Author s response to reviews

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1 Author s response to reviews Title: Comparison of the Prevalence of Respiratory Viruses in Patients with Acute Respiratory Infections at Different Hospital Settings in North China, Authors: Jianwei Wang (wangjw28@163.com) Jianxing Yu (jianxing_yu1981@sina.com) Zhengde Xie (xiezhengde@bch.com.cn) Tiegang Zhang (ztg628@126.com) Yanqin Lu (yanqinlu@163.com) Hongwei Fan (homewayfun@gmail.com) Donghong Yang (shunydh@126.com) Thomas Bénet (thomas.benet@chu-lyon.fr) Philippe Vanhems (philippe.vanhems@chu-lyon.fr) Kunling Shen (kunling_shen@hotmail.com) Fang Huang (hhffxdd@126.com) Jinxiang Han (jxhan@sdu.edu.cn) Taisheng Li (litsh@263.net) Zhancheng Gao (gaozhancheng5446@163.com) Lili Ren (renliliipb@163.com) Version: 1 Date: 19 Sep 2017 Author s response to reviews: Re: [INFD-D ] Comparison of the Prevalence of Respiratory Viruses in Patients with Acute Respiratory Infections at Different Hospital Settings in North China, Dear Editors,

2 Thank you for commenting on our manuscript Comparison of the Prevalence of Respiratory Viruses in Patients with Acute Respiratory Infections at Different Hospital Settings in North China, Based on the reviewers comments and requests, we have made extensive modification on the original manuscript. All the questions were answered below. Yours sincerely, Jianwei Wang Responses to Reviewers' Comments: Motoi Suzuki, MD, PhD (Reviewer 1) The study is properly conducted and the paper is well written. I have some minor comments. Q1. line 193 "To reduce type I error, 99% CI for aors were used." Please clarify the reasons why multiple comparisons are considered in this context. Response: Thank you for the comments.to assess the contribution of a specific virus without regard to the presence of other pathogens, we included all respiratory viruses and their two-way interactions in the model by adding cross-product terms for pairs of viruses (n=28). By doing this, type I errors and overfitting will be significant problems in our study. To reduce the errors and identify factors that were most likely associated with hospitalization due to ARIs, we used 99% CI for aors instead. We have made this clear in the manuscript (page 11, line ). Q2. line 304 "If our hypothesis is true, the immunization of young children with seasonal flu vaccine would certainly offer additional benefits on the overall burden of ARIs in pediatric population." What is the authors' hypothesis? The benefit of seasonal flu vaccination for children has been established. Please describe the logic behind this statement. The influenza vaccination policy in China should be described. Response: Based on the observation that RSV infection and IFVs infection had interactive relationships on hospitalization in young children in our study, we hypothesis that co-infection of RSV with IFVs might cause more severe ARIs among young children. If this hypothesis is true, hospitalizations caused by RSV and IFVs co-infection would far outnumber the hospitalizations caused by either virus. So, providing seasonal flu vaccine to young children would offer additional benefits by preventing not only influenza virus-associated hospitalizations, by also the excessive hospitalizations caused by RSV and IFVs co-infection. We have made this clear in the

3 manuscript (page 11, line ), as well as the backgroud information of influenza vaccination policy in China (page 11, line ). Thank you. Q3. line 312 "As the age of children increased, infection and co-infection of RVs became less frequent and were less likely to be associated with hospitalization. This observation supports the utility of vaccines, when available, to control and prevent the infection of RVs." As above, I don't understand this logic. Please clarify. Response: Thank you for the comments. We believe that the observation, the age of children increased, infection and co-infection of RVs became less frequent and were less likely to be associated with hospitalization, is explainable. As the children s age grows, they have experienced frequent respiratory viruses infections. The frequent respiratory viruses infection produced immunity that protected them from further infection or severe ARIs, namely the decreased frequency of RVs infection and hospitatlization among older age group. Based on these evidence, we concluded that natural acquried respiratory viruses infection, as well as active vaccination, could prevent future infection or severe infection of RVs. We have made this clear in the manuscript (page 17, line ). Q4. Viral infection was more common in inpatients than outpatients among younger age group but not older age group. Please discuss about the potential mechanisms. Response: Thank you. We added discussion on this matter in our manuscript In our study, viral infection was more common in inpatients than outpatients among younger age group but not older age group. This observation suggests that RVs infection is common among young children and is more likely to be associated with severe ARIs when compared with other age groups, while in adults and elderly people, though RVs infection is not uncommon, RVs are less likely to cause severe ARIs in this age group. (page 17, line ) Q5. I would like to see a table showing the number (%) of positive cases for each virus for total patients and by three age groups. Response: Accepted. Table.3 has been added in our manuscript to show the number (%) of positeve cases for total patients and by three age groups (page 29). Thank you. Q6. Figure 2 does not add any information to this paper. It can be moved to supplementary material. Response: Accepted. We moved Figure 2 to supplementary material. Thank you. Florette Treurnicht (Reviewer 2) The authors describe the contribution of respiratory viruses as single or multiple infections to hospitalization of both adult and pediatric patients with acute respiratory illness (ARI) when

4 compared to ARI patients attended to at outpatients and emergency departments in North China in this well written manuscript. Other similar studies conducted in China and relevant to the study described here has been referenced appropriately. Tables and figures to present study results are well presented highlighting the study outcomes. Analysing the virological data in grouped manner (single versus multiple/ co-infections) allowed them to identify the factors contributing to hospitalization versus outpatient care and for adult versus pediatric patients. This study contributes to our understanding of the role of viral infections in respiratory illness and burden of hospitalization for pneumonia. Here the contribution of adenovirus infections to hospitalization with ARI in adults are also highlighted although the causal role of adenoviruses to severe illness may be questioned by others. In results the authors talk about outpatient/ed visits and not cases or patients- this must be address where relevant throughout manuscript and will be higlighted in review comments below. Response: We acknowledge the comments made by the reviewer. The word "visits" was misused by us in the manuscript. We have changed outpatient/ed visits to outpatient/ed patients throughout the revised manuscript. Thank you. Abstract Q1. pg 5, line 73: change "was" to "is" Response: Accepted. We have changed the word "was" to "is" (page 5, line 73). Thank you. Q2. line 87: write out "aor" and "CI" when used first time Response: Accepted. We have written out the full name of "aor" and "CI" (page 5, line 87). Thank you. Introduction Q3. pg 7, line 1, complete reference 1 in reference list Response: Thank you. We have corrected the format of reference 1 according to the style of the journal (page 22, line ). Q4. line 1:?shouldnt it be 18.8 billion Response: Yes. We have corrected the word (page 7, line 101). Thank you. Q5. line :? delete sentence starting "Among the aetiological agents..." as next sentence says the same Response: Accepted. We have deleted the sentence. Thank you.

5 Q6. line : change sentence to read "In a substantial portion of patients ARIs are..." Response: Accepted. We have changed the sentence to read "In a substantial proportion of patients with ARIs, respiratory viruses (RVs) are commonly found" (page 7, line ). Thank you. Methods Q7. pg 8, line 133: write out "WBC" 1st time Response: Accepted. The words have been written out in full (page 8, line ). Thank you. Q8. pg 11: check and delete 1 pg 11 as its duplicated Response: Sorry, we didn t quite understand what you mean by duplicated 1. What should we delete? Could you please help by give us the specific line number? Q9. line 195: complete reference quoted in reference list- add website address Response: Accepted. We have corrected the format of reference 22 according to the style of the journal (page 23, line ). Thank you. Results Q10. Change outpatient/ed visits to outpatient/ed patients or cases as appropriate throughout the results. Response: Accepted. We have changed outpatient/ed visits to outpatient/ed patients throughout the revised manuscript. Thank you. Q11. pg 12, line : Move sentences starting with "The prevalence of specific RVs...frequent in outpatient/ed patients (Figure 1 & Additional file 1) " to Line 221 after "p<0.001) (Table 2)." Response: Accepted. We moved the sentences to the corresponding position accordingly (page 12, line ). Thank you. Q12. pg 13, line 231: change to read "...(7.6%) cases, of which 534 (70.6%) were dualinfection..." Response: Accepted. We changed the word "in" to "of" (page 13, line 233). Thank you. Q13. line 233: replace "kind of" with "different"

6 Response: Accepted. Thank you. (page 13, line 235) Discussion Q14. pg 15, line 275: change to read "...we simultaneously screened for the presence..." Response: Accepted. Thank you. (page 15, line 277) Q15. pg 16, line 304: change to read "...overlapping for winter months..." Response: Accepted. We changed the word "at" to "for" (page 16, line 307). Thank you. Q16. line 305: write "influenza" not "flu" Response: Accepted (page 16, line 310). Thank you. Q17. line 307: delete "that" Response: Accepted. Thank you. Q18. pg 18, line 342: write out "COPD" Response: Accepted (page 18, line 359). Thank you. Q19. line 354: suggest to change to read: "pathogenesis and provide guidance for good clinical management..." Response: Accepted (page 19, line 371). Thank you. References Q20. line 396: incomplete reference-?add website address Response: Thank you. We have added website address according to the style of the journal (page 22, line ). Q21. line 466: incomplete reference- add website address Response: Thank you. We have added website address according to the style of the journal (page 23, line ).

RSV Surveillance in the U.S.

RSV Surveillance in the U.S. Susan I. Gerber, MD Respiratory Virus Program Division of Viral Diseases National Center for Immunization and Respiratory Diseases Centers for Disease Control and Prevention