Kwok-Hung Chan

Increased Risk of Noninfluenza Respiratory Virus Infections Associated With Receipt of Inactivated Influenza Vaccine

Abstract We randomized 115 children to trivalent inactivated influenza vaccine (TIV) or placebo. Over the following 9 months, TIV recipients had an increased risk of virologically-confirmed non-influenza infections (relative risk: 4.40; 95% confidence interval: 1.31-14.8). Being protected against influenza, TIV recipients may lack temporary non-specific immunity that protected against other respiratory viruses.

Prevention of nosocomial transmission of swine-origin pandemic influenza virus A/H1N1 by infection control bundle

n Summaryn n After the outbreak of severe acute respiratory syndrome in Hong Kong, the importance of preventing nosocomial transmission of respiratory viruses has become a top priority in infection control. During the containment and early mitigation phases of the swine-origin influenza virus (S-OIV) A H1N1 pandemic, an infection control bundle consisting of multiple coherent measures was organised by our infection control team to minimise nosocomial transmission. This included repeated open staff forum achieving high attendance; early recognition of index cases among inpatients by liberal testing; early relief of sick staff from work; directly observed hand hygiene practice during outbreaks; and monitoring of compliance with infection control practice. During the first 100 days (from 1 May to 8 August 2009) when the first 100 laboratory-confirmed patients with S-OIV and 12 infected healthcare workers (HCWs) were identified, a total of 836 asymptomatic exposed persons (184 patients and 652 HCWs) were required to undergo a seven-day medical surveillance. The infection control nurses monitored them for the onset of symptoms. Four (0.48%) exposed persons (one house officer, two non-clinical staff, and one patient) were virologically confirmed with S-OIV. Not wearing a surgical mask either by the exposed persons during contact with the index cases (4/4 vs 264/832, Pn =0.010) or vice versa (4/4 vs 300/832, Pn =0.017, Fishers exact test) were found to be significant risk factors for nosocomial acquisition of S-OIV.n n

Epstein–Barr virus (EBV) infection in infancy

BACKGROUNDnEpstein-Barr virus (EBV) has been shown to be the cause of infectious mononucleosis (IM) and has more complicated associations with several malignant diseases. These EBV associated diseases provide a strong incentive for the development of an EBV vaccine. Most primary EBV infection during infancy and early childhood is mild or subclinical. Little is known about its infection in infancy. The pattern of EBV serological response during infancy may be important for vaccine management.nnnOBJECTIVESnthis study has served to clarify the epidemiology and serology of primary EBV infection during early infancy.nnnSTUDY DESIGNnlongitudinal serum samples from 66 Hong Kong infants were tested for EBV antibodies by immunofluorescence. Cord blood and sequential serum samples from these infants were taken at birth and then at 4-month intervals up to 2 years of age.nnnRESULTSnmaternal antibodies were present at different levels in all cord blood specimens and in serum samples of 8 infants at 4-month of age. Evidenced by VCA-IgG seroconversion, 60.6% (40/66) infants were infected during the first 2 years of life. One episode occurred before 8 months of age but, thereafter and for the remaining 16 months of follow-up until the infants were 2 years of age, the infection occurred at essentially a constant rate affecting about 20% of the remaining seronegative infants every 4 months.nnnCONCLUSIONSnthe abrupt onset of the infection after a delay of 8 months is a remarkable feature of primary EBV infection during infancy, which implicates a protective role for maternal antibodies. Persisting maternal antibodies may additionally serve to contain the infection once it occurred. This may partly explain why, unlike during adolescence, primary EBV infection early in life is usually asymptomatic.

Clinical and Virological Factors Associated with Viremia in Pandemic Influenza A/H1N1/2009 Virus Infection

Background Positive detection of viral RNA in blood and other non-respiratory specimens occurs in severe human influenza A/H5N1 viral infection but is not known to occur commonly in seasonal human influenza infection. Recently, viral RNA was detected in the blood of patients suffering from severe pandemic influenza A/H1N1/2009 viral infection, although the significance of viremia had not been previously studied. Our study aims to explore the clinical and virological factors associated with pandemic influenza A/H1N1/2009 viremia and to determine its clinical significance. Methodology/Principal Findings Clinical data of patients admitted to hospitals in Hong Kong between May 2009 and April 2010 and tested positive for pandemic influenza A/H1N1/2009 was collected. Viral RNA was detected by reverse-transcription polymerase chain reactions (RT-PCR) targeting the matrix (M) and HA genes of pandemic influenza A/H1N1/2009 virus from the following specimens: nasopharyngeal aspirate (NPA), endotracheal aspirate (ETA), blood, stool and rectal swab. Stool and/ or rectal swab was obtained only if the patient complained of any gastrointestinal symptoms. A total of 139 patients were included in the study, with viral RNA being detected in the blood of 14 patients by RT-PCR. The occurrence of viremia was strongly associated with a severe clinical presentation and a higher mortality rate, although the latter association was not statistically significant. D222G/N quasispecies were observed in 90% of the blood samples. Conclusion Presence of pandemic influenza A/H1N1/2009 viremia is an indicator of disease severity and strongly associated with D222G/N mutation in the viral hemagglutinin protein.

Analytical Sensitivity of Seven Point-of-Care Influenza Virus Detection Tests and Two Molecular Tests for Detection of Avian Origin H7N9 and Swine Origin H3N2 Variant Influenza A Viruses

Rapid virological diagnosis is important for early case identification, initiation of specific antiviral therapy, and implementation of infection control measures for patients suffering from influenza. Most point-of-care (POC) test kits commonly used at the outpatient setting which provide results

Crouching Tiger, Hidden Dragon: The Laboratory Diagnosis of Severe Acute Respiratory Syndrome

enza pandemic to emerge from southern China, nature, as always, caught us by surprise. The unusual atypical pneumonia, subsequently called severe acute respiratory syndrome (SARS), that emerged out of southern China in late 2002 was not caused by influenza, but was, in fact, caused by a novel coronavirus [13]. Epidemiologically, infection with the SARS coronavirus (SARS-CoV) is closely linked with SARS [1, 4], and experimental infection of cynomolgus macaques (Macaca fascicularis) results in pathology reminiscent of the human disease [4, 5]. Human coronaviruses 229E and OC43 are known to be causes of the common cold and have received scant attention, either diagnostically or research wise, in the past few decades. Coronaviruses also cause disease in animals that varies from trans-

Structure-based discovery of clinically approved drugs as Zika virus NS2B-NS3 protease inhibitors that potently inhibit Zika virus infection in vitro and in vivo

&NA; Zika virus (ZIKV) infection may be associated with severe complications in fetuses and adults, but treatment options are limited. We performed an in silico structure‐based screening of a large chemical library to identify potential ZIKV NS2B‐NS3 protease inhibitors. Clinically approved drugs belonging to different drug classes were selected among the 100 primary hit compounds with the highest predicted binding affinities to ZIKV NS2B‐NS3‐protease for validation studies. ZIKV NS2B‐NS3 protease inhibitory activity was validated in most of the selected drugs and in vitro anti‐ZIKV activity was identified in two of them (novobiocin and lopinavir‐ritonavir). Molecular docking and molecular dynamics simulations predicted that novobiocin bound to ZIKV NS2B‐NS3‐protease with high stability. Dexamethasone‐immunosuppressed mice with disseminated ZIKV infection and novobiocin treatment had significantly (P < 0.05) higher survival rate (100% vs 0%), lower mean blood and tissue viral loads, and less severe histopathological changes than untreated controls. This structure‐based drug discovery platform should facilitate the identification of additional enzyme inhibitors of ZIKV.

The Effect of Age and Recent Influenza Vaccination History on the Immunogenicity and Efficacy of 2009–10 Seasonal Trivalent Inactivated Influenza Vaccination in Children

Background There is some evidence that annual vaccination of trivalent inactivated influenza vaccine (TIV) may lead to reduced vaccine immunogenicity but evidence is lacking on whether vaccine efficacy is affected by prior vaccination history. The efficacy of one dose of TIV in children 6–8 y of age against influenza B is uncertain. We examined whether immunogenicity and efficacy of influenza vaccination in school-age children varied by age and past vaccination history. Methods and Findings We conducted a randomized controlled trial of 2009–10 TIV. Influenza vaccination history in the two preceding years was recorded. Immunogenicity was assessed by comparison of HI titers before and one month after receipt of TIV/placebo. Subjects were followed up for 11 months with symptom diaries, and respiratory specimens were collected during acute respiratory illnesses to permit confirmation of influenza virus infections. We found that previous vaccination was associated with reduced antibody responses to TIV against seasonal A(H1N1) and A(H3N2) particularly in children 9–17 y of age, but increased antibody responses to the same lineage of influenza B virus in children 6–8 y of age. Serological responses to the influenza A vaccine viruses were high regardless of vaccination history. One dose of TIV appeared to be efficacious against confirmed influenza B in children 6–8 y of age regardless of vaccination history. Conclusions Prior vaccination was associated with lower antibody titer rises following vaccination against seasonal influenza A vaccine viruses, but higher responses to influenza B among individuals primed with viruses from the same lineage in preceding years. In a year in which influenza B virus predominated, no impact of prior vaccination history was observed on vaccine efficacy against influenza B. The strains that circulated in the year of study did not allow us to study the effect of prior vaccination on vaccine efficacy against influenza A.

Influenza A virus shedding and infectivity in households

BACKGROUNDnViral shedding is often considered to correlate with the infectivity of influenza, but the evidence for this is limited.nnnMETHODSnIn a detailed study of influenza virus transmission within households in 2008-2012, index case patients with confirmed influenza were identified in outpatient clinics, and we collected nose and throat swab specimens for testing by reverse-transcription polymerase chain reaction from all household members regardless of illness. We used individual-based hazard models to characterize the relationship between viral load (V) and infectivity.nnnRESULTSnAssuming that infectivity was proportional to viral load V gave the worst fit, because it strongly overestimated the proportion of transmission occurring at symptom onset. Alternative models assuming that infectivity was proportional to a various functions of V provided better fits, although they all overestimated the proportion of transmission occurring >3 days after symptom onset. The best fitting model assumed that infectivity was proportion to V(γ), with estimates of γ = 0.136 and γ = 0.156 for seasonal influenza A(H1N1) and A(H3N2) respectively.nnnCONCLUSIONSnAll the models we considered that used viral loads to approximate infectivity of a case imperfectly explained the timing of influenza secondary infections in households. Identification of more accurate correlates of infectivity will be important to inform control policies and disease modeling.

Model Selection in Time Series Studies of Influenza-Associated Mortality

Background Poisson regression modeling has been widely used to estimate influenza-associated disease burden, as it has the advantage of adjusting for multiple seasonal confounders. However, few studies have discussed how to judge the adequacy of confounding adjustment. This study aims to compare the performance of commonly adopted model selection criteria in terms of providing a reliable and valid estimate for the health impact of influenza. Methods We assessed four model selection criteria: quasi Akaike information criterion (QAIC), quasi Bayesian information criterion (QBIC), partial autocorrelation functions of residuals (PACF), and generalized cross-validation (GCV), by separately applying them to select the Poisson model best fitted to the mortality datasets that were simulated under the different assumptions of seasonal confounding. The performance of these criteria was evaluated by the bias and root-mean-square error (RMSE) of estimates from the pre-determined coefficients of influenza proxy variable. These four criteria were subsequently applied to an empirical hospitalization dataset to confirm the findings of simulation study. Results GCV consistently provided smaller biases and RMSEs for the influenza coefficient estimates than QAIC, QBIC and PACF, under the different simulation scenarios. Sensitivity analysis of different pre-determined influenza coefficients, study periods and lag weeks showed that GCV consistently outperformed the other criteria. Similar results were found in applying these selection criteria to estimate influenza-associated hospitalization. Conclusions GCV criterion is recommended for selection of Poisson models to estimate influenza-associated mortality and morbidity burden with proper adjustment for confounding. These findings shall help standardize the Poisson modeling approach for influenza disease burden studies.