Interactive effects between CDHR3 genotype and rhinovirus species for diagnosis and severity of respiratory tract infections in hospitalized children.

Rhinovirus (RV) is the leading pathogen causing childhood wheezing, with rhinovirus C (RV-C) species reported to cause asthma exacerbation. Allele A of single-nucleotide polymorphism (SNP) CDHR3_rs6967330 upregulates epithelial expression of RV-C receptors which results in more severe asthma exacerbations in children. Nevertheless, there are limited data on interactions between CDHR3 variants and their impact on severity of RV-related pediatric respiratory tract infections (RTIs). Medical records of RV-related RTIs in children aged below 18 years who were hospitalized in two public hospitals in 2015-2016 were independently reviewed by two paediatricians. Archived nasopharyngeal aspirates were retrieved for RV detection and sequencing as well as CDHR3 genotyping. HaploView v.5.0 and generalized multifactor dimensionality reduction (GMDR) analysis were employed for haplotypic assignment and gene-environment interaction analyses. Among 1019 studied cases, our results confirmed the relationship between RV-C species and more severe RTIs. Besides the top risk variant rs6967330-A, we identified rs140154310-T to be associated with RV-C susceptibility under the additive model [odds ratio (OR) 2.53, 95% CI 1.15-5.56; P = 0.021]. Rs140154310 was associated with wheezing illness (OR 2.38, 95% CI 1.12-5.04; P = 0.024), with such association being stronger in subjects who wheezed due to RV-C infections (OR 2.71, 95% CI 1.32-5.58; P = 0.007). Haplotype GAG constructed from rs4730125, rs6967330, and rs73195665 was associated with increased risk of RV-C infection (OR 1.71, 95% CI 1.11-2.65; P = 0.016) and oxygen supplementation (OR 1.93, 95% CI 1.13-3.30; P = 0.016). GMDR analyses revealed epistatic interaction between rs140154310 and rs6967330 of CDHR3 for RV-C infection (P = 0.001), RV-C-associated lower RTI (P = 0.004), and RV-C-associated wheeze (P = 0.007). There was synergistic gene-environmental interaction between rs3887998 and RV-C for more severe clinical outcomes (P < 0.001). To conclude, rs140154310-T is another risk variant for RV-C susceptibility and more severe RTIs. Synergistic epistatic interaction is found between CDHR3 SNPs and RV-C for RTI severity, which is likely mediated by susceptibility to RV-C. Haplotypic analysis and GMDR should be included in identifying prediction models of CDHR3 for childhood asthma and RTIs. IMPORTANCE This case-control study investigated the interaction between CDHR3 genotypes and rhinovirus (RV) species on disease severity in Hong Kong children hospitalized for respiratory tract infection (RTI). There were synergistic effects between RV-C and CDHR3 SNPs for RTI severity, which was mainly driven by RV-C. Specifically, rs6967330 and rs140154310 alone and their epistatic interaction were associated with RV-C-related and severe RTIs in our subjects. Therefore, genotyping of CDHR3 SNPs may help physicians formulate prediction models for severity of RV-associated RTIs.

Seafood Allergy in Asia: Geographical Specificity and Beyond.

Asian countries have unique ways of food processing and dietary habits that may explain the observed differences in the prevalence, natural history, epidemiology and sensitization pattern of food allergic diseases when compared to western countries. Per capita consumption of seafood, including fish and shellfish, is well above the global average for many Asian countries because of their coastal geographical location and rich seafood supply. The wide availability and high abundance of seafood in Asian countries have shaped a diverse way of processing and eating this major food group. Such unique features have significant impact on the sensitization profile and allergenicity of Asians to fish and shellfish. For example, fish and shellfish are eaten raw in some countries that may promote sensitization to heat-labile allergens not otherwise seen in other regions. Fermented fish sauce is commonly used as a condiment in some countries which may promote fish sensitization. Shrimp head and shrimp roe are regarded as delicacies in some countries, but their allergen profiles are yet to be characterized. Freshwater fish and shellfish are a common food source in many Asian countries but the allergenicity of many such species remains unknown. In this review, we discuss factors that may contribute to differences in molecular profile and sensitization pattern for fish and shellfish that are observed in Asian populations and revisit the current status of seafood allergy in this part of the world. Acknowledging the similarities and differences of seafood allergy patterns between Asian and western populations can help us refine a better strategy for diagnosing and managing seafood allergy.

A randomized controlled trial of different young child formulas on upper respiratory and gastrointestinal tract infections in Chinese toddlers.

BACKGROUND: Bioactive proteins and human milk oligosaccharides (HMOs), important ingredients in breast milk, that protect against infections are lacking in young child formula (YCF). This study investigated the effects of new YCFs on respiratory and gastrointestinal infections in toddlers. METHODS: Four hundred and sixty one healthy Chinese children aged 1-2.5 years were recruited in this randomized, controlled, double-blind, parallel-group clinical trial of different YCFs. They were randomly assigned to either standard milk formula (YCF-Ref) or one of three new YCFs containing bioactive proteins and/or the HMO 2'-fucosyllactose (2'-FL) and/or milk fat for six months. Primary outcomes were incidence of upper respiratory tract infection (URTI) and duration of gastrointestinal tract infections (GITI). RESULTS: There were no significant between-group differences in primary outcomes. For secondary outcomes, subjects receiving 2'-FL-supplemented YCF had longer URTI. Subjects receiving YCF supplemented with milk fat and intact bioactive proteins, and 2'-FL at levels found in breast milk, had more GITI episodes and shorter time to first GITI but similar effects on URTI duration than YCF-Ref recipients. No effects on URTI and GITI were observed in toddlers receiving YCF with bioactive proteins at lower levels than breast milk. Occurrence of adverse events and anthropometry were similar in all groups. CONCLUSIONS: All three YCFs supplemented with different combinations of intact bioactive proteins, 2'-FL, and milk fat are safe in toddlers. No difference is detected among YCFs on URTI incidence and GITI duration. Further studies are needed to verify these findings especially in infants who may benefit most from the immune-boosting effects of bioactive proteins and HMOs.

Higher Viral Load of Emerging Norovirus GII.P16-GII.2 than Pandemic GII.4 and Epidemic GII.17, Hong Kong, China.

We compared viral load of emerging recombinant norovirus GII.P16-GII.2 with those for pandemic GII.Pe-GII.4 and epidemic GII.P17-GII.17 genotypes among inpatients in Hong Kong. Viral load of GII.P16-GII.2 was higher than those for other genotypes in different age groups. GII.P16-GII.2 is as replication competent as the pandemic genotype, explaining its high transmissibility and widespread circulation.

Bimodal Seasonality and Alternating Predominance of Norovirus GII.4 and Non-GII.4, Hong Kong, China, 2014-20171.

We report emerging subtropical bimodal seasonality and alternating predominance of norovirus GII.4 and non-GII.4 genotypes in Hong Kong. GII.4 predominated in summer and autumn months and affected young children, whereas emergent non-GII.4 genotypes predominated in winter months and affected all age groups. This highly dynamic epidemiology should inform vaccination strategies.

Trajectory of spirometric and exhaled nitric oxide measurements in Chinese schoolchildren with asthma.

BACKGROUND: Lung function growth occurs in most asthmatic children. A subgroup has subnormal lung function trajectory, but such data are limited in children. This prospective study characterized longitudinal changes of spirometric indices and fractional exhaled nitric oxide level (FeNO) among asthmatic children and identified their genetic and environmental determinants. METHODS: Chinese asthmatic children recruited from pediatric clinics underwent 5-year follow-up for pre-bronchodilator spirometric indices and FeNO. Fourteen asthma-associated single nucleotide polymorphisms (SNPs) were genotyped. Generalized estimating equation was used to analyze longitudinal changes of spirometric indices and FeNO. RESULTS: One hundred and ninety-three asthmatic children, aged 9.7 (1.9) years, had significant annual decline of 1.3% for forced vital capacity (FVC) and annual increase of 1.2% and 3.6% for FEV1 /FVC and FEF25-75 , respectively. Patients who received inhaled corticosteroid (ICS) had 2.4% lower baseline FEV1 /FVC but 0.81% higher annual increase in FEV1 . Body mass index (BMI) was associated inversely with FEV1 /FVC but positively with FEV1 % and FVC% changes. Asthma exacerbation was associated with lower FEV1 % and FVC% but not their longitudinal changes. When classified by FEV1 curve, one-quarter of patients had reduced lung function growth which was associated with female gender and lower spirometric and higher FeNO values at baseline. IL33_rs1342326 was associated with spirometric indices and FeNO, whereas GSDMB_rs2305480 was significantly associated with FEV1 /FVC change. CONCLUSION: Asthmatic children have annual decline in FVC and increase in FEV1 /FVC and FEF25-75 . Their lung function trajectory is influenced by gender, ICS treatment, BMI, and asthma exacerbations. IL33 and GSDMB may be candidate genes for their lung function growth.

Increased Detection of Emergent Recombinant Norovirus GII.P16-GII.2 Strains in Young Adults, Hong Kong, China, 2016-2017.

A new recombinant norovirus GII.P16-GII.2 outnumbered pandemic GII.4 as the predominant GII genotype in the winter of 2016-2017 in Hong Kong, China. Half of hospitalized case-patients were older children and adults, including 13 young adults. This emergent norovirus targets a wider age population compared with circulating pandemic GII.4 strains.

Global respiratory syncytial virus-associated mortality in young children (RSV GOLD): a retrospective case series.

BACKGROUND: Respiratory syncytial virus (RSV) infection is an important cause of pneumonia mortality in young children. However, clinical data for fatal RSV infection are scarce. We aimed to identify clinical and socioeconomic characteristics of children aged younger than 5 years with RSV-related mortality using individual patient data. METHODS: In this retrospective case series, we developed an online questionnaire to obtain individual patient data for clinical and socioeconomic characteristics of children aged younger than 5 years who died with community-acquired RSV infection between Jan 1, 1995, and Oct 31, 2015, through leading research groups for child pneumonia identified through a comprehensive literature search and existing research networks. For the literature search, we searched PubMed for articles published up to Feb 3, 2015, using the key terms "RSV", "respiratory syncytial virus", or "respiratory syncytial viral" combined with "mortality", "fatality", "death", "died", "deaths", or "CFR" for articles published in English. We invited researchers and clinicians identified to participate between Nov 1, 2014, and Oct 31, 2015. We calculated descriptive statistics for all variables. FINDINGS: We studied 358 children with RSV-related in-hospital death from 23 countries across the world, with data contributed from 31 research groups. 117 (33%) children were from low-income or lower middle-income countries, 77 (22%) were from upper middle-income countries, and 164 (46%) were from high-income countries. 190 (53%) were male. Data for comorbidities were missing for some children in low-income and middle-income countries. Available data showed that comorbidities were present in at least 33 (28%) children from low-income or lower middle-income countries, 36 (47%) from upper middle-income countries, and 114 (70%) from high-income countries. Median age for RSV-related deaths was 5·0 months (IQR 2·3-11·0) in low-income or lower middle-income countries, 4·0 years (2·0-10·0) in upper middle-income countries, and 7·0 years (3·6-16·8) in high-income countries. INTERPRETATION: This study is the first large case series of children who died with community-acquired RSV infection. A substantial proportion of children with RSV-related death had comorbidities. Our results show that perinatal immunisation strategies for children aged younger than 6 months could have a substantial impact on RSV-related child mortality in low-income and middle-income countries. FUNDING: Bill & Melinda Gates Foundation.

School-based surveillance for influenza vaccine effectiveness during 2014-2015 seasons in Hong Kong.

BACKGROUND: Influenza imposes substantial healthcare burden in children, which can be prevented by vaccination. Influenza vaccination coverage varies widely among childhood populations worldwide, which has significant impact on herd immunity and usefulness of influenza vaccine. However, there are limited real-life data on influenza vaccine effectiveness (VE) in children. OBJECTIVE: This prospective study aimed to investigate clinical spectrum of childhood influenza and VE in preventing influenza in Hong Kong children. METHODS: A total of 623 children were recruited from 15 kindergartens and primary schools. Parents completed a questionnaire on subjects' health and influenza vaccination history. Flocked nasopharyngeal swabs (FNPSs) were collected in biweekly school visits during 2014-2015 influenza seasons. Influenza A and B viruses were detected and typed by molecular assays. RESULTS: A total of 2633 FNPS samples were collected, with two or more samples being obtained from 607 (97.4%) of subjects. Thirty-six (11.2%) subjects had influenza A or B in 2014, whereas all 19 (6.3%) subjects identified in 2015 had influenza A. Ninety-nine subjects reported influenza-like illness (ILI), and nine illness visits were arranged. Influenza vaccination was protective against ILI but not mild laboratory-confirmed influenza by surveillance. Moderate overall influenza VE of 42%-52% was observed for ILI, and subgroup analyses showed much higher VE for both ILI (70.9% vs 34.6%) and mild laboratory-confirmed influenza (44.0% vs -6.2%) in school-age children than preschoolers who were vaccinated within 12 months. CONCLUSIONS: Mild laboratory-confirmed influenza infection is common in children during influenza seasons. Influenza vaccination is effective against ILI but not mild infection identified by surveillance.

Aberrant Expression of Novel Cytokine IL-38 and Regulatory T Lymphocytes in Childhood Asthma.

We investigated the expression of novel anti-inflammatory interleukin (IL)-38 and regulatory T (Treg) lymphocytes in childhood asthma patients. The protein and mRNA expression level of IL-38, periostin, peripheral CD4⁺CD25⁺CD134⁺ T lymphocytes as well as CD4⁺CD25(high)FoxP3⁺ and CD4⁺CD25(high)CD127(-) Treg lymphocytes from 40 asthmatic patients and 20 normal control (NC) subjects were studied using ELISA, qPCR and flow cytometry. Serum and supernatant cytokines/chemokines were determined by multiplex assay. Serum IL-38, IL-5, IL-17, IL-6, interferon-γ, periostin, IL-1ß and IL-13 concentrations were significantly higher in asthmatic patients with or without steroid treatment than those in controls (all p < 0.05). The percentages of both CD4⁺CD25(high)FoxP3⁺ and CD4⁺CD25(high)CD127(-) Treg lymphocytes were markedly decreased in asthmatic patients with and without steroid treatment than those in controls (all p < 0.05). The elevated IL-38 concentration negatively correlated with the percentage of Treg lymphocytes in asthmatic patients with high level (>40 ng/mL) of periostin (p < 0.05). Although the comparable mRNA levels of IL-38 and its receptor IL-36R were found between patients and controls, the mRNA level of IL-38 positively correlated with IL-36R and negatively correlated with IL-10 in all asthmatic patients (both p < 0.05). The percentage of CD4⁺CD25⁺CD134⁺ activated T lymphocytes was also significantly higher in asthmatic patients with steroid treatment than those in controls (p < 0.05). This cross-sectional study demonstrated that the overexpression of circulating IL-38 may play a role in the immunopathogenesis in asthma.

Rapid emergence and predominance of a broadly recognizing and fast-evolving norovirus GII.17 variant in late 2014.

Norovirus genogroup II genotype 4 (GII.4) has been the predominant cause of viral gastroenteritis since 1996. Here we show that during the winter of 2014-2015, an emergent variant of a previously rare norovirus GII.17 genotype, Kawasaki 2014, predominated in Hong Kong and outcompeted contemporary GII.4 Sydney 2012 in hospitalized cases. GII.17 cases were significantly older than GII.4 cases. Root-to-tip and Bayesian BEAST analyses estimate GII.17 viral protein 1 (VP1) evolves one order of magnitude faster than GII.4 VP1. Residue substitutions and insertion occur in four of five inferred antigenic epitopes, suggesting immune evasion. Sequential GII.4-GII.17 infections are noted, implicating a lack of cross-protection. Virus bound to saliva of secretor histo-blood groups A, B and O, indicating broad susceptibility. This fast-evolving, broadly recognizing and probably immune-escaped emergent GII.17 variant causes severe gastroenteritis and hospitalization across all age groups, including populations who were previously less vulnerable to GII.4 variants; therefore, the global spread of GII.17 Kawasaki 2014 needs to be monitored.

Virus Genotype Distribution and Virus Burden in Children and Adults Hospitalized for Norovirus Gastroenteritis, 2012-2014, Hong Kong.

We conducted a 2-year hospital-based study on norovirus gastroenteritis among children and adults between August 2012 and September 2014. A total of 1,146 norovirus cases were identified. Young children (aged ≤ 5 years) accounted for a majority (53.3%) of cases. Hospitalization incidence exhibited a U-shaped pattern with the highest rate in young children (1,475 per 100,000 person-years), followed by the elderly aged > 84 years (581 per 100,000 person-years). A subset (n = 395, 34.5%) of cases were selected for norovirus genotyping and noroviral load measurement. Non-GII.4 infections were more commonly observed in young children than in older adults (aged > 65 years) (20.5% versus 9.2%; p < 0.05). In young children, the median noroviral load of GII.4 and non-GII.4 cases was indistinguishably high (cycle threshold value, median [interquartile range]: 16.6 [15.2-19.3] versus 16.6 [14.9-21.6]; p = 0.45). Two age-specific non-GII.4 genotypes (GII.3 and GII.6) were identified among young children. These findings may have implications in norovirus vaccination strategy.

Characteristics of patients infected with norovirus GII.4 Sydney 2012, Hong Kong, China.

Norovirus GII.4 Sydney 2012 has spread globally since late 2012. We report hospitalization of patients infected with this strain skewed toward infants and young children among 174 cases during August 2012-July 2013 in Hong Kong, China. This group had higher fecal viral load (≈10-fold) than did older children and adults.

Clinical and virologic factors associated with reduced sensitivity of rapid influenza diagnostic tests in hospitalized elderly patients and young children.

Rapid influenza diagnostic tests (RIDTs) are commonly used by clinicians to guide patient management. Data on sensitivities among hospitalized patients are limited. Here, we evaluated the clinical and virologic factors affecting the sensitivities of 2 commercially available RIDTs (BinaxNOW Influenza A&B and QuickVue Influenza A+B) on nasopharyngeal aspirate (NPA) specimens collected from elderly patients and young children hospitalized for influenza. Influenza cases and age-matched negative controls were prospectively enrolled during the 2011-2012 influenza season in Hong Kong. NPA specimens were collected at presentation before antiviral treatment. Real-time reverse transcription-PCR (RT-PCR) results were used as references for the sensitivity analyses. One hundred patients (57 influenza cases and 43 controls) were studied. Both RIDTs had 100% specificities. The sensitivities of the BinaxNOW Influenza A&B and QuickVue Influenza A+B tests were 70% and 82%, respectively. For both tests, the sensitivities were lower in cases with presentation times beyond 2 days of illness onset than for those within this time (50 to 71% versus 85 to 91%, respectively). There were trends toward lower sensitivities for influenza B than for influenza A (66 to 81% versus 76 to 84%, respectively), among young children than among the elderly patients (63 to 78% versus 80 to 88%, respectively), and among cases with pneumonia than those without pneumonia (75% versus 82 to 94%, respectively). The sensitivities of the RIDTs decreased with reduced NPA viral RNA levels (5.6 to 15.0% reduction per 1-log decrease), which declined progressively after illness onset (Spearman's rho, -0.47 [P < 0.05] and -0.66 [P < 0.001] for influenza A and B, respectively). Collectively, late presentation, a low NPA viral load, and probably lower respiratory manifestation are factors associated with reduced sensitivities of RIDTs for diagnosing influenza in hospitalized patients. A negative RIDT result should be interpreted with caution.

Differences in asthma genetics between Chinese and other populations.

Asthma is caused by complex gene-gene and gene-environment interactions. Most asthma genes are not replicable across populations, which is possibly because of differences in the epidemiology of these genes. Our case-control association and next-generation sequencing studies revealed substantial discrepancies in the frequencies of single nucleotide polymorphisms (SNPs) and haplotype blocks for asthma genes between Chinese and other populations. The minor allele frequencies for nearly half of our studied SNPs differed by 0.2 or greater between southern Chinese subjects in Hong Kong and European white populations, African populations, or both. Because genome-wide association studies for asthma have not been performed in Chinese subjects, we cannot tell whether the genomic findings of recent consortium-based genome-wide association studies are applicable to our population. In addition, our group performed Roche 454 pyrosequencing on a 100-kb area spanning each of 10 asthma loci in 24 healthy Hong Kong children. For the 17q21 locus, there was substantial variation in the haplotype structures that were constructed from 224 common SNPs among Hong Kong subjects and 6 ethnic groups under the 1000 Genomes Project. Sixteen mostly small haplotype blocks were formed in Hong Kong, whereas 6 haplotype blocks were identified in Han Chinese in Beijing and central European subjects and 11 and 19 blocks were identified in Puerto Rican and Yoruba African subjects. In conclusion, differences in allele frequencies of asthma genes and haplotype structures of asthma loci are found between Chinese subjects and other ethnic groups. These sequence variations must be considered during the selection of tagging SNPs for replicating genetic associations between populations.

Recent advances in asthma biomarker research.

Asthma is characterized by recurrent and reversible airflow obstruction, which is routinely monitored by history and physical examination, spirometry and home peak flow diaries. As airway inflammation is central to asthma pathogenesis, its monitoring should be part of patient management plans. Fractional exhaled nitric oxide level (FeNO) is the most extensively studied biomarker of airway inflammation, and FeNO references were higher in Chinese (Asians) than Whites. Published evidence was inconclusive as to whether FeNO is a useful management strategy for asthma. Other biomarkers include direct (histamine, methacholine) and indirect (adenosine, hypertonic saline) challenges of bronchial hyperresponsiveness (BHR), induced sputum and exhaled breath condensate (EBC). A management strategy that normalized sputum eosinophils among adult patients resulted in reductions of BHR and asthma exacerbations. However, subsequent adult and pediatric studies failed to replicate these benefits. Asthma phenotypes as defined by inflammatory cell populations in sputum were also not stable over a 12-month period. A recent meta-analysis concluded that induced sputum is not accurate enough to be applied in routine monitoring of childhood asthma. There is poor correlation between biomarkers that reflect different asthma dimensions: spirometry (airway caliber), BHR (airway reactivity) and FeNO or induced sputum (airway inflammation). Lastly, EBC is easily obtained noninvasively by cooling expired air. Many biomarkers ranging from acidity (pH), leukotrienes, aldehydes, cytokines to growth factors have been described. However, significant overlap between groups and technical difficulty in measuring low levels of inflammatory molecules are the major obstacles for EBC research. Metabolomics is an emerging analytical method for EBC biomarkers. In conclusion, both FeNO and induced sputum are useful asthma biomarkers. However, they will only form part of the clinical picture. Longitudinal studies with focused hypotheses and well-designed protocols are needed to establish the roles of these biomarkers in asthma management. The measurement of biomarkers in EBC remains a research tool.

Relationship between passive smoking exposure and urinary heavy metals and lung functions in preschool children.

Environmental tobacco smoke (ETS) exposure is a risk factor for asthma in school-age children, but there is limited data of ETS exposure on respiratory health in preschool children. This study investigated the relationship between ETS, lead (Pb), and cadmium (Cd) exposures and asthma symptoms and spirometric indices in Chinese preschoolers. Preschool children from 30 nurseries and kindergartens performed spirometry with incentives of animation programs, and their urinary cotinine, Pb and Cd concentrations were measured by immunoassay and inductively coupled plasma-mass spectrometry, respectively. Two thousand seven hundred sixty-three preschoolers participated, and 1,505 and 893 provided valid spirometric data and urine samples, respectively. Current domestic smoking was reported in 37.5% of children, but only 95 (10.6%) had high urinary cotinine-to-creatinine ratio (≥30 ng/mg). Pb was measurable in 3.9% of samples, whereas 406 (45.5%) children had high Cd. Reported ETS exposure was not associated with any spirometric index, whereas cotinine-to-creatinine ratio was inversely associated with forced expiratory volume in 0.5-sec (ß = -0.093, P = 0.003), forced expiratory flow between 25% and 75% of expiration (ß = -0.138, P = 0.002) and peak expiratory flow (ß = -0.106, P = 0.002). Cd exposure was not associated with reported respiratory symptom or spirometric indices. This community study shows that ETS exposure defined by urinary cotinine is a strong risk factor for lung function impairment measured by spirometry in Chinese preschool children. Urinary cotinine is more reliable than questionnaire for assessing ETS exposure in young children. Although high urinary Cd is common in Hong Kong preschoolers, such biomarker is not associated with any clinical or spirometric outcome.

Rotavirus activity and meteorological variations in an Asian subtropical city, Hong Kong, 1995-2009.

Rotavirus is a leading cause of severe infectious diarrhea in infants and young children aged <5 years. Rotavirus infections have minimal to strong seasonality depending on geographical locations. In this study, a comprehensive retrospective analysis was performed to evaluate the association between rotavirus admission and multiple key meteorological variables, including air temperature, relative humidity, atmospheric pressure, and solar radiation over a 15-year period from 1995 to 2009 in Hong Kong. Rotavirus infections were found to show a distinct cyclical pattern with an annual peak in cold season. The weekly number of cases showed the strongest correlation with average air temperature of the previous 7 days (rho=-0.69; P<0.0001), followed by atmospheric pressure (rho=+0.67; P<0.0001); whereas only weak correlation with relative humidity (rho=-0.252; P<0.0001) and solar radiation (rho=-0.312; P<0.0001) was observed. Curve fitting regression analysis suggested that the correlation was nonlinear in nature in which the effect was more profound towards lower air temperature and higher atmospheric pressure conditions. In binary logistic regression analysis, a final model that included air temperature (≤ 20°C) and atmospheric pressure (≥ 1,013 hPa) predicted correctly 85.3% and 82.6% of weeks with rotavirus activity above and below the baseline level, respectively. In multivariate Poisson model, air temperature and solar radiation were independent factors associated with the weekly number of rotavirus cases, adjusted for seasonal variation. In summary, the current study provides evidence suggesting that local seasonal activity of rotavirus correlated strongly with air temperature, followed by atmospheric pressure but only minimally with relative humidity in pre-vaccine era.