Population-Based Pediatric Hospitalization Burden of Lineage-Specific Influenza B in Hong Kong, 2004-2014.

BACKGROUND: Influenza B virus has been perceived to cause less disease burden and milder disease compared with influenza A, but recent studies suggest that influenza B does have a significant impact. We aimed to estimate the burden of influenza B virus infections on hospitalizations in Hong Kong, in the context of virus lineage changes over time. METHODS: The pediatric age-specific rates of influenza B hospitalization in Hong Kong for 2004-2014 were estimated based on admissions to 2 hospitals that together catered for 72.5% of all pediatric admissions on Hong Kong Island. Influenza B virus was detected by immunofluorescence and culture on nasopharyngeal aspirates. Lineage typing was performed by real-time reverse-transcription polymerase chain reaction. RESULTS: A total of 5085 children were recruited on 1 designated day each week, year-round during the 11 years, and 221 (4.3%) tested positive for influenza B. Hospitalization rates were highest in children aged 2 to <5 years with year-to-year variation. Victoria-lineage viruses appeared to be associated with a greater fraction of influenza B hospitalizations in children than of influenza B infections in the general community. Influenza B did not cause significant hospitalization in infants <1 year of age. CONCLUSIONS: We report one of the first population-based, age- and lineage-specific studies of pediatric hospitalization for influenza B. We found that changes in lineage were associated with higher hospitalization rates and documented that Victoria lineage viruses were associated with greater pediatric hospitalization burden compared with Yamagata lineage viruses.

Molecular epidemiology of human coronavirus OC43 reveals evolution of different genotypes over time and recent emergence of a novel genotype due to natural recombination.

Although human coronavirus OC43-OC43 (HCoV-OC43) is the coronavirus most commonly associated with human infections, little is known about its molecular epidemiology and evolution. We conducted a molecular epidemiology study to investigate different genotypes and potential recombination in HCoV-OC43. Twenty-nine HCoV-OC43 strains from nasopharyngeal aspirates, collected from 2004 to 2011, were subjected to RNA-dependent RNA polymerase (RdRp), spike, and nucleocapsid gene analysis. Phylogenetic analysis showed at least three distinct clusters of HCoV-OC43, although 10 unusual strains displayed incongruent phylogenetic positions between RdRp and spike genes. This suggested the presence of four HCoV-OC43 genotypes (A to D), with genotype D most likely arising from recombination. The complete genome sequencing of two genotype C and D strains and bootscan analysis showed recombination events between genotypes B and C in the generation of genotype D. Of the 29 strains, none belonged to the more ancient genotype A, 5 from 2004 belonged to genotype B, 15 from 2004 to 2006 belonged to genotype C, and 1 from 2004 and all 8 from 2008 to 2011 belonged to the recombinant genotype D. Molecular clock analysis using spike and nucleocapsid genes dated the most recent common ancestor of all genotypes to the 1950s, genotype B and C to the 1980s, genotype B to the 1990s, and genotype C to the late 1990s to early 2000s, while the recombinant genotype D strains were detected as early as 2004. This represents the first study to describe natural recombination in HCoV-OC43 and the evolution of different genotypes over time, leading to the emergence of novel genotype D, which is associated with pneumonia in our elderly population.

Clinical and molecular epidemiology of human parainfluenza virus 4 infections in hong kong: subtype 4B as common as subtype 4A.

In this 1-year study, 35 (1.2%) of 2,912 nasopharyngeal aspirates were positive for human parainfluenza virus 4 (HPIV4) by reverse transcription-PCR. Patients with HPIV4 infection were mainly young children and immunocompromised adults. In contrast to the reported predominance of HPIV4A infection, molecular subtyping revealed that 15 (44%) cases were caused by HPIV4B.

Hospital-based vaccine effectiveness against influenza B lineages, Hong Kong, 2009-14.

BACKGROUND: We estimated vaccine effectiveness (VE) against pediatric influenza B hospitalizations in Hong Kong year round between November 2001 and October 2014. METHODS: We conducted a test-negative year-round study, enrolling children 6 months to 17 years of age admitted to two hospitals in Hong Kong with a febrile acute respiratory infection. Children were tested for influenza A and B. Conditional logistic regression was used to estimate overall and lineage-specific vaccine effectiveness comparing influenza vaccination history of the trivalent influenza vaccine (TIV) among patients testing positive for influenza B versus negative for influenza A and B, adjusting for age and sex and matching by calendar week of recruitment. RESULTS: Of the 6013 children included in the analysis, 262 tested positive for influenza B. Vaccination coverage was low: 6.5% in the influenza B positive children when compared with 8.8% in children who tested negative for both influenza A and B (p=0.248). Overall, VE was 47.6% (95% CI: 10.0, 69.4%) against influenza B hospitalization despite variable co-circulation of both lineages in all years. VE for Victoria-like virus calculated from 3 years when the vaccine was lineage-matched was 59.1% (95% CI: 6.2, 82.2%). Lineage-matched VE for Yamagata-like virus was -8.8% (95% CI: -215.4, 62.5%) in a clade mismatch season. With wide confidence intervals, we were unable to demonstrate cross-lineage protection: VE against the mismatched B/Yamagata-like virus was 9.5% (95% CI: -240.4, 76.0%) in 2011/12 and against mismatched B/Victoria-like virus in 2013/14 was 42.7% (95% CI: -368.6, 93.0%). CONCLUSIONS: TIV conferred an overall VE of 47.6% (95% CI: 10.0, 69.4%) against influenza B hospitalization in children despite variable co-circulation of both lineages in all years. Lineage-matched VE for Yamagata-like virus was poor and may be related to clade mismatch. Cross-lineage protection was not observed.

Population-based incidence of community-acquired pneumonia hospitalization in Hong Kong children younger than 5 years before universal conjugate pneumococcal immunization.

OBJECTIVES: We sought to document the incidence of pediatric hospitalization for bacterial pneumonia before universal childhood conjugate pneumococcal vaccination using two different methods of diagnosis. METHODS: By following the World Health Organization (WHO) chest radiography (CXR) protocol, two radiologists independently read the CXRs of a cohort of systematically recruited children younger than 5 years. The children had acute respiratory infections and were admitted to one of two hospitals that care for 72.5% of all pediatric admissions on Hong Kong Island. Medical records were reviewed for clinical manifestation and to identify bacterial pneumonia diagnosed by pediatricians. RESULTS: In children younger than 5 years, the incidences of bacterial pneumonia, as diagnosed by pediatricians and by the WHO CXR standard, were 775.7 per 100,000 population [95% confidence interval (CI, 591.8-998.3)] and 439.5 per 100,000 population (95% CI, 304.6-614.5), respectively. The study period was from 2002 to 2004. CONCLUSION: This study provided a reliable baseline estimate of the hospitalization burden of pneumococcal pneumonia in Hong Kong children before the advent of universal conjugate pneumococcal vaccination.

A six-year descriptive epidemiological study of human coronavirus infections in hospitalized patients in Hong Kong.

We conducted a six-year epidemiological study on human coronaviruses (HCoVs) circulating in Hong Kong, using 8275 nasopharyngeal samples from patients with acute respiratory tract infections. HCoVs were detected in 77 (0.93%) of the samples by a pan-HCoV RT-PCR assay. The most frequently detected HCoV species was HCoV-OC43 (0.58%), followed by HCoV-229E (0.15%), HCoV-HKU1 (0.13%) and HCoV-NL63 (0.07%). HCoVs were detected throughout the study period (September 2008-August 2014), with the highest detection rate from September 2010 to August 2011 (22/1500, 1.47%). Different seasonal patterns of each HCoV species in Hong Kong were noted. HCoV-OC43 was predominant in the fall and winter, whereas HCoV-HKU1 showed peak activity in winter, with a few cases occurred in spring and summer. HCoV-229E mainly occurred in winter and spring, while HCoV-NL63 was predominant in summer and autumn. HCoVs most commonly infect the elderly and young children, with median age of 79.5 years (range, 22 days to 95 years). Intriguingly, the detection rate of HCoV-OC43 in the age group of > 80 years (26/2380, 1.09%) was significantly higher than that in the age group of 0-10 years (12/2529, 0.47%) (P < 0.05). These data provides new insight into the epidemiology of coronaviruses.

Population-based hospitalization burden of influenza a virus subtypes and antigenic drift variants in children in Hong Kong (2004-2011).

OBJECTIVES: We aim to document and analyze influenza hospitalization burden in light of antigenic changes in circulating influenza viruses in Hong Kong. METHODS: The pediatric age-specific rates of influenza A hospitalization in Hong Kong for 2004-2011 which encompassed the emergence of H1N1pdm09 were extrapolated from admissions to 2 hospitals that together catered for 72.5% of all pediatric admissions on Hong Kong Island. Influenza A was detected by immunofluorescence, culture and/or PCR on nasopharyngeal aspirates. RESULTS: Influenza A caused high rates of hospitalization in children with year to year fluctuations. The highest hospitalization burden was seen with H1N1pdm09 in 2009. Additional factors affecting hospitalization were the proportion of viral circulation among different subtypes, and antigenic drifts. Taking these into effect, an H3N2 dominated year was not always associated with more hospitalizations than a 'seasonal' H1N1 year. Hospitalization burden was higher in seasons when drifted viruses of H1N1 or H3N2 dominated. No hospitalization was documented in infants <6 months of age during years when an undrifted virus circulated (2006 for H1N1 and 2008 for H3N2) but significant hospitalization was observed with a drifted or shifted virus (2004, 2005, 2007 and 2010 for H3N2, and 2009 for H1N1pdm09). CONCLUSIONS: We documented a consistently high pediatric hospitalization burden of influenza A. Knowledge of antigenic changes and their proportion of circulation aids in the interpretation of impact of the subtypes. Year-to-year variation in hospitalization rates in young infants appeared to correlate with antigenic variation, lending support to the role of protection from maternal antibodies.

The population based socioeconomic burden of pediatric influenza-associated hospitalization in Hong Kong.

We described the monetary and non-monetary cost incurred by children hospitalized for virologically confirmed influenza virus infection in a population-based prospective 3-year study. The mean direct and indirect cost of each child hospitalized was $1217.82 (95% CI, 1111.54-1324.23) and $1328.33 (95% CI, $1136.79-1520.00) for influenza A and B, respectively. School age patients took a mean (SD) of 4.70 (3.05) days and 5.31 (3.62) days of sick leave for influenza A and B infection, respectively. Pediatric influenza A and B hospitalization was associated with 662-1046 days of school absenteeism and 214-336 days of parental work loss per 10,000 population <18 years of age per year. We showed that the cost incurred by hospitalization alone, was comparable to the cost of annual universal pediatric influenza vaccination especially in children 6 months to under 6 years of age and vaccination would result in much larger cost-savings when non-monetary costs are included.

Clinical and molecular epidemiology of human rhinovirus C in children and adults in Hong Kong reveals a possible distinct human rhinovirus C subgroup.

BACKGROUND: A novel human rhinovirus (HRV) species, HRV-C, was recently discovered, but its clinical features and epidemiology, compared with HRV-A and HRV-B, remains poorly understood, especially in adults. METHODS: One thousand two hundred nasopharyngeal aspirate samples obtained from hospitalized children and adults during a 1-year period were subject to reverse-transcriptase polymerase chain reaction to detect HRV. The clinical and molecular epidemiology of the 3 HRV species was analyzed. RESULTS: HRVs were detected in 178 (29.7%) of 600 nasopharyngeal aspirate samples from children and 42 (7%) of 600 nasopharyngeal aspirate samples from adults. HRV-A was most prevalent (n=11), followed by HRV-C (n=91) and HRV-B (n=18). Although upper respiratory tract infection was the most common presentation in children, 8 (62%) of the 13 adults with HRV-C infection had pneumonia, compared with 6 (27%) of the 22 adults with HRV-A infection (P<.05). Wheezing episodes were also more common among individuals with HRV-C (37%) and HRV-A (20%) infection than among those with HRV-B (0%) infection (P<.05). Clinical and molecular data analysis revealed HRV-C as a frequent cause of community and institutionalized outbreaks. A diverse set of HRV-C genotypes was circulating throughout the year, among which a potential distinct subgroup of strains was observed. CONCLUSION: HRV-C is associated with pneumonia in adults and outbreaks of respiratory infections requiring hospitalization. A potential novel HRV-C subgroup was identified.

Clinical features and complete genome characterization of a distinct human rhinovirus (HRV) genetic cluster, probably representing a previously undetected HRV species, HRV-C, associated with acute respiratory illness in children.

Although human rhinoviruses (HRVs) are common causes of respiratory illness, their molecular epidemiology has been poorly investigated. Despite the recent findings of new HRV genotypes, their clinical disease spectrum and phylogenetic positions were not fully understood. In this study, 203 prospectively collected nasopharyngeal aspirates (NPAs), negative for common respiratory viruses (83 were human bocavirus [HBoV] positive and 120 HBoV negative), from hospitalized children during a 1-year period were subjected to reverse transcription-PCR for HRV. HRV was detected in 14 NPAs positive and 12 NPAs negative for HBoV. Upon VP4 gene analysis, 5 of these 26 HRV strains were found to belong to HRV-A while 21 belonged to a genetic clade probably representing a previously undetected HRV species, HRV-C, that is phylogenetically distinct from the two known HRV species, HRV-A and HRV-B. The VP4 sequences of these HRV-C strains were closely related to the newly identified HRV strains from the United States and Australia. Febrile wheeze or asthma was the most common presentation (76%) of HRV-C infection, which peaked in fall and winter. Complete genome sequencing of three HRV-C strains revealed that HRV-C represents an additional HRV species, with features distinct from HRV-A and HRV-B. Analysis of VP1 of HRV-C revealed major deletions in regions important for neutralization in other HRVs, which may be signs of a distinct species, while within-clade amino acid variation in potentially antigenic regions may indicate the existence of different serotypes among HRV-C strains. A newly identified HRV species, HRV-C, is circulating worldwide and is an important cause of febrile wheeze and asthmatic exacerbations in children requiring hospitalization.

Clinical and molecular epidemiology of human bocavirus in respiratory and fecal samples from children in Hong Kong.

BACKGROUND: Human bocavirus (HBoV) is a recently discovered parvovirus associated with respiratory tract infections in children. We conducted the first systematic prospective clinical and molecular study using nasopharyngeal aspirates (NPAs) and fecal samples. METHODS: NPAs negative for influenza virus, parainfluenza virus, respiratory syncytial virus, adenovirus, and coronavirus and fecal samples from patients with acute gastroenteritis were included. On the basis of results from a pilot study using 400 NPAs from all age groups, a prospective 12-month study was conducted to detect HBoV in 1,200 NPAs and 1,435 fecal samples from patients <18 years old by polymerase chain reaction. The complete genome sequences of HBoVs from 12 NPAs and 12 fecal samples were determined. RESULTS: Of the 400 NPAs collected in the pilot study, 20 (5.0%) were found to contain HBoV, all from children <5 years old. In the subsequent prospective study of pediatric patients, HBoV was detected in 83 (6.9%) of 1,200 NPAs. Upper and lower respiratory tract infections were equally common. HBoV was detected in 30 (2.1%) of 1,435 fecal samples. Fever and watery diarrhea were the most common symptoms. The seasonality of HBoV in NPAs and fecal samples was similar. Codetection with other pathogens occurred in 33% and 56% of NPAs and fecal samples, respectively, from patients with HBoV infection. Genomes of HBoVs from NPAs and fecal samples displayed minimal sequence variations. CONCLUSIONS: HBoV was detected in fecal specimens in children with acute gastroenteritis. A single lineage of HBoV was associated with both respiratory tract and enteric infections.

Coronavirus HKU1 and other coronavirus infections in Hong Kong.

We have recently described the discovery of a novel coronavirus, coronavirus HKU1 (CoV-HKU1), associated with community-acquired pneumonia. However, the clinical spectrum of disease and the epidemiology of CoV-HKU1 infections in relation to infections with other respiratory viruses are unknown. In this 12-month prospective study, 4,181 nasopharyngeal aspirates from patients with acute respiratory tract infections were subjected to reverse transcription-PCRs specific for CoV-HKU1 and human coronaviruses NL63 (HCoV-NL63), OC43 (HCoV-OC43), and 229E (HCoV-229E). Coronaviruses were detected in 87 (2.1%) patients, with 13 (0.3%) positive for CoV-HKU1, 17 (0.4%) positive for HCoV-NL63, 53 (1.3%) positive for HCoV-OC43, and 4 (0.1%) positive for HCoV-229E. Of the 13 patients with CoV-HKU1 infections, 11 were children and 8 had underlying diseases. Similar to the case for other coronaviruses, upper respiratory infection was the most common presentation of CoV-HKU1 infections, although pneumonia, acute bronchiolitis, and asthmatic exacerbation also occurred. Despite a shorter duration of fever (mean, 1.7 days) and no difference in maximum temperature in children with CoV-HKU1 infections compared to patients with most other respiratory virus infections, a high incidence of febrile seizures (50%) was noted, which was significantly higher than those for HCoV-OC43 (14%), adenovirus (9%), human parainfluenza virus 1 (0%), and respiratory syncytial virus (8%) infections. CoV-HKU1 and HCoV-OC43 infections peaked in winter, although cases of the former also occurred in spring to early summer. This is in contrast to HCoV-NL63 infections, which mainly occurred in early summer and autumn but were absent in winter. Two genotypes of CoV-HKU1 cocirculated during the study period. Continuous studies over a longer period are warranted to ascertain the seasonal variation and relative importance of the different coronaviruses. Similar studies in other countries are required to better determine the epidemiology and genetic diversity of CoV-HKU1.