key: cord-0827651-9h8qohko
authors: Zhao, Guo-zhen; Li, Bo; Wang, Ya-fan; Guo, Shi-qi; Du, Yuan; Ma, Qiu-xiao; Guo, Yu-hong; Liu, Qing-quan
title: Reduning Injection versus Neuraminidase Inhibitors in the Treatment of Influenza: A Systematic Review and Meta-Analysis
date: 2022-05-04
journal: Chin J Integr Med
DOI: 10.1007/s11655-022-3524-9
sha: cae44ca339472c0293cb9ffd2da675992c917450
doc_id: 827651
cord_uid: 9h8qohko

OBJECTIVE: To perform a systematic review to assess the effectiveness and safety of Reduning Injection versus neuraminidase inhibitors in treatment of influenza. METHODS: The MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Chinese Bio-medical Literature and Retrieval System (Sinomed), China National Knowledge Infrastructure Database (CNKI), China Science and Technology Journal Database (VIP), Wanfang Data Knowledge Service Platform and ClinicalTrails.gov were systematically searched from inception dates to May 2021 for randomized controlled trials (RCTs) exploring Reduning Injection alone or in combination with neuraminidase inhibitors in patients with influenza. Statistical analysis was performed using RevMan 5.4 and Stata 15.1. The qualities of the involved studies were assessed by the risk of bias according to the Cochrane handbook. The evidence quality of each outcome was evaluated by GRADEpro GDT. RESULTS: Twelve trials with 1,460 patients were included. The included studies had a certain unclear or high risk of bias. Reduning Injection appeared to be more effective in shortening the fever clearance time (MD: −16.20 h, 95% CI: −19.40 to −12.99, 7 trials, 814 patients, I(2)=94%, very low certainty), fever alleviation time (MD: −4.09 h, 95% CI: −4.22 to −3.96, 3 trials, 366 patients, I(2)=0%, low certainty), cough alleviation time (MD: −21.34 h, 95% CI: −41.56 to −1.11, 2 trials, 228 patients, I(2)=89%, very low certainty), fatigue alleviation time (MD: −31.83 h, 95% CI: −36.88 to −26.77, 2 trials, 270 patients, I(2)=0%, low certainty), sore throat alleviation time (MD: −28.66 h, 95% CI: −32.23 to −25.10, 1 trial, 150 patients, low certainty), and improving the total effective rate (RR: 1.15, 95% CI: 1.06 to 1.25, 10 trials, 1,074 patients, I(2)=76%, very low certainty). Besides, Reduning Injection seemed generally safe. CONCLUSIONS: This study provided low or very low evidence indicating Reduning Injection may be effective in the treatment of influenza and might be safe. Further rigorously designed studies are needed to confirm the effectiveness and safety of Reduning Injection and support it as a recommendation for influenza. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material (Appendixes 1 and 2) are available in the online version of this article at DOI: 10.1007/s11655-022-3524-9.

after the onset of symptoms; (8) the severity of symptoms and infl uenza virus strains affected the effect of NALs; (9) and extensive use of NALs may increase the risk of drug resistance. (10) Because of these, more alternative therapies have been considered.

In China, Chinese medicine (CM) has played an important role in the treatment of influenza. In clinical practice guideline (CPG) on treating infl uenza in adult patients with Chinese patent medicines (CPMs), (11) 5 CPMs have been recommended to be used alone in mild infl uenza patients, not necessarily in combination with Western medicine. However, the recommendations of this CPG were all oral CPMs, and there was no recommendation for CPM injections.

Reduning Injection (热毒宁, RDN) is extracted from 3 Chinese herbs including Artemisia annua L, Lonicera japonica T. and Gardenia jasminoides E. It has been reported that the components of RDN have potential antiviral, anti-inflammatory and immunomodulatory functions, (12) (13) (14) and is often clinically used to treat infl uenza patients with external contraction of wind-heat syndrome or heat-toxin attacking the Lung (Fei) syndrome. Previously published clinical trials have proved the effect of RDN on treating influenza, such as shortening the clearance time of fever and alleviation time of influenza symptoms. (15, 16) However, there has been no critical evaluation of current evidence from RCTs for RDN in treatment of infl uenza. Therefore, we performed a systematic review and meta-analysis to clarify the effectiveness and safety of RDN use alone or in combination with NALs.

T h e r e v i e w p r o t o c o l w a s r e g i s t e r e d i n PROSPERO platform (No. CRD42021228626, available at: https://www.crd.york.ac.uk/PROSPERO/). We followed the reporting standard for systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement checklist. (17) 

We identifi ed all relevant articles in accordance with the Cochrane Handbook. (18) and originally searched publications in the following electronic databases from inception dates to May 1st, 2021 including MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Chinese Bio-medical Literature and Retrieval System (Sinomed), China National Knowledge Infrastructure Database (CNKI), China Science and Technology Journal Database (VIP) and WanFang Data Knowledge Service Platform. We also searched ClinicalTrails.gov for relevant ongoing or unpublished trials. The following search terms were used: "influenza", "human flu" and "Reduning Injection", etc. The search strategy of MEDLINE as an example is presented in Appendix 1. The references of the included articles were searched to fi nd any additional articles.

Randomized controlled trials (RCTs), regardless of the usage of blinding, language, and publication type, were included. Studies were excluded in the case of duplicate studies, non-RCT, no definite diagnosis of infl uenza and unable to obtain full-text.

To be included in the review, patients should be diagnosed as influenza, irrespective of the patient's gender and age. The diagnostic criteria of influenza included feeling unwell within 36 h, having fever ( 38 ℃ if age <65 years; 37.5 ℃ if age 65 years), and at least two infl uenza symptoms (one respiratory symptom: cough, sore throat or coryza; and general symptom: headache, myalgia, sweats or chills, or fatigue).

The interventions were RDN, at any dose or with any duration, used alone or in combination with NALs (oseltamivir, peramivir and zanamivir), without restriction on dosage or treatment duration.

The interventions used in control group were NALs therapies.

The primary outcomes were fever clearance time. The secondary outcomes included the fever alleviation time, other symptoms alleviation time, total effective rate, and adverse events (AEs). The fever clearance time was defined as time from baseline to the first time when axillary temperature decreased to <37.4 ℃ and maintenance of stable temperature (<37.4 ℃) more than 24 h, and the fever alleviation time was defined as time from baseline to the first time when axillary temperature descended more than 0.5 ℃.

Considering that there are 7 common symptoms of infl uenza: nasal congestion, sore throat, cough, aches and pains, fatigue, headaches, and chills or sweats, (19) we conducted meta-analysis for each symptom reported in the included studies for the outcome of symptoms alleviation time. Effective was defi ned as a decrease in body temperature and symptom relief.

T w o a u t h o r s ( Z h a o G Z a n d M a Q X ) independently screened titles/abstracts and read the full text of potential studies in duplicate to identify articles that met the inclusion criteria. The authors resolved any disagreements through discussion, and if disagreements were not resolved, a third author (Li B) was invited to arbitrate.

A pre-defined form was designed and used to extract information from the selected studies, including study characteristics (e.g., author name, published year, sample size), patients' information (e.g., gender, age), interventions and control characteristics (e.g., specific medication, dose, duration), and outcomes (primary and secondary outcomes specifically mentioned above). Data extractions were performed by two independent authors (Wang YF and Guo SQ). Any disagreements were resolved by discussion or asked a third author (Guo YH) to arbitrate.

Authors (Zhao GZ and Du Y) independently assessed risks of bias of included RCTs using the Cochrane Collaboration risk of bias tool by RevMan 5.4. (18, 20) The 7 domains were assessed including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and other sources of bias. Each domain was judged as "low", "high", or "unclear" risk of bias.

Stata (version 15.1) was used for data analysis. Risk ratios (RR) with 95% confi dence interval (CI) was calculated for dichotomous variables. For continuous variables, the weighted mean difference (WMD) with 95% CI was used if the measurement method and unit were the same, otherwise the standard mean difference (SMD) with 95% CI was used. Intentionto-treat (ITT) analysis was conducted. The Cochran's Chi-square test and I 2 statistic was used to evaluate heterogeneity. If statistical heterogeneity was present (P<0.10, or I 2 >50%), the random-effects model was used, otherwise the fi xed-effect model was adopted. (21) For the primary outcomes, consideration that the included studies had differences in study population and intervention, random-effects model as the primary analysis and fixed-effect model as the sensitive analyses were used. The funnel plot, begg's text and egger text were used to assess the publication bias if more than 10 RCTs were included for each outcome.

Grading of Recommendations Assessment, Development and Evaluation (GRADE) system approach was used to rate the certainty of evidence for each outcome. According to the GRADE guideline, (22) (23) (24) (25) (26) (27) the initial certainty of evidence body begins with high on RCTs, and may be decreased if they meet the downgrade criteria (risk of bias, inconsistency, indirectness, imprecision, and publication bias). The certainty of evidence was rated as high, moderate, low, and very low. The summary of fi ndings table was created by the GRADEpro GDT (https://gradepro.org/).

The search processes are shown in Figure 1 according to PRISMA fl owchart. A total of 485 articles was initially identifi ed, and 345 were potentially eligible after removal of duplications. According to inclusion criteria, 290 references were removed by screening title and abstract, and additional 43 studies were excluded after reading full-texts. Finally, 12 studies (15, 16, (28) (29) (30) (31) (32) (33) (34) (35) (36) (37) met the eligibility criteria and were included.

The characteristics of the included studies are summarized in Table 1 . One trial (16) was published in English and the rest were in Chinese. A total of 1,460 patients with influenza were included, 734 in the RDN group and 726 in the control group. The sample size of included trials ranged from 38 to 236. The duration of treatments ranged from 3 to 7 days, with an average of 4.33 days. The participants of 5 studies (28) (29) (30) 32, 34) were children, while the others were adults. Five included studies reported CM symptom, and 4 (15, 33, 34, 36) of them were heat-toxin attacking Fei and 1 (35) was external contraction of wind-heat symptom. One RCT (36) explored the effects of RDN used alone, 3 RCTs (15, 16, 33) used RDN plus oseltamivir placebo, while the others used RDN plus oseltamivir. For control group, all articles used oseltamivir alone or in combination with RDN placebo.

The methodological quality of included RCTs is summarized in Figure 2 . Six trials (16, 30, (33) (34) (35) 37) specifi ed the method on sequence generation of randomization which were assessed as low risk. Because of central randomization design, 2 trials (16, 33) were evaluated as low risk on allocation concealment. For blinding assessment, considering the use of placebo and choice of objective outcomes, 8 trials (15, 16, 29, (33) (34) (35) 37, 39) were assessed as low risk. All studies had low attrition bias because all participants were accounted. As protocol or registration information of trials were unavailable, 11 RCTs (15, (28) (29) (30) (31) (32) (33) (34) (35) (36) (37) were assessed as unclear on reporting bias. Another one RCT is available for registration information and has no risk of bias, then it is rated as low. Two trials (15, 16) which sponsored by pharmaceutical companies were assessed as high risk, 2 trials (35, 36) with sponsorship of government were assessed as low risk, and the other studies were as unclear risk.

Seven studies (15, 29, 30, (33) (34) (35) 37) involving 814 patients Figure 4A ).

Two studies (30, 34) 

Three studies (15, 33, 37) including 366 patients reported the outcome of fever alleviation time. The total meta-analysis showed favorable effects of RDN group with no statistical heterogeneity (MD: -4.09 h, 95% CI: -4.22 to -3.96, I 2 =0%, P=0.74; Figure 3C ).

Among the common symptoms of infl uenza, there are 3 were mentioned in included studies, which are cough, fatigue, and sore throat. We conducted metaanalyses on the alleviation time of these 3 symptoms.

Two studies (29, 34) of 228 patients reported Figure 4B ). Alleviation Time for Sore Throat Only one study (34) reported the outcome of sore throat alleviation time. The result showed that compared with the control group, the sore throat alleviation time was signifi cantly shorter in the treatment group (MD: -28.66 h, 95% CI: -32.23 to -25.10).

Ten studies (15, (28) (29) (30) (31) (32) (33) (35) (36) (37) involving 1,074 patients reported the outcome of total effective rate. The random-effects model was used because of the signifi cant heterogeneity. The meta-analysis showed a signifi cant higher effective rate in the RDN group compared with the control group (RR: 1.15, 95% CI: 1.06 to 1.25, I 2 =76%, P<0.0001; Figure 5 ).

Seven out of the 12 studies reported AEs, of which 3 studies (31, 33, 36) indicated that there were no obvious AEs. Four studies (15, 16, 28, 30) reported AEs such as transfusion reaction, descended leukopenia, and increased lymphocytes, etc. A meta-analysis of these 4 studies involving 756 patients reported case numbers of AEs, and showed no significant differences between two groups (RR: 0.90, 95% CI: 0.30 to 2.68, I 2 =70%, P=0.02; Figure 6 ).

As we only included more than 10 trials with potential antiviral function, as well as signifi cant antiinfl ammatory and immunomodulatory function. (43, 44) Relevant studies showed that there was no significant difference in changes of viral titer when compared CM with NALs in the treatment of influenza. (45) However, this study found that RDN can shorten the onset of some flu symptoms, such as fever, cough, sore throat, and fatigue. Therefore, clinicians can use RDN with reference to the results of this study for fl u patients with severe symptoms.

According to CPG on treating infl uenza in adult patients with CPM, (11) infl uenza patients can be divided into mild, severe, and critical cases, and staged treatment may be performed. However, few studies clearly indicated the stage of influenza, making it difficult to judge the severity of disease and provide treatment recommendations. Further studies should be carried out on influenza patients with different severity, to further evaluate the effectiveness and safety of RDN on different stages of infl uenza.

There are some limitations in this study. Firstly, the combined results of some outcomes were statistically heterogeneous, but we cannot perform subgroup analysis or sensitive analysis due to insufficient number of original studies, the random-effects model was chosed for meta-analysis. Secondly, most of the included studies had flaws in methodological design, such as unclear allocation concealment or lack of clinical trial registration, so whether there was a selection bias or reporting bias was unclear. Thirdly, all included RCTs were from China, which may limit the application of the results.

Due to the heterogeneity and bias risk of the included trials, the certainty level of evidence was downgraded. Therefore, it is necessary to carry out large sample, high-quality, multi-center clinical trials. In order to reduce the risk of bias and improve the evidence level, it is necessary to register the research protocol, use computer-generated random sequences, conceal the allocation scheme, and imply blind for participants and outcome evaluators. Among them, blinding of patient can be achieved through using saline as RDN simulation, using brown infusion tube in infusion operation, and so on. Additionally, more rigorous researches are needed to evaluate the safety of RDN, such as phase Ⅳ clinical trials.

The overall evidence on 7 outcomes were evaluated by GRADE (Appendix 2). Generally, the evidence quality was low for alleviation time of fever, fatigue, and sore throat, and very low for fever clearance time, cough alleviation time, total effective rate, and AEs.

This study included 12 RCTs and systematically evaluated the effectiveness and safety of RDN for influenza. The results showed that compared with NALs, the RDN use alone or in combination with NALs could shorten the fever clearance time by 16.20 (19.40-12.99 ) h, which has certain clinical significance. In addition, RDN showed better effects on fever and symptoms alleviation time as well as total effective rate. Besides, RDN seemed generally safe.

For infl uenza patients, fever, cough, sore throat, fatigue, and other symptoms caused by infl uenza virus are the most important factors affecting the quality of life of patients, and fever is the most important factor. Therefore, the strength of this systematic review is that we used the remission time of influenza-related symptoms as outcomes to evaluate the efficacy of RDN.

Relevant studies showed that RDN may have potential advantages on other diseases. (38) As the development of a new antiviral drug is generally slow, (39) it may not be timely to provide a suitable antiviral drug in face of a new and acute respiratory viral infection, such as coronavirus disease 2019 pandemic. (40) Considering the mechanism of RDN, it may have effects on acute respiratory infectious diseases caused by other viruses. However, the conclusion needs to be confi rmed by relevant clinical studies.

We speculate that the signifi cant effects of RDN in treating infl uenza may be explained by the following reasons. Firstly, RDN could alleviate lung damage and improve survival by reducing the viral titers in lungs, and reducing key inflammation-regulating factors including interleukin (IL) -1β, IL-6, IL-10 and IL-18. (41, 42) Secondly, the components of RDN, including Artemisia annua L, Lonicera japonica T. and Gardenia jasminoides E, have been proven to have This meta-analysis provided low or very low evidence indicating RDN may have effects in treatment of infl uenza on shortening the clearance time of fever, the alleviation time of fever, cough, fatigue, and sore throat, as well as increasing the total effective rate, and might be safe. More large-scale, high-quality, multicenter clinical trials with appropriate outcome indicators are needed to prove the effectiveness and safety of RDN.

The datasets analyzed in this study are supported by the published articles in opening electronic databases (details in search strategy). 

Infl uenza seasonal

Overview of influenza viruses

Pandemic and Avian Influenza A viruses in humans: epidemiology, virology, clinical characteristics, and treatment strategy

Estimates of global seasonal infl uenza-associated respiratory mortality: a modelling study

Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal infl uenzaa

What you should know about fl u antiviral drugs

Early versus late oseltamivir treatment in severely ill patients with 2009 pandemic infl uenza A (H1N1): speed is life

Antiviral agents for the treatment and chemoprophylaxis of influenzarecommendations of the Advisory Committee on Immunization Practices (ACIP)

New advances in the drug treatment of infl uenza

Clinical practice guideline on treating influenza in adult patients with Chinese patent medicines

Geniposide inhibits airway infl ammation and hyperresponsiveness in a mouse model of asthma

Anti-inflammatory and immunomodulatory mechanisms of artemisinin on contact hypersensitivity

Intravenous infusion of Reduning Injection in the treatment of 108 cases of infl uenza

Effi cacy and safety of Re-Du-Ning Injection in the treatment of seasonal infl uenza: results from a randomized, double-blinded, multicenter, oseltamivircontrolled trial

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

Cochrane handbook for systematic reviews of interventions

Oseltamivir treatment for influenza in adults: a meta-analysis of randomized controlled trials

The Cochrane Collaboration's tool for assessing risk of bias in randomized trials

Quantifying heterogeneity in a meta-analysis

GRADE guidelines: 3. Rating the quality of evidence

GRADE guidelines: 4. Rating the quality of evidence-study limitations (risk of bias)

GRADE guidelines: 5. Rating the quality of evidence-publication bias

GRADE guidelines: 6. Rating the quality of evidence-imprecision

GRADE guidelines: 7. Rating the quality of evidence-inconsistency

GRADE guidelines: 8. Rating the quality of evidence-indirectness

Clinical effect and safety analysis of oseltamivir phosphate combined with Reduning Injection in the treatment of infl uenza

Observation on the efficacy of Reduning Injection in the treatment of children with infl uenza A H1N1 combined with pneumonia

Evaluation of laboratory indicators for the treatment of infantile influenza virus infection by Reduning combined with oseltamivir

Observation on the clinical effect of Reduning Injection in the auxiliary treatment of influenza

Observation on the clinical efficacy of oseltamivir combined with Reduning Injection in the treatment of severe infl uenza in children

Clinical observation on the treatment of influenza high fever (fever attacking syndrome) by Reduning Injection

Observation on the effect of oseltamivir phosphate combined with Reduning on improving the clinical symptoms of children with seasonal infl uenza

Clinical study of Reduning Injection combined with oseltamivir phosphate in the treatment of exogenous wind-heat syndrome

Observation on the efficacy of Reduning Injection in the treatment of influenza

Intravenous drip of Reduning Injection in the treatment of 108 cases of infl uenza

Comparative study of the effi cacy and pharmacokinetics of Reduning Injection and atomization inhalation

Newer infl uenza antivirals, biotherapeutics and combinations

Chinese Medical Association Respiratory Medicine Branch, Chinese Medical Doctor Association Respiratory Physician Branch. Guidelines for the diagnosis, treatment, prevention, and control of COVID-19 in Chinese adults

Combination of ribavirin and Reduning protects mice against severe pneumonia induced by H1N1 infl uenza A virus

Reduning plus ribavirin display synergistic activity against severe pneumonia induced by H1N1 infl uenza A virus in mice

Lonicera japonica Thunb: ethnopharmacology, phytochemistry and pharmacology of an important traditional Chinese medicine

Geniposide inhibits airway infl ammation and hyperresponsiveness in a mouse model of asthma

Oseltamivir compared with the Chinese traditional therapy maxingshigan-yinqiaosan in the treatment of H1N1 infl uenza: a randomized trial