1N1pdm infection is likely to be substantial for older individuals. Revised pandemic influenza preparedness plans should include prospective serological cohort studies. Many individuals, of all ages, remained susceptible to H1N1pdm after the main 2009 wave in Hong Kong. Please see later in the article for the Editors' Summary. [ABSTRACT FROM AUTHOR]

Swine influenza A viruses (SwIV) cause significant economic losses in animal husbandry as well as instances of human disease and occasionally give rise to human pandemics, including that caused by the H1N1/2009 virus. The lack of systematic and longitudinal influenza surveillance in pigs has hampered attempts to reconstruct the origins of this pandemic. Most existing swine data were derived from opportunistic samples collected from diseased pigs in disparate geographical regions, not from prospective studies in defined locations, hence the evolutionary and transmission dynamics of SwIV are poorly understood. Here we quantify the epidemiological, genetic and antigenic dynamics of SwIV in Hong Kong using a data set of more than 650 SwIV isolates and more than 800 swine sera from 12 years of systematic surveillance in this region, supplemented with data stretching back 34 years. Intercontinental virus movement has led to reassortment and lineage replacement, creating an antigenically and genetically diverse virus population whose dynamics are quantitatively different from those previously observed for human influenza viruses. Our findings indicate that increased antigenic drift is associated with reassortment events and offer insights into the emergence of influenza viruses with epidemic potential in swine and humans. [ABSTRACT FROM AUTHOR]

Background. The relationship between seasonal influenza vaccine and susceptibility to 2009 pandemic A/H1N1 virus infection is not fully understood. Methods. One child 6-15 years of age from each of 119 households was randomized to receive 1 dose of inactivated trivalent seasonal influenza vaccine (TIV) or saline placebo in November 2008. Serum samples were collected from study subjects and their household contacts before and 1 month after vaccination (December 2008), after winter (April 2009) and summer influenza (September-October 2009) seasons. Seasonal and pandemic influenza were confirmed by serum hemagglutinination inhibition, viral neutralization titers, and reverse-transcription polymerase chain reaction performed on nasal and throat swab samples collected during illness episodes. Results. TIV recipients had lower rates of serologically confirmed seasonal A/H1N1 infection (TIV group, 8%; placebo group, 21%; P=.10) and A/H3N2 infection (7% vs 12%; P=.49), but higher rates of pandemic A/ H1N1 infection (32% vs 17%; P=.09). In multivariable analysis, those infected with seasonal influenza A during the study had a lower risk of laboratory-confirmed pandemic A/H1N1 infection (adjusted odds ratio [OR], 0.35; 95% confidence interval [CI], 0.14-0.87), and receipt of seasonal TIV was unassociated with risk of pandemic A/ H1N1 infection (adjusted OR, 1.11; 95% CI, 0.54-2.26). Conclusions. TIV protected against strain-matched infection in children. Seasonal influenza infection appeared to confer cross-protection against pandemic influenza. Whether prior seasonal influenza vaccination affects the risk of infection with the pandemic strain requires additional study. [ABSTRACT FROM AUTHOR]

Background. Volunteer challenge studies have provided detailed data on viral shedding from the respiratory tract before and through the course of experimental influenza virus infection. There are no comparable quantitative data to our knowledge on naturally acquired infections. Methods. In a community-based study in Hong Kong in 2008, we followed up initially healthy individuals to quantify trends in viral shedding on the basis of cultures and reverse-transcription polymerase chain reaction (RT-PCR) through the course of illness associated with seasonal influenza A and B virus infection. Results. Trends in symptom scores more closely matched changes in molecular viral loads measured with RT-PCR for influenza A than for influenza B. For influenza A virus infections, the replicating viral loads determined with cultures decreased to undetectable levels earlier after illness onset than did molecular viral loads. Most viral shedding occurred during the first 2-3 days after illness onset, and we estimated that 1%-8% of infectiousness occurs prior to illness onset. Only 14% of infections with detectable shedding at RT-PCR were asymptomatic, and viral shedding was low in these cases. Conclusions. Our results suggest that "silent spreaders" (ie, individuals who are infectious while asymptomatic or presymptomatic) may be less important in the spread of influenza epidemics than previously thought. [ABSTRACT FROM AUTHOR]

Background: Few data are available about the effectiveness of nonpharmaceutical interventions for preventing influenza virus transmission. Objective: To investigate whether hand hygiene and use of facemasks prevents household transmission of influenza. Design: Cluster randomized, controlled trial. Randomization was computer generated; allocation was concealed from treating physicians and clinics and implemented by study nurses at the time of the initial household visit. Participants and personnel administering the interventions were not blinded to group assignment. (Clinical- Trials.gov registration number: NCT00425893) Setting: Households in Hong Kong. Patients: 407 people presenting to outpatient clinics with influenz alike illness who were positive for influenza A or B virus by rapid testing (index patients) and 794 household members (contacts) in 259 households. Intervention: Lifestyle education (control) (134 households), hand hygiene (136 households), or surgical facemasks plus hand hygiene (137 households) for all household members. Measurements: Influenza virus infection in contacts, as confirmed by reverse-transcription polymerase chain reaction (RT-PCR) or diagnosed clinically after 7 days. Results: Sixty (8%) contacts in the 259 households had RT-PCR- confirmed influenza virus infection in the 7 days after intervention. Hand hygiene with or without facemasks seemed to reduce influenza transmission, but the differences compared with the control group were not significant. In 154 households in which interventions were implemented within 36 hours of symptom onset in the index patient, transmission of RT-PCR-confirmed infection seemed reduced, an effect attributable to fewer infections among participants using facemasks plus hand hygiene (adjusted odds ratio, 0.33 [95% CI, 0.13 to 0.87]). Adherence to interventions varied. Limitation: The delay from index patient symptom onset to intervention and variable adherence may have mitigated intervention effectiveness. Conclusion: Hand hygiene and facemasks seemed to prevent household transmission of influenza virus when implemented within 36 hours of index patient symptom onset. These findings suggest that nonpharmaceutical interventions are important for mitigation of pandemic and interpandemic influenza. Primary Funding Source: Centers for Disease Control and Prevention. [ABSTRACT FROM AUTHOR]

From January 2004 through June 2008, surveillance of dead wild birds in Hong Kong, People's Republic of China, periodically detected highly pathogenic avian influenza (HPAI) viruses (H5N1) in individual birds from different species. During this period, no viruses of subtype H5N1 were detected in poultry on farms and in markets in Hong Kong despite intensive surveillance. Thus, these findings in wild birds demonstrate the potential for wild birds to disseminate HPAI viruses (H5N1) to areas otherwise free from the viruses. Genetic and antigenic characterization of 47 HPAI (H5N1) viruses isolated from dead wild birds in Hong Kong showed that these isolates belonged to 2 antigenically distinct virus groups: clades 2.3.4 and 2.3.2. Although research has shown that clade 2.3.4 viruses are established in poultry in Asia, the emergence of clade 2.3.2 viruses in nonpasserine birds from Hong Kong, Japan, and Russia raises the possibility that this virus lineage may have become established in wild birds. [ABSTRACT FROM AUTHOR]

Background. The impact of influenza on mortality in countries in subtropical and tropical regions is poorly quantified. Estimation of influenza-related illness in warm-climate regions is more difficult, because the seasonality of virus circulation is less well-defined. Partly as a result of these factors, influenza vaccine is grossly underutilized in the tropics, even for individuals ⩾65 years of age. Methods. Weekly numbers of deaths were modeled by Poisson regression, and excess deaths attributable to influenza in Hong Kong were estimated for 1996-1999. Comparison of weekly mortality during periods of influenza predominance and periods of low influenza activity was used to derive an alternative estimate of influenza-associated mortality. Results. Estimates derived from the Poisson model indicated that influenza resulted in 7.3 deaths per 100,000 population per year (95% confidence interval [1], 3.1-11.4) from cardiorespiratory disease among individuals aged 40-65 years and 102.0 deaths per 100,000 per population per year (95% CI, 61.2-142.7) among individuals aged ⩾ 65 years. Although respiratory diseases accounted for the majority of influenza-related deaths, influenza also contributed to 13.8% (95% CI, 4.8%- 22.7%) and 5.3% (95% CI, 1.2%-9.3%) of deaths related to ischemic heart disease. Conclusion. Influenza is associated with deaths due to ischemic heart disease as well from respiratory diseases. Overall influenza-associated mortality in a region with a warm climate, such as Hong Kong, is comparable with that documented in temperate regions. The need for influenza vaccination in tropical regions needs to be reassessed. [ABSTRACT FROM AUTHOR]

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We analyzed =12 years of surveillance data on avian influenza in Hong Kong live poultry markets. A ban on keeping live poultry overnight in these markets reduced virus isolation rates by 84% in chickens (p = 0.006) and 100% (p = 0.01) in minor poultry. [ABSTRACT FROM AUTHOR]

In winter 2008, kindergartens and primary schools in Hong Kong were closed for 2 weeks after media coverage indicated that 3 children had died, apparently from influenza. We examined prospective influenza surveillance data before, during, and after the closure. We did not find a substantial effect on community transmission. [ABSTRACT FROM AUTHOR]

Background: Since 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.Methods: We 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.Results: We 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.Conclusions: Our 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. [ABSTRACT FROM AUTHOR]

A response by Benjamin J. Cowling and colleagues to a letter to the editor about an article related to the infection attack rate and severity of the 2009 H1N1 influenza in Hong Kong, China, in a previous issue of the periodical is presented.

Background: The SARS outbreak in 2003 provides a unique opportunity for the study of human responses to a novel virus. We have previously reported that dendritic cells (DCs) might be involved in the immune escape mechanisms for SARS-CoV. In this study, we focussed on the gene expression of toll-like receptors (TLRs), chemokine receptors (CCRs) and death receptor ligands in SARS-CoV infected DCs. We also compared adult and cord blood (CB) DCs to find a possible explanation for the age-dependent severity of SARS., Results: Our results demonstrates that SARS-CoV did not modulate TLR-1 to TLR-10 gene expression but significantly induced the expression of CCR-1, CCR-3, and CCR-5. There was also strong induction of TNF-related apoptosis-inducing ligand (TRAIL), but not Fas ligand gene expression in SARS-CoV infected DCs. Interestingly, the expressions of most genes studied were higher in CB DCs than adult DCs., Conclusion: The upregulation of chemokines and CCRs may facilitate DC migration from the infection site to the lymph nodes, whereas the increase of TRAIL may induce lymphocyte apoptosis. These findings may explain the increased lung infiltrations and lymphoid depletion in SARS patients. Further explorations of the biological significance of these findings are warranted.

Astroviruses infect humans and many different animal species and are associated with gastroenteritis. Recent studies first detected the virus from bat species in Hong Kong. To understand astrovirus distribution in the wider region further, we examined the prevalence of this virus family in bat specimens collected from a large geographical region of mainland China. We collected 500 anal swabs from 20 bat species in 51 natural habitats from 11 provinces of China and tested these for astroviruses. Our study revealed a remarkably high genetic diversity of astroviruses; five monophyletic groups were identified in bats, including two novel groups. Evidence for varying degrees of host restriction for astroviruses from bats has been found. Phylogenetic analyses also provided insight into the inter-species transmission of Mamastrovirus.

Background: Chemokines play important roles in inflammation and antiviral action. We examined whether polymorphisms of RANTES, IP-10 and Mig affect the susceptibility to and outcome of severe acute respiratory syndrome (SARS)., Methods: We tested the polymorphisms of RANTES, IP-10 and Mig for their associations with SARS in 495 Hong Kong Chinese SARS patients and 578 controls. Then we tried to confirm the results in 356 Beijing Chinese SARS patients and 367 controls., Results: RANTES -28 G allele was associated with SARS susceptibility in Hong Kong Chinese (P < 0.0001, OR = 2.80, 95%CI:2.11-3.71). Individuals with RANTES -28 CG and GG genotypes had a 3.28-fold (95%CI:2.32-4.64) and 3.06-fold (95%CI:1.47-6.39) increased risk of developing SARS respectively (P < 0.0001). This -28 G allele conferred risk of death in a gene-dosage dependent manner (P = 0.014) with CG and GG individuals having a 2.12-fold (95% CI: 1.11-4.06) and 4.01-fold (95% CI: 1.30-12.4) increased risk. For the replication of RANTES data in Beijing Chinese, the -28 G allele was not associated with susceptibility to SARS. However, -28 CG (OR = 4.27, 95%CI:1.64-11.1) and GG (OR = 3.34, 95%CI:0.37-30.7) were associated with admission to intensive care units or death due to SARS (P = 0.011)., Conclusion: RANTES -28 G allele plays a role in the pathogenesis of SARS.

Background: The worldwide outbreak of severe acute respiratory syndrome (SARS) is associated with a newly discovered coronavirus, SARS-associated coronavirus (SARS-CoV). We did clinical and experimental studies to assess the role of this virus in the cause of SARS., Methods: We tested clinical and postmortem samples from 436 SARS patients in six countries for infection with SARS-CoV, human metapneumovirus, and other respiratory pathogens. We infected four cynomolgus macaques (Macaca fascicularis) with SARS-CoV in an attempt to replicate SARS and did necropsies on day 6 after infection., Findings: SARS-CoV infection was diagnosed in 329 (75%) of 436 patients fitting the case definition of SARS; human metapneumovirus was diagnosed in 41 (12%) of 335, and other respiratory pathogens were diagnosed only sporadically. SARS-CoV was, therefore, the most likely causal agent of SARS. The four SARS-CoV-infected macaques excreted SARS-CoV from nose, mouth, and pharynx from 2 days after infection. Three of four macaques developed diffuse alveolar damage, similar to that in SARS patients, and characterised by epithelial necrosis, serosanguineous exudate, formation of hyaline membranes, type 2 pneumocyte hyperplasia, and the presence of syncytia. SARS-CoV was detected in pneumonic areas by virus isolation and RT-PCR, and was localised to alveolar epithelial cells and syncytia by immunohistochemistry and transmission electron microscopy., Interpretation: Replication in SARS-CoV-infected macaques of pneumonia similar to that in human beings with SARS, combined with the high prevalence of SARS-CoV infection in SARS patients, fulfill the criteria required to prove that SARS-CoV is the primary cause of SARS.