Comparative efficacy of Chinese herbal injections for treating severe pneumonia: A protocol for systematic review and Bayesian network meta-analysis of randomized controlled trials.

BACKGROUND: Severe pneumonia (SP) has a high mortality and is responsible for significant healthcare cost. Chinese herbal injections (CHIs) have been widely used in China as a novel and promising treatment option for SP. Therefore, this study will assess and rank the effectiveness of CHIs to provide more sights for the selection of SP treatment.
METHOD: Seven databases will be searched, including PubMed, the Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Database, and the Chinese Scientific Journal Database (VIP) from their inception up to October, 2021. The literatures screening, data extraction and the quality assessment of included studies will be conducted independently by two reviewers. Then Bayesian network meta-analysis (NMA) will be performed by WinBUGS 14.0 and STATA 14.0 software. Surface under the cumulative ranking curve (SUCRA) probability values will be applied to rank the examined treatments. The risk of bias of each included study will be evaluated using the Revised Cochrane risk-of-bias tool for randomized trials (ROB 2). Publication bias will be reflected by a funnel plot.
RESULTS: The results of this NMA will be disseminated through a peer-reviewed journal publication.
CONCLUSION: Our study findings maybe reveal which CHI or CHIs will be better in the treatment of SP and provide more therapy strategies for clinical practitioners and patients. PROSPERO REGISTRATION NUMBER: CRD42021244587. STRENGTHS AND LIMITATIONS OF THIS STUDY: Bayesian network meta-analysis (NMA) can integrate direct evidence with indirect evidence of severe pneumonia treated by Chinese herbal injections to generate a clinically useful ranking of these regimens. This NMA will address Chinese herbal injections for SP and its findings may help to provide more sights for selection of SP treatment. Evidence drawn from an NMA is limited and should be interpreted with caution. We only included studies in Chinese and English languages, which may increase the publication bias.

Introduction

Pneumonia is a persistent and pervasive burden of disease. In the US, pneumonia continues to be associated with significant morbidity and mortality, accounting for more than 1 million hospital admissions per year [1]. In China, the prevalence of pneumonia in 2 weeks was 1.1‰ according to China Health Statistics Yearbook in 2013. Though not fatal, pneumonia can be severe. A fifth of the patients hospitalized for pneumonia need to be admitted to intensive care units (ICU)and a third of those require mechanical ventilation [2,3]. Severe pneumonia (SP) remains a major cause of mortality and has a high mortality up to 30%-50% [1,4,5]. In addition, due to combined antibiotics, long mechanical ventilation, and hospitalization time, SP is responsible for significant healthcare costs [6].

Currently, therapies for SP mainly depend on antibiotics, mechanical ventilation, and corticosteroid [7]. Antibiotic therapy is the backbone of the management of SP. It must be started on an empiric basis and often a combined therapy, since the causative agent is not identified in a considerable proportion of patients and the delay in the administration of adequate antimicrobials is clearly associated with higher mortality in patients [8]. However, adequate initial antibiotics may elevate the risk of antibiotic resistance and the mortality [9,10]. The severity of pneumonia is determined by interacting processes of immune resistance and tissue resilience such as anti-inflammatory [11]. Corticosteroids could inhibit the expression and action of many cytokines involved in the inflammatory response associated with pneumonia [12]. However, the use of corticosteroids in clinical practice with SP remains controversial as the presence of adverse effects [13,14]. Therefore, there is an urgent need for combined and adjunctive therapeutic options to improve outcomes.

In recent years, Chinese herbal injections (CHIs) as adjuvant treatments for SP are widely applied in China [15-17]. Even in the treatment of COVID-19, CHIs display more superiority [18,19]. Currently, several CHIs including Xuebijing injection (XBJ), Tanreqing injection (TRQ), Reduning injection (RDN), Xiyanping injection (XYP), Shenfu injection (SF), Shenmai injection (SM), and so on have been widely used in SP because of their remarkable effects. Their efficacy has been evidenced with systematic reviews [20-22]. CHIs combined with conventional Western medicine (WM) can greatly improve clinical symptoms and interrupt the vicious cycle of inflammation onset by blocking the uncontrolled release of endogenic inflammatory mediators like IL-6, IL-8, and TNF-α [16,18,23,24]. In addition, a meta-analysis showed that CHIs had less adverse drug reactions and adverse drug events (ADRs/ADEs), and the majority of the ADRs/ADEs had been resolved after drug withdrawal [20]. However, the head-to-head clinical trials comparing the efficacy and safety of the six CHIs are lacking up to now. It is difficult to identify the most effective one for patients with SP when the direct evidence is not enough. As a new method of evidence-based medical statistical methods, network meta-analysis (NMA) extends principles of conventional meta-analysis to the evaluation of multiple treatments in a single analysis by combining the direct and indirect evidence [25,26]. Another major value of NMA is that it can rank each CHI according to its effectiveness, which is important for clinicians to make the best treatment choices. Therefore, the purpose of this study is to assess the clinical efficacy and safety of different CHIs combined with WM and provide more evidence for rational selection of CHIs for SP using NMA.

Methods

Study registration

This protocol has been prepared under the guidance of the Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) Protocols guidelines [27], and it has been registered on PROSPERO platform (https://www.crd.york.ac.uk/prospero/) with an assigned registration number CRD42021244587.

Ethics and dissemination

For all eligible studies were approved by local institutional review boards and ethical committees, and participants included were required to complete written informed consents, this study requires no further ethical approval.

Eligibility criteria

The PICOS (participant, intervention, comparison, outcome and study design) principle has been applied in the study design.

Type of included studies

Randomized controlled trials (RCTs) regarding CHIs for the treatment of severe pneumonia will be included for analysis. There will be not limitations on language. Studies with non-RCT design, unobtainable data, duplicate publications and reviews will be excluded.

Participants

Adults (aged 18 years or older) with severe pneumonia, which should be confirmed according to the diagnostic criteria [28,29], patients with other critical diseases (tumor, pulmonary fibrosis, tuberculosis, and secondary respiratory failure of other systems) will be excluded. No limitations exist in gender, race, or nationality.

Intervention

All experimental groups must have been treated with CHI or CHI combined with conventional Western medicine. The control groups must have been treated with different types of CHI, or different types of CHI combined with conventional Western medicine, or only conventional Western medicine.

Outcomes

The primary outcome includes 28-day mortality and clinical effective rate. The 28-day mortality is death from any cause and is assessed 28 days after the start of treatment. The mortality at 28 to 30 days is considered equivalent to 28-day mortality. The clinical effective rate is calculated by the following formula: (number of cured patients + number of improved patients)/total number of patients × 100%. Patients are regarded as cured when their clinical symptoms disappear and the objective indicators return to normal. Patients are regarded as improved when their clinical symptoms alleviate and the objective indicators are improved. If the clinical symptoms and objective indicators are either unchanged or aggravated, the patients are considered to be an invalid effectiveness status. The secondary outcomes include length of stay in ICU, duration of mechanical ventilation, C-reactive protein (CRP), procalcitonin (PCT), leukocyte (WBC) and ADRs/ADEs.

Data sources

The study search will be mainly based on electronic databases, including PubMed, the Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Database, and the Chinese Scientific Journal Database (VIP) from their inception up to October, 2021. The medical subject headings (MeSH) and free text words will be used. Language restriction do not exist in this study. Search terms are severe pneumonia, Chinese herbal injection and others. Full details of the search strategy in PubMed are shown in Table 1 and other strategies for the remaining databases are shown in supporting information (S2).

Table 1

PubMed search strategy.

Number	Search terms
#1	Severe pneumonia[MeSH Terms]
#2	Severe pneumonia[Title/Abstract]
#3	#1 OR #2
#4	Chinese herbal injection[MeSH Terms]
#5	Chinese herbal injection[Title/Abstract]
#6	Traditional Chinese medicine injection[Title/Abstract]
#7	Traditional Chinese medicine[Title/Abstract]
#8	xuebijing[Title/Abstract]
#9	tanreqing[Title/Abstract]
#10	xiyanping[Title/Abstract]
#11	reduning[Title/Abstract]
#12	shenfu[Title/Abstract]
#13	shenmai[Title/Abstract]
#14	#4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13
#15	randomized controlled trial[Publication Type]
#16	controlled clinical trial[Publication Type]
#17	random*[All Fields]
#18	#15 OR #16 OR #17
#19	#3 AND #14 AND #18

Study selection and data extraction

Two researchers (LQ Niu and L Xiao) will independently screen the studies according to theeligibility criteria. After checking for duplicate studies, the researchers will eliminate reviews and irrelevant studies by reading the titles and abstracts. Then, the full text will be read to select studies that meet the eligibility criteria. The reasons for exclusion of trials in full-text review will be reported in the excluded studies list. Any disagreement will be resolved by discussion or a third researcher (XZ Liu). The references of included studies will be tracked to identify other relevant studies. A data spreadsheet will be developed with Microsoft Excel 2019 to collect relevant information. The information, including eligible studies characteristics (e.g., first author, year of publication, country where the study was conducted), participant characteristics (e.g., gender, age, sample), interventions (e.g., name of CHI, duration, frequency of drugs) and outcomes will be extracted and entered into the spreadsheet. The literature selection process is illustrated in Fig 1.

Fig 1

Flow diagram of study inclusion.

Risk of bias assessment

The risk of bias of each included study will be evaluated with Revised Cochrane risk-of-bias tool for randomized trials (ROB 2) [30]. The domains include the following: (1) randomisation process; (2) deviations from intended interventions; (3) missing outcome data; (4) measurement of the outcome; (5) selection of the reported result. There are some signalling questions required to answer “Yes (Y)”, “Probably Yes (PY)”, “Probably No (PN)”, “No (N)”, or “No Information (NI)” for each domain. After that, the risk of bias is categorized into 3 levels: high risk, some concerns, and low risk. These domain-level judgements will inform an overall risk of bias judgment for the outcome. The risk of bias assessment will be performed by two independent reviewers (LQ Niu and L Xiao), and disagreements will be resolved by consensus or a third opinion.

Assessment of the certainty of evidence

The overall certainty of evidence for each outcome collected will be assessed using the five GRADE considerations (bias of the trials, consistency of effect, imprecision, indirectness, and publication bias) by two reviewers. In addition, intransitivity and incoherence should be considered as well. Four steps will be utilized to assess the certainty of treatment effect estimates from NMA including direct and indirect treatment estimates for each comparison of the evidence network, rating the quality of each direct and indirect effect estimate, presenting the NMA estimate for each comparison of the evidence network and rating the quality of each NMA effect estimate [31]. The certainty of evidence will be rated ‘high’, ‘moderate’, ‘low’ and ‘very low’ according to the GRADE rating standards. Then, a minimally contextualised framework of GRADE approach will be used to draw conclusions from the NMA. The framework includes five steps involving choosing reference intervention and decision threshold, first classification of interventions based on comparison with reference, second classification based on comparisons between pairs of interventions, separating interventions into two main groups according to certainty of evidence, and checking consistency with pairwise comparisons and rankings [32]. Finally, we will communicate our findings using language that GRADE suggests to convey higher certainty (interventions are among the most effective) and language appropriate for lower certainty (interventions may be among the most effective) [33].

Data synthesis

Dealing with missing data

If required data is elusive or missing, the reviewer will contact the corresponding author of the original study by email. If data remains unobtainable, a systematic narrative review will be conducted through qualitative analysis. The potential impact of missing data will be assessed with a sensitivity analysis.

Measures of treatment effect

For binary outcomes, the combined results will be calculated as odds ratios (ORs) and 95% credible intervals (95% CIs). For continuous outcomes, mean differences (MD) or standardized mean differences (SMD) and their 95% CIs will be used. When the 95% CIs of the ORs do not include one and the 95% CIs of the MDs or SMDs do not contain zero, the differences between the groups will be considered statistically significant.

Assessment of heterogeneity

Clinical and methodological heterogeneity will be evaluated by closely checking the features of the participants, interventions, outcome measures, methods, and comparing fit of the fixed effect model and random effect model [34]. The Cochrane Q statistic and I statistic will be employed to assess statistical heterogeneity between different studies [35]. I2 value of 25%, 50%, and 75% is representative of low, moderate, and high heterogeneity, respectively. If the heterogeneity exists significantly (P<0.05, I2>50%), the sources of heterogeneity will be explored by subgroup analyses or meta regression. If we can’t identify the cause of heterogeneity, a narrative analysis will be conducted [34].

Assessment of similarity and consistency

An assessment of similarity and consistency will be performed to produce a credible and valid result. Since it is difficult to determine similarity using statistical analysis, the assessment will be based on clinical and methodological characteristics, including study designs, participant characteristics and interventions. If exist closed loops, we will use the loop-specific approach or the node-splitting approach to examine the consistency between direct and indirect evidences. If the inconsistency factor (IF) values and their 95% CIs are truncated at zero in the loop-specific approach or P>0.05 in the node-splitting approach, they indicate that the 2 sources are in agreement [36,37]. Otherwise, it exists inconsistency between direct and indirect evidences. If so, we will revisit the studies to assess again the plausibility of the similarity assumption. If we identify possible reasons for this inconsistency, we will account for it by performing subgroup analyses or meta regression. If we can’t identify the cause of inconsistency, we will refrain from performing an NMA [38].

Network meta-analysis

WinBUGS 14.0 (MRC Biostatistics Unit, Cambridge, UK) and STATA 14.0 (Stata Corporation, College Station, TX, USA) software will be employed to compute calculations and prepare graphs. The Markov chain Monte Carlo method will be performed by using the WinBUGS to carry out the NMA. In WinBUGS, the number of iterations will be set to 300 000, and the first 100 000 iterations will be used for the annealing algorithm to eliminate the impact of the initial value. The network graph will be constructed using STATA software to show a comparative relationship between different interventions. Surface under the cumulative ranking curve (SUCRA) probability values will be applied to rank the examined treatments, and the SUCRA value of 100% and 0% will be assigned to the best and worst treatments, respectively [39-41]. Furthermore, a comparison clustering analysis will be utilized to compare the effect of CHIs between different outcomes.

Assessment of publication bias

For each treatment comparison, the comparison-adjusted funnel plot will be used to assess the presence of small-study effects and publication bias if more than 10 studies are included. And its asymmetry will be evaluated with Egger’s test [34,42].

Sensitivity analysis

We will perform sensitivity analysis to assess the robustness of the pooled results on outcomes according to sample size, missing data, or risk of bias (excluding studies with “high risk” as determined using the Revised Cochrane risk-of-bias tool for randomized trials) [30]. We will remove each study from the meta-analysis one at a time and recalculate the summary effect. A study will be considered influential if its removal changes the magnitude of the pooled effect by >10% [43].

Discussion

Severe pneumonia, an important public health problem, is the leading infectious cause of death worldwide. For severe pneumonia, adequate initial antibiotics and long use in patients have increase the risk of antibiotic resistance. A number of studies have shown that the Chinese herbal injections have effects of decreasing the risk of antibiotic resistance by shortening the length of stay in ICU, duration of mechanical ventilation and so on [15-17,44-46]. Two systematic reviews have been conducted to assess the effectiveness of Chinese herbal injections for pneumonia [20,47]. However, as the worldwide spread of COVID-19, SP is given to more attention as its high mortality. Compared with community-acquired pneumonia (CAP), SP is more serious and requires to be treated in ICU. One of the studies only included elderly patients with pneumonia [47]. SP is associated with substantial morbidity and mortality, particularly in older adults or those with comorbid conditions. Nevertheless, SP can also occur in previously healthy young subjects originating distressing situations for its poor outcome [48]. Because of different disease severity and different ages of included participants, the CHIs being analyzed will be different compared with the other two reviews. Our study will include three extra injections: Xuebijing injection, Shenfu injection and Shenmai injection which are widely used in either CAP or SP and proved to be effective by lots of RCTs [15-17,49]. In addition, for SP, patients are mostly in the stage of immunosuppression. According to the theory of traditional Chinese medicine, those patients are diagnosed with deficiency syndrome. Therefore, Shenfu injection and Shenmai injection which were not included by the two previous reviews will be involved for analysis in our study. What’s more, the risk of bias will be evaluated with the ROB 2 and the overall quality of evidence for each outcome collected will be assessed using the GRADE. Hence, in order to generate reliable evidence based on a larger scale as compared with limited types of single studies, we will conduct a Bayesian NMA to combined direct and indirect comparisons of CHIs treating SP and rank the effectiveness and safety of the different CHIs. We expect to provide credible evidence and support of CHIs utility reasonably for clinical practitioners and patients in SP decision-making.

PRISMA-P 2015 checklist.

(DOC)

Click here for additional data file.

Search strategy.

(DOCX)

Click here for additional data file.

The draft of minimal dataset.

(DOCX)

Click here for additional data file.

28 Sep 2021

Comparative efficacy of Chinese herbal injections for treating severe pneumonia: A protocol for systematic review and Bayesian network meta-analysis of randomized controlled trials

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This work is supported by the support program of National Program on Key Basic Research Project (973 Program, No.2009CB522702) and First Teaching Hospital of Tianjin University of Traditional Chinese Medicine (No.201928). Xinqiao Liu received  award of the former and Lu Xiao received the latter.

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4. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

- https://journals.lww.com/co-pulmonarymedicine/Abstract/2017/05000/Pathogenesis_of_severe_pneumonia__advances_and.2.aspx

- https://www.tandfonline.com/doi/abs/10.1080/14787210.2018.1512403?journalCode=ierz20

- https://bmjopen.bmj.com/content/11/2/e039122.full

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Partly

Reviewer #2: Partly

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Partly

Reviewer #2: Partly

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: No

Reviewer #2: No

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Reviewer #2: No

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Reviewer #2: No

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Reviewer #1: 1. The author restricted the search date up until April 2021, which’s been more than half year until now. Consider update this.

2. The authors listed six CHIs and stated that “the head-to-head clinical trials comparing the efficacy of the six CHIs are lacking up to now.” If these six CHIs are the main ones of current use, it’s better to integrate these terms into the Search Strategy (i.e. specific CHIs as free text words)

3. Cochrane risk of bias tool is tailored for risk of bias assessment. Suggest use risk of bias throughout the manuscript instead of methodological quality, as these two could be different in some aspects.

4. In the eligibility criteria, the primary outcome “clinical effective rate” is unclear. Would be good to see the exact definition. By the way, if SP is a leading infectious cause of death as the author said, why not to collect the mortality? Also, why not to collect the adverse event? How did the authors decide the importance of the outcomes for patients?

5. Not sure how will the authors use GRADE. Under “Evaluation of study quality and risk of bias”, it would be good to see a detailed description of the overall process. Also, NMA has more considerations than for conventional MA. From what the authors referred in citation 31, there is nothing about GRADE for NMA (the first paper was published in 2014 https://www.bmj.com/content/349/bmj.g5630). So it’s really unclear how will this work.

6. Under Data synthesis, “If data remains unobtainable, the reviewer will exclude the study”. This may not appropriate since this is not in your eligible criteria and will of course lead to more reporting bias. You may consider include and report them descriptively and explain why they are not included in the data synthesis.

7. Under “Measures of treatment effect.”: “All outcomes will be presented with their 95% credible intervals (95% CIs) and as well.” Is there anything missing?

8. Under “Network meta-analysis” “After that, Publication bias will be reflected by a funnel plot” better to explain when is it appropriate to conduct a funnel plot, as the number of studies is not always enough for this analysis.

9. For the limitations, why include only RCT is a limitation when qualified RCTs are among the highest level of evidence. Include Chinese and English may increase the “risk of bias”, do you mean “publication bias”?

10. The funders had and will not have a role in study design… Do you mean the funder had a role in the study design? Or it’s a mistake?

11. In the background, “The largest challenge in the next few years will be to diminish this high and unacceptable mortality rate.” Suggest delete as it didn’t add more useful information.

12. In the background, the authors mentioned the effectiveness and benefits of CHIs, what about the potential AEs of CHIs? Suggest to explain.

13. In the discussion, “The application of Chinese herbal injections could be promoted because of the risk of antibiotic resistance” is unclear. Do you mean because of the risk of antibiotic resistance from antibiotics? Otherwise, it reads like CHI has the risk.

14. What does “experimentally based evidence” mean in the Discussion?

15. The authors stated “…this study will be the first Bayesian NMA of CHIs for the treatment of SP”, is there any existing frequentist NMA? Better to explain this point. If yes, may need to state why it’s necessary to do a new one.

16. Under the assessment of homogeneity, “I2≤ P≥0.1, 50%), If with homogeneity ( a fixed effect model will be adopted; If with obvious heterogeneity (P<0.01, I2 >50%), a random effect model will be applied.” is inappropriate. The choice between a fixed-effect and a random-effects meta-analysis should never be made on the basis of a statistical test for heterogeneity. Suggest refer to the Cochrane handbook. https://handbook-5-1.cochrane.org/chapter_9/9_5_4_incorporating_heterogeneity_into_random_effects_models.htm

17. Under “Assessment of similarity and consistency.”. What’s the method used to generate inconsistency factor? I didn’t find relevant information from citation 33. In addition, there is no consideration of the incoherence of each NMA and corresponding option to deal with the possible incoherence.

18. There are several language problems, including grammar issue and the accuracy of the wording. For examples, 1) the conclusion in the abstract, “Our study findings will reveal which CHIs is the best” where CHIs should be CHI as the author assume there is only one best (By the way, how could we know there will not be two equal effective CHIs?); 2) “…can integrate direct evidence with indirect evidence from currently applied Chinese herbal injections into severe pneumonia (SP) to generate a clinically useful ranking …”, should from be “of”? What means “injections into SP (a disease)”? 3) mortality has already covered the meaning of “rate” so mortality itself is appropriate instead of “mortality rate” 4) mixed tense in one sentence such as “A fifth of the patients hospitalized for pneumonia need to be admitted to intensive care units (ICU), and a third of those require mechanical ventilation, while 21% of the patients from the community needed admission to the ICU and 26% of them needed mechanical ventilation. 5) “…the delay in the administration of adequate antimicrobials is clearly associated with mortality in patients…” do you mean “with higher mortality…”? 6) “criterias” under “Study selection and data extraction”. There are many others. This manuscript would benefit from further language editing.

Reviewer #2: I would like to thank the authors for the opportunity to review their manuscript “Comparative efficacy of Chinese herbal injections for treating severe pneumonia: A

protocol for systematic review and Bayesian network meta-analysis of randomized

controlled trials” This Network meta-analysis sought out conduct a network meta-analysis approach in order to conclude the optimal mode of Chinese herbal injection for improving well-being among patients with severe pneumonia. This study is similar to those presented by previous studies, and therefore lack novelty. Authors should substantial revision with this article and recommend addressing the following concerns:

1. This study lacks innovation. This manuscript is highly similarly to other systematic review, including disease types, analysis methods and research objects. A problem not fully addressed in discussion is mainly the similarity and the consistency evidence compared to the previous publications. I recommend that you can cite two studies for your information(1.《Huang Xingyue,Duan Xiaojiao,Zhu Yingli et al. Comparative efficacy of Chinese herbal injections for the treatment of community-acquired pneumonia: A Bayesian network meta-analysis of randomized controlled trials.[J] .Phytomedicine, 2019, 63: 153009.》2.《Yuan Yang,Zheng Quan,Si Zhilin et al. Efficacy of Chinese Herbal Injections for Elderly Patients With pneumonia-A Bayesian Network Meta-analysis of Randomized Control Trials.[J] .Front Pharmacol, 2021, 12: 610745.》)

2. The ethical statement for meta-analysis should be added.

3. A series of statement are similar to existing findings. I suggest you add more content to your paper.

4. For full transparency and reproducibility, search strategies should include other strategies for the remaining database. Furthermore, the authors list the search strategy regarding text-term for Pubmed is too simple and incomprehensive, they mentioned they restricted their included studies in RCT while the search strategy was presented without study design.

5. Pubmed is not a database, but a search engine, please correct the association between pubmed and Medline.

6. The English writing needs to be improved. This manuscript is so hard to read due to some description is too simple.

7. Some statement is too absolute that should be interpreted cautiously, such as lines39 and lines197.

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Reviewer #1: No

Reviewer #2: Yes: Jinghong Liang

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22 Oct 2021

We would like to express our sincere thanks to the reviewers for the constructive and positive comments.

Replies to Reviewer #1

1. The author restricted the search date up until April 2021, which’s been more than half year until now. Consider update this.

Answer: The search data has been updated to October, 2021 (line 24 and line 135) in the revised version.

2. The authors listed six CHIs and stated that “the head-to-head clinical trials comparing the efficacy of the six CHIs are lacking up to now.” If these six CHIs are the main ones of current use, it’s better to integrate these terms into the Search Strategy (i.e. specific CHIs as free text words)

Answer: We have added these terms into the Search Strategy and the whole strategy in PubMed are shown in Table 1. In addition, we have uploaded other strategies in remaining databases as a separate supporting information file.

3. Cochrane risk of bias tool is tailored for risk of bias assessment. Suggest use risk of bias throughout the manuscript instead of methodological quality, as these two could be different in some aspects.

Answer: We have use risk of bias instead of methodological quality in the revised version.

4. In the eligibility criteria, the primary outcome “clinical effective rate” is unclear. Would be good to see the exact definition. By the way, if SP is a leading infectious cause of death as the author said, why not to collect the mortality? Also, why not to collect the adverse event? How did the authors decide the importance of the outcomes for patients?

Answer: The exact definition of “clinical effective rate” has been added in Outcomes. We did only collect adverse drug reactions and adverse drug events will be included. The relative statements have been added in the revised version. As for outcomes, we decided the importance of the outcomes for patients by considering the outcomes of original studies, characteristics of the disease, clinical experiences and therapeutic advantage of the intervention. Actually, we considered 28 days mortality as the primary outcome at first. However, CHIs had more advantages in improving symptoms and signs as an adjuvant therapy. In addition, we found that there were few clinical studies reporting mortality by searching databases. Almost all studies reported the clinical effective rate, and we thought this outcome would be an alternative indicator to lower the death rate comparing with the mortality. As a result, we decided to collect clinical effective rate as the primary outcome.

5. Not sure how will the authors use GRADE. Under “Evaluation of study quality and risk of bias”, it would be good to see a detailed description of the overall process. Also, NMA has more considerations than for conventional MA. From what the authors referred in citation 31, there is nothing about GRADE for NMA (the first paper was published in 2014 https://www.bmj.com/content/349/bmj.g5630). So it’s really unclear how will this work.

Answer: The statement of GRADE approach for NMA has been added in “Evaluation of study quality and risk of bias” and the correct reference has been cited in 31.

6. Under Data synthesis, “If data remains unobtainable, the reviewer will exclude the study”. This may not appropriate since this is not in your eligible criteria and will of course lead to more reporting bias. You may consider include and report them descriptively and explain why they are not included in the data synthesis.

Answer: The correct statement has been made in the Data synthesis.

7. Under “Measures of treatment effect.”: “All outcomes will be presented with their 95% credible intervals (95% CIs) and as well.” Is there anything missing?

Answer: The correction has been made in the revised version.

8. Under “Network meta-analysis” “After that, Publication bias will be reflected by a funnel plot” better to explain when is it appropriate to conduct a funnel plot, as the number of studies is not always enough for this analysis.

Answer: Correction has been made under “Assessment of publication bias” in the revised version.

9. For the limitations, why include only RCT is a limitation when qualified RCTs are among the highest level of evidence. Include Chinese and English may increase the “risk of bias”, do you mean “publication bias”?

Answer: Yes, the “risk of bias” means “publication bias” and correction has been made in the revised version. It’s our mistake to say only RCT is a limitation and we have deleted this sentence from Strengths and limitations of this study.

10. The funders had and will not have a role in study design… Do you mean the funder had a role in the study design? Or it’s a mistake?

Answer: It seems that the paper requires to write that and I just copy it. When I submitted my manuscript, the paper required to include this sentence at the end of funding statement if the funders didn’t have a role in study design.

11. In the background, “The largest challenge in the next few years will be to diminish this high and unacceptable mortality rate.” Suggest delete as it didn’t add more useful information.

Answer: This sentence has been deleted in the revised version.

12. In the background, the authors mentioned the effectiveness and benefits of CHIs, what about the potential AEs of CHIs? Suggest to explain.

Answer: The statements of AEs of CHIs has been added in introduction in the revised version.

13. In the discussion, “The application of Chinese herbal injections could be promoted because of the risk of antibiotic resistance” is unclear. Do you mean because of the risk of antibiotic resistance from antibiotics? Otherwise, it reads like CHI has the risk.

Answer: Yes, it means because of the risk of antibiotic resistance from antibiotics. This sentence has been revised in the discussion.

14. What does “experimentally based evidence” mean in the Discussion?

Answer: It means “to generate reliable evidence based on a larger scale” and it has been revised in the revised version.

15. The authors stated “…this study will be the first Bayesian NMA of CHIs for the treatment of SP”, is there any existing frequentist NMA? Better to explain this point. If yes, may need to state why it’s necessary to do a new one.

Answer: There is not any existing frequentist NMA of CHIs for the treatment of SP by searching electronic databases. Maybe the statement of the first Bayesian NMA is too absolute and the meaning is unclear. So it has been corrected in the revised version.

16. Under the assessment of homogeneity, “I2≤ P≥0.1, 50%), If with homogeneity ( a fixed effect model will be adopted; If with obvious heterogeneity (P<0.01, I2 >50%), a random effect model will be applied.” is inappropriate. The choice between a fixed-effect and a random-effects meta-analysis should never be made on the basis of a statistical test for heterogeneity. Suggest refer to the Cochrane handbook. https://handbook-5-1.cochrane.org/chapter_9/9_5_4_incorporating_heterogeneity_into_random_effects_models.htm

Answer: The heterogeneity consists of clinical heterogeneity, methodological heterogeneity and statistical heterogeneity. The choice between a fixed-effect and a random-effects meta-analysis would not only be made on the basis of a statistical test for heterogeneity. Corrections have been made in the revised version.

17. Under “Assessment of similarity and consistency.”. What’s the method used to generate inconsistency factor? I didn’t find relevant information from citation 33. In addition, there is no consideration of the incoherence of each NMA and corresponding option to deal with the possible incoherence.

Answer: The loop-specific approach or node-splitting approach will be utilized to examine the loop inconsistency and the correct citations have been added in citation 33 and 34. The statement of incoherence has been added in the revised version.

18. There are several language problems, including grammar issue and the accuracy of the wording. For examples, 1) the conclusion in the abstract, “Our study findings will reveal which CHIs is the best” where CHIs should be CHI as the author assume there is only one best (By the way, how could we know there will not be two equal effective CHIs?); 2) “…can integrate direct evidence with indirect evidence from currently applied Chinese herbal injections into severe pneumonia (SP) to generate a clinically useful ranking …”, should from be “of”? What means “injections into SP (a disease)”? 3) mortality has already covered the meaning of “rate” so mortality itself is appropriate instead of “mortality rate” 4) mixed tense in one sentence such as “A fifth of the patients hospitalized for pneumonia need to be admitted to intensive care units (ICU), and a third of those require mechanical ventilation, while 21% of the patients from the community needed admission to the ICU and 26% of them needed mechanical ventilation. 5) “…the delay in the administration of adequate antimicrobials is clearly associated with mortality in patients…” do you mean “with higher mortality…”? 6) “criterias” under “Study selection and data extraction”. There are many others. This manuscript would benefit from further language editing.

Answer: Corrections have been made in the revised version and the English writing has been improved carefully.

Replies to Reviewer #2

1. This study lacks innovation. This manuscript is highly similarly to other systematic review, including disease types, analysis methods and research objects. A problem not fully addressed in discussion is mainly the similarity and the consistency evidence compared to the previous publications. I recommend that you can cite two studies for your information(1.《Huang Xingyue,Duan Xiaojiao,Zhu Yingli et al. Comparative efficacy of Chinese herbal injections for the treatment of community-acquired pneumonia: A Bayesian network meta-analysis of randomized controlled trials.[J] .Phytomedicine, 2019, 63: 153009.》2.《Yuan Yang,Zheng Quan,Si Zhilin et al. Efficacy of Chinese Herbal Injections for Elderly Patients With pneumonia-A Bayesian Network Meta-analysis of Randomized Control Trials.[J] .Front Pharmacol, 2021, 12: 610745.》)

Answer: Two systematic reviews have been conducted to assess the effectiveness of Chinese herbal injections for pneumonia. But participants included by one of the studies were mainly suffered from community-acquired pneumonia (CAP) whom were not needed to be hospitalized in ICU. As the worldwide spread of COVID-19, SP is given to more attention as its high mortality. Compared with CAP, SP is more serious and requires to be treated in ICU. Another study only included elderly patients with pneumonia. SP is associated with substantial morbidity and mortality, particularly in older adults or those with comorbid conditions. Nevertheless, SP can also occur in previously healthy young subjects originating distressing situations for its poor outcome. As for different disease severity and different ages of included participants, the CHIs being analyzed were different compared with the other two reviews. Our study will include three extra injections: Xuebijing injection, Shenfu injection and Shenmai injection which were widely used in either CAP or SP and proved to be effective by lots of high quality RCTs. In addition, for SP, patients were mostly in the stage of immunosuppression. According to the theory of traditional Chinese medicine, those patients were diagnosed with deficiency syndrome. Therefore, Shenfu injection and Shenmai injection which were not included by the two previous reviews will be included for analysis in our study. What’s more, the risk of bias will be evaluated with the Revised Cochrane risk-of-bias tool for randomized trials (ROB 2) and the overall quality of evidence for each outcome collected will be assessed using the GRADE which were not assessed in previous reviews. The statement has been added in discussion.

2. The ethical statement for meta-analysis should be added.

Answer: The ethical statement had been written in Ethics and dissemination under Methods.

3. A series of statement are similar to existing findings. I suggest you add more content to your paper.

Answer: We have added more contents like ADRs/ADEs of CHIs in introduction, the definition of clinical effective rate in outcomes, the GRADE approach in NMA, the distinction between our study and previous studies in the revised version.

4. For full transparency and reproducibility, search strategies should include other strategies for the remaining database. Furthermore, the authors list the search strategy regarding text-term for Pubmed is too simple and incomprehensive, they mentioned they restricted their included studies in RCT while the search strategy was presented without study design.

Answer: The search strategy of PubMed has been added completely in Table 1 and other strategies for the remaining database has been uploaded as a supporting information file.

5. Pubmed is not a database, but a search engine, please correct the association between pubmed and Medline.

Answer: We are very grateful for your teaching and have been clear about the association between PubMed and Medline.

6. The English writing needs to be improved. This manuscript is so hard to read due to some description is too simple.

Answer: The English writing has been improved carefully.

7. Some statement is too absolute that should be interpreted cautiously, such as lines39 and lines197.

Answer: Corrections have been made in the revised version.

Submitted filename: response to reviewers.docx

Click here for additional data file.

17 Dec 2021

20 Dec 2021

We would like to express our sincere thanks to the reviewers for the constructive and positive comments.

Replies to Reviewer 1

1. lines 227-228 “…(CAP) whom were not all needed to be…”

Answer: The correction has been made in the revised version and the English writing has been improved carefully.

2. Line 48 Authors focused on CHIs for severe pneumonia. CHIs are mostly used in China, I would suggest add background information about prevalence of pneumonia/ severe pneumonia in China or at least globally rather than just data in US.

Answer: The prevalence of pneumonia/severe pneumonia in China is deficiency. The only data was about the prevalence of pneumonia in 2 weeks recorded in China Health Statistics Yearbook in 2013 and we have added this content in introduction.

3. Line 113 for the primary outcomes. I knew why authors choose clinical effective rate rather than mortality. But I would still say collecting data for mortality is important if this is an important outcome. If no study reported this, this should be clarified and discussed.

Answer: The 28-day mortality has been added in the revised version as one of the primary outcomes. If we find that there are not enough original studies reporting 28-day mortality when we conduct this NMA, we will discuss and clarify this problem.

4. Line 134 under “Study selection and data extraction”:…screen the studies according to the inclusion criteria. The “inclusion criteria” is not accurate as you will refer to both inclusion and exclusion criteria. Consider “eligible criteria”. Same in line 136

Answer: The correction has been made in the revised version.

5. Line 146 “Evaluation of study quality and risk of bias” What is study quality mean? If you use aOB to assess risk of bias then it’s risk of bias. There are still mixing use of study quality and risk of bias in the method. If you used GRADE to assess certainty of evidence (more used in latest GRADE series than “quality of evidence”), then it’s certainty of the evidence. Please refer to https://www.bmj.com/content/371/bmj.m3900.abstract. Also, authors may consider how to draw the conclusion according to the GRADE approach (article in same link).

Answer: The correction has been made in the revised version and the details about how to draw the conclusion according to the GRADE approach have been added in the revised version.

6. Line 175, authors considered statistically significant. Will there any consideration on clinical significant based on minimal important difference (MID)? Better to clarify.

Answer: Minimal important difference (MID) is mainly used to explain the results of scores or scales. However, our primary outcomes are 28-day mortality and clinical effective rate, which do not involve scores or scales. Moreover, we don’t find recognized MID of our outcomes by searching databases. Hence, we don’t consider the clinical significant based on minimal important difference.

7. Lines 221-223 Need citations to support the sentence “a large number of studies…”

Answer: The relevant citations have been added in the revised version.

8. Lines 224-225 The results are yet to come, how could we know CHIs “could be widely used because of its efficacy and safety”? Even when you have data that shows very good benefit in your final NMA, you will still need to consider the certainty of the evidence to give the conclusion cautiously.

Answer: This sentence has been deleted in discussion.

9. Lines 226-228: according to authors’ description, SP is covered by CAP, which could also be seen in the references 28-29. It seems to me that the NMA in 2019 by Huang X et al has already included all the CAP populations and you are selecting a group of patients from the whole bunch. I did not see a high value of this point now.

Answer: Actually, we aim to express that SP is more serious than CAP and therefore the CHIs utilized between them are different. Maybe it is repetitive with the following contents. Hence, we decide to delete these sentences after considering your advice.

10. Lines 236-237 “…proved to be effective by lots of high quality RCTs[15-17, 44]”. What does this “high quality” mean? Have you assessed them already? I would not say any quality thing without any assessment.

Answer: We have deleted “high quality” in this sentence.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

5 Jan 2022

Comparative efficacy of Chinese herbal injections for treating severe pneumonia: A protocol for systematic review and Bayesian network meta-analysis of randomized controlled trials

PONE-D-21-21402R2

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Reviewer #1: Yes

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The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: Yes: Xiaoqin Wang

13 May 2022

PONE-D-21-21402R2

Comparative efficacy of Chinese herbal injections for treating severe pneumonia: A protocol for systematic review and Bayesian network meta-analysis of randomized controlled trials

Dear Dr. Liu:

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