Epidemiological and clinical features of human metapneumovirus in hospitalised paediatric patients with acute respiratory illness: a cross-sectional study in Southern China, from 2013 to 2016

Objectives Human metapneumovirus (HMPV) is one of the most important respiratory viral pathogens affecting infants and children worldwide. Our study describes the epidemiological and clinical characteristics of HMPV present in patients hospitalised with acute respiratory illness (ARI) in Guangzhou, Southern China. Study design A cross-sectional study. Setting Two tertiary hospitals in Guangzhou. Participants and methods Throat swabs were collected over a 3-year period from 5133 paediatric patients (≤14 years) hospitalised with ARI. Patients who are HMPV positive with clinical presentations (101/103) were recorded for further analysis. Results Of the 5133 patients included in the study, 103 (2.0%) were positive for HMPV. HMPV was more prevalent in children ≤5 years (2.2%, 98/4399) compared with older children (>5–14 years) (0.7%, 5/734) (P=0.004). Two seasonal HMPV peaks were observed each year and mainly occurred in spring and early summer. Overall, 18.4% (19/103) of patients who are HMPV positive were codetected with other pathogens, most frequently respiratory syncytial virus (36.8%, 7/19). Patients who are HMPV positive presented with a wide spectrum of clinical features, including cough (100.0%, 101/101), abnormal pulmonary breath sound (91.1%, 92/101), fever (88.1%, 89/101), expectoration (77.2%, 78/101), coryza (50.5%, 51/101) and wheezing (46.5%, 47/101). The main diagnosis of patients who are HMPV positive was bronchopneumonia (66.7%, 56/84). Fever (≥38˚C) (91.6%, 76/83) was detected more often in patients with only HMPV detected than in patients with HMPV plus other pathogen(s) detected (72.2%, 13/18) (P=0.037), whereas diarrhoea was more common in patients with HMPV plus other pathogen(s) detected (22.2%, 4/18), compared with patients with HMPV only (3.6%, 3/83) (P=0.018). Conclusions HMPV is an important respiratory pathogen in children with ARI in Guangzhou, particularly in children ≤5 years old. HMPV has a seasonal variation. Bronchopneumonia is a major diagnosis in patients who are HMPV positive.


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The study had some limitations: the characteristics of HMPV3negative patients 59 were not further analyzed, and bacterial pathogens were not detected in 60 HMPV3positive patients. Lack of these data may affect our comprehensively 61 understanding the clinical characteristics caused by this pathogen. 62 For detail, the patients were divided into six age groups: 0-3 months, >3-6 173 months, >6-12 months, >1-2 years, >2-5 years, and >5-14 years. The distribution of 174 HMPV3positive rates among these age groups was significantly different ( 0.03) 175 (/ Viruses are the most frequent cause of respiratory infection. 20 HMPV has been 206 recognized as an important respiratory pathogen causing ARI since its discovery in 207 2001. It has been reported that HMPV was responsible for approximately 5-10% of 208 hospitalizations of children suffering from ARI, 14 creating considerable clinical and 209 economic burden worldwide. HMPV detection rates vary according to geographic 210 location, and the incidence of HMPV may show seasonal or annual patterns in the 211 same area. In the previous studies, 21330 the HMPV detection rate was approximately 212 1-17% of ARI cases. In this 33year study, 103 of 5133 (2.0%) patients were positive 213 for HMPV, which is similar to previous reports of HMPV in patients with ARI in 214 southern China 31 and Japan. 32 215 HMPV is commonly found in the pediatric population; Children younger than 5 216 years of age are most susceptible to HMPV infection, and those younger than 2 years 217 of age at the greatest risk of developing serious conditions. 15 In our study, HMPV 218 positive cases appeared more frequently in patients ≤5 year3old (2.2%, 98/4399) than 219 in patients >5 year3old (0.7%, 5/734) ( =0.004), which is consistent with many 220 previous studies. 3 30 33 34 In detail, HMPV positive rate was high in children of 3 months 221 to 5 years (2.4%, 93/3920) (/ ). This may be explained by that the immunity 222 against HMPV passed down from mother gradually subsided as time goes on; 223 moreover, children were more contact with outside world as they grew older. 224 Therefore, children of this age need more attention to prevent HMPV infection. 225 Moreover, our findings suggested no gender predominance, there was no significant 226 Most of the HMPV3positive patients had a fever (88.1%, 89/101); it appeared in 266 the single HMPV3positive patients more frequently than in the co3pathogens3positive 267 patients( =0.037) (+ # ). Although diarrhea was not a major symptom in 268 HMPV3positive patients (7.0%, 7/101), but it had a higher incidence rate in 269 co3pathogen3positive patients than in single HMPV3positive patients (p=0.018), 270 that HMPV/RSV co3infection can cause more severe bronchiolitis in patients. In our 279 study, no significant difference in the diagnosis of pneumonia was observed between 280 single HMPV3positive and co3pathogens3positive patients. It has been confirmed that 281 a history of prematurity, particular age groups, and the presence of chronic diseases 282 increases the risk of severe LRTI among HMPV3 and RSV3infected children. 51 Our 283 study also suggested that the clinical manifestations of HMPV infection are complex 284 and diverse; the data might be helpful in the diagnosis of HMPV. 285 The study had some limitations. Firstly, collection of symptoms and physical 286 findings in infants and young children often requires the experience of medical staff, 287 patient's cooperation, and the knowledge of patient's guardian; but it is still possible to 288 have incomplete or even false description of patients' manifestations. Secondly, 289 because our study mainly focused on HMPV, other common respiratory pathogens 290 including bacterial pathogens were not tested in all samples, and accordingly, our 291 study could not give a fully picture of respiratory pathogen infection in hospitalized 292

HMPV is a common respiratory pathogen in children with ARI in Guangzhou， 301
China, particularly in children from 3 month to 5 years old. HMPV epidemic has a 302 seasonal variation. The clinical characteristics of HMPV infection has its own pattern 303 in children aged from infants to juveniles. Bronchopneumonia is the major clinical 304 diagnosis. In the future, our data should be taken into account when local public 305 health authority and medical community try to manage HMPV infection in children. 306 .6 < . 2 = > : . 350 : . . 6 . ?

STROBE 2007 (v4)Statement-Checklist of items that should be included in reports of cross-sectional studies
Section/Topic Item # Recommendation Reported on page # Title and abstract 1 (a) Indicate the study's design with a commonly used term in the title or the abstract 1 (b) Provide in the abstract an informative and balanced summary of what was done and what was found 2-3

Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 4 Objectives 3 State specific objectives, including any prespecified hypotheses 4-5

Study design 4
Present key elements of study design early in the paper 6 Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection 6 Participants 6 (a) Give the eligibility criteria, and the sources and methods of selection of participants 6 Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if applicable 6-7 Data sources/ measurement 8* For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group 7 Bias 9 Describe any efforts to address potential sources of bias 6 Study size 10 Explain how the study size was arrived at 6 Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47 o n l y Participants 13* (a) Report numbers of individuals at each stage of study-eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed 9 (b) Give reasons for non-participation at each stage 10 (c) Consider use of a flow diagram Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders [9][10][11] (b) Indicate number of participants with missing data for each variable of interest 9 Outcome data 15* Report numbers of outcome events or summary measures 9-11 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were included 9-11 (b) Report category boundaries when continuous variables were categorized 9-10 (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period Other analyses 17 Report other analyses done-eg analyses of subgroups and interactions, and sensitivity analyses

Discussion
Key results 18 Summarise key results with reference to study objectives 12-15 Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias

15-16
Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence

Other information
Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based 18 *Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  The patients were divided into six age groups: 0-3 months, >3-6 months, >6-12 166 months, >1-2 years, >2-5 years, and >5-14 years. The distribution of HMPV 167 prevalence between these age groups was significantly different ( 0.03), and 168 children >1-2 years had the highest prevalence (2.8%, 21/752) (. detected. It has been confirmed that a history of prematurity, particular age groups, 268 and the presence of chronic diseases increases the risk of severe LRTI among 269 HMPV3 and RSV3infected children. 51 Our study suggests that the clinical 270 manifestations of HMPV infection are complex and diverse; our data will be helpful in 271 the diagnosis of HMPV. 272 In this study, we analyzed the epidemiological characteristics and clinical 273 characteristics of HMPV in more than 5000 children with ARI in two tertiary hospitals 274 in Guangzhou, which is an international metropolis and the most important political, 275 economic and cultural center in southern China. Therefore, the results are not limited 276 to the two hospital cases, but also represent and reflect HMPV infection in children 277 with ARI in south China and play a positive role in the prevention and diagnosis of 278

Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 4 Objectives 3 State specific objectives, including any prespecified hypotheses 4-5

Study design 4
Present key elements of study design early in the paper 6 Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data collection 6 Participants 6 (a) Give the eligibility criteria, and the sources and methods of selection of participants 6 o n l y Participants 13* (a) Report numbers of individuals at each stage of study-eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed 9 (b) Give reasons for non-participation at each stage 10 (c) Consider use of a flow diagram Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders [9][10][11] (b) Indicate number of participants with missing data for each variable of interest 9 Outcome data 15* Report numbers of outcome events or summary measures 9-11 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were included 9-11 (b) Report category boundaries when continuous variables were categorized 9-10 (c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period Other analyses 17 Report other analyses done-eg analyses of subgroups and interactions, and sensitivity analyses

Discussion
Key results 18 Summarise key results with reference to study objectives 12-15 Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias

15-16
Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence

Other information
Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on which the present article is based 18 *Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.