Shufeng Jiedu capsules for treating acute exacerbations of chronic obstructive pulmonary disease: a systematic review and meta-analysis

Background Chinese herbal medicine is widely used in combination with usual care for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in China. Chinese patent medicine Shufeng Jiedu (SFJD) capsules is widely used for respiratory infectious diseases. This review aims to evaluate effectiveness and safety of SFJD for AECOPD. Methods A systematic review of randomised controlled trials (RCTs) in patients with AECOPD, who received SFJD as a single intervention or as add-on treatment to usual care. PubMed, the Cochrane Library, EMBASE, Scopus, Web of Science and four Chinese databases were searched from inception to April 2019. Two authors screened trials, extracted data, and assessed risk of bias, independently. Meta-analysis was performed using RevMan 5.3 software. We performed subgroup analyses and sensitivity analyses according to the predefined protocol. Quality of evidence was assessed using GRADE. Results Thirteen RCTs (1036 patients, with 936 inpatients) were included, all compared SFJD in combination with usual care (including antibiotics) to usual care alone. The mean age of participants ranged from 52 to 67 years, with approximately 60% male. Due to lack of blinding and other factors, all trials were of high risk of bias. SFJD was associated with a significant reduction in treatment failure, from 20.1 to 8.3% (11 trials; 815 patients; relative risk 0.43, 95% confidence interval [CI] 0.30 to 0.62), and duration of hospital stay (2 trials; 79 patients; mean difference − 4.32 days, 95% CI − 5.89 to − 2.75 days). No significant difference in adverse events was found between SFJD and control groups. Conclusion Low certainty evidence suggests SFJD may bring additional benefit in reducing treatment failure, shorten hospital stay, and improving symptoms. Further large, high quality RCTs are needed to confirm its benefit and safety. Trial registration PROSPERO CRD42019133682.


Background
Chronic obstructive pulmonary disease (COPD) is one of most common causes of impaired health [1]. In China, around 99.9 million people, 8.6% of the Chinese population aged 20 years or older, live with COPD [2]. In the UK there is an estimation of 3 million COPD patients, among whom 1.2 million have been diagnosed, costing the National Health Service over 800 million pounds per year [3,4]. Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are defined as an acute worsening of respiratory symptoms that require additional therapy [5][6][7][8][9]. Patients with COPD on average experience 0.5-3.5 acute exacerbations per year [10]. Acute exacerbations lead to a decline in lung function and quality of life, increased need for hospitalisation, and are associated with increased risk of death [11,12], therefore account for the greatest proportion of the total COPD burden on healthcare system [13,14]. AECOPD can be triggered by several factors, with the most common causes being respiratory infections caused by bacteria or viruses (which may coexist) and noninfectious environmental factors such as pollution or allergens. Severe exacerbations may require hospitalisation or visits to the emergency department and may be associated with acute respiratory failure. Bronchodilators are commonly prescribed in combination with systemic corticosteroids, antibiotics and other respiratory support in the treatment of AECOPD. These therapies are supported by evidence from randomised controlled trials and are recommended by guidelines [9,15]. However, these interventions are known to cause a variety of adverse effects, including, dry mouth, tremor, hyperglycaemia, diarrhoea, and antibiotic resistance [16][17][18].
Shufeng Jiedu (SFJD) capsule is an oral patent Chinese herbal medicine widely used in China for the treatment of respiratory infections (a list of all ingredients of Shufeng Jiedu is available in Additional file 1: Table 1). Published systematic reviews [19][20][21][22][23][24][25][26] have evaluated the effects of many traditional Chinese herbal medicine decoctions and injections on clinical outcomes including symptoms, pulmonary function and quality of life in patients with AECOPD. However, there is no published systematic review evaluating the effectiveness and safety of SFJD as a treatment for AECOPD. In light of the recently published randomised controlled trials (RCTs) on SFJD, we aimed to evaluate the effectiveness and safety of SFJD for AECOPD by conducting a systematic review and meta-analysis where appropriate.

Methods
This systematic review is reported in accordance with the PRISMA statement [27] and has been prospectively registered on PROSPERO [28].

Eligibility criteria
We included RCTs of SFJD as a single intervention or in combination with usual treatment (e.g. bronchodilators and antibiotics), compared to usual treatment alone, placebo, waiting list or no treatment. Participants were patients with a clinical diagnosis of AECOPD. The primary outcome was treatment failure as observed at the end of treatment. Treatment failure was defined as no resolution or deterioration of symptoms after trial medication of any duration, or death (when explicitly stated, due to exacerbation) or additional course of antibiotics or another medication for the treatment of AECOPD [17].
Secondary outcomes included all-cause mortality, duration of hospital stay (for inpatients), admission to an intensive care unit (ICU), re-exacerbations within two to 6 weeks of index exacerbation (inpatient or outpatient treatment, rates or time to event), time to resolution of clinical symptoms (e.g. dyspnoea, cough, wheezing, sputum, or fever), arterial blood gas measurements at the end of treatment (partial pressure of oxygen in arterial blood (PaO2) and partial pressure of carbon dioxide in arterial blood (PaCO2)), lung function -forced expiratory volume in 1 s (FEV1) / forced vital capacity (FVC) ratio, markers of infection (white blood cell count, proportion of neutrophils, C-reactive protein, procalcitonin), antibiotic usage (change of modes of administration of antibiotics, change of antibiotic, duration of antibiotic treatment or number of patients who used antibiotics), health related quality of life and adverse events (unintended symptoms or signs, e.g. abnormal liver/ kidney function or ECG, or disease).

Information sources
We searched English databases PubMed, the Cochrane Library, EMBASE, Scopus, Web of Science, and Chinese databases China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), SinoMed and Wanfang from their inception to April 2019. The PubMed search used the following words in Title/Abstract field: "Shufengjiedu" or "Shu Feng Jie Du" or "Shu-Feng-Jie-Du" or "Shufeng Jiedu" or "Shufeng-Jiedu". We conducted searches of ClinicalTrials.gov (www.ClinicalTrials.gov) and Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx). We also searched reference lists of included studies and existing systematic reviews.
Literature screening, data extraction and quality assessment After removing duplicates, paired trained reviewers independently screened titles and abstracts of all potential studies identified from searches. When there were uncertainties, insufficient information, or in cases of disagreement, we obtained full texts of the articles, then determined eligibility by screening the full texts. Reasons for excluding articles at full text screening stage were recorded.
After identifying eligible studies, paired reviewers independently extracted trial characteristics on sample size, setting and source of funding, characteristics of the trial population on age and sex, information about the illness including diagnostic criteria and illness duration, trial inclusion and exclusion criteria, details of interventions in all trial arms, outcome measures, and risk of bias domains from included trials using standardised pilot tested forms with detailed instructions.
Quality of the eligible studies was assessed by two reviewers using a modified Cochrane Risk of Bias Tool with four response options: "probably no", "no", "probably yes", and "yes" [29,30]. We also used the five GRADE (Grading of Recommendations Assessment, Development and Evaluation) considerations (risk of bias, directness, precision, consistency, and the possibility of publication bias) to assess methodological confidence of a body of evidence for prespecified outcomes [31]. For all phases of the review, we dealt with discrepancies through discussion or adjudication by a third reviewer when necessary. Chance-corrected Kappa [32] was calculated as a measure of agreement among reviewers' judgements.

Data synthesis and analysis
We conducted analyses using risk ratio (RR) with 95% confidence intervals (CI) for dichotomous data; mean difference (MD) or standard mean difference (SMD) with 95% CI for continuous data. We pooled data quantitatively through Review Manager (version 5.3) when the trials had admissible clinical homogeneity and statistical heterogeneity as measured by Cochrane χ 2 test and I 2 statistic, or where heterogeneity could be explained by predefined subgroup analysis [29,33]. Otherwise only qualitative description of the data was presented. A fixed-effects model was considered when I 2 was < 30%, otherwise, a random-effects model was utilised.
To explain heterogeneity, we conducted subgroup analyses predefined via AECOPD severity (outpatients, inpatients and patients admitted to the ICU), treatment duration (≤7 days or > 7 days), mode of administration of antibiotics, and complications. We conducted sensitivity analyses to challenge the robustness of the results when there were clinically meaningful differences in primary outcomes considering: multi-centre versus single centre, clear versus unclear randomisation concealment, placebo used versus not used, reported loss-to-follow-up versus not reported, assumed worst plausible case results for patients in intervention groups with missing data [34].
We generated a funnel plot through Review Manager (version 5.3), and performed Begg's test and Egger's test through R (version 3.6.1) when ten or more studies were presented in a meta-analysis to examine publication bias.

Results
The literature search identified 688 unique citations, among which 20 were judged potentially eligible at title and abstract screening. Further screening of full text identified 13 RCTs involving 1036 patients, of which 936 were hospitalised patients ( Fig. 1). Chance-corrected Kappa for agreements is 0.95 for title and abstract screening, 0.77 for full text screening, and 0.91 for assessment of risk of bias of included studies.

Trial characteristics
All studies were single centre trials and conducted in China, and none reported sources of funding or conflicts of interest. Sample size ranged from 40 to 130, more than half of the participants were male in each trial, and the mean age ranged from 52 to 67 years (Table 1) [35][36][37][38][39][40][41][42][43][44][45][46][47]. Patients in intervention groups all received SFJD along with antibiotics and symptomatic treatments (such as bronchodilators and supplemental oxygen), while the comparison groups all received antibiotics and symptomatic treatments without SFJD. The duration of treatment ranged from 6 [47] to 14 days [41,46]. In all included trials, the dose of SFJD was 4 capsules per time, 3 times daily.

Risk of Bias assessment
Three trials reported clear randomisation concealment [40,41,47]. Placebo was not used in any of the studies, so there was no blinding of patients or clinicians. Loss to follow-up was rarely reported; two trials had more than 5% attrition [35,36] (Table 2).

Outcomes
No trial reported information about all-cause mortality, re-exacerbation or antibiotic dosage.

ICU admission
Only one trial [36] (120 patients) provided data on admission to an ICU for mechanical ventilation among patients not in an ICU at the time of enrolment. Six of 60 patients in the SFJD group and seven of 60 patients in the control group were admitted to an ICU respectively.

PaO2 and PaCO2
Significant benefits were found for improvement in PaO2 (4 trials, 390 patients, MD 7.69 mmHg, 3.68 to 11.70 mmHg; I 2 = 92%; very low certainty) and reduction in PaCO2 at end of therapy (4 trials, 390 patients, MD − 3.73 mmHg, − 6.01 to − 1.45 mmHg; I 2 = 69%; very low certainty) in SFJD group compared to control group (Additional file 1: Table 4). Subgroup analysis did not have a meaningful impact on the results.

White cell counts and inflammatory markers
Three trials [43,44,47] (159 patients) investigated white blood cell counts in patients at the end of treatment.
Two trials [39,43] (160 patients) provided data on procalcitonin among patients. Pooled results showed no significantly difference (MD − 0.61 ng/L, − 1.26 to 0.04 ng/L; I 2 = 93%; very low certainty) at the end of treatment in the SFJD group and the usual care group (Additional file 1: Table 4).

Health related quality of life
Only one trial [35] (77 patients) investigated quality of life. COPD Assessment Test (CAT) score reduced from 21.7 to 15.3 in patients treated with SFJD and from 22.3 to 17.3 in the control group (MD between two groups at the end of treatment − 2.00, − 4.30 to − 0.30). Previous study has shown that the minimum clinical important difference is a decrease in CAT score of 2 points [48].

Adverse events
No difference in the incidence of adverse events was found between those who did and did not take SFJD (8 trials; 605 patients; RR 1.41, 0.46 to 4.33; I 2 = 0%; low certainty). Subgroup analyses did not have a meaningful  impact on the results (Additional file 1: Table 4). The adverse events reported in these trials included transient gastrointestinal tract reactions, including nausea and diarrhoea. No serious adverse event was reported.

Main findings
Our systematic review found low certainty evidence suggesting possible benefits from SFJD in combination with usual care for patients with AECOPD, compared to usual care. However, these effects can only be reported with low or very low certainty due to high risk of bias, mainly from lack of blinding, and the insufficient number of trials. Our findings suggested a significant reduction in the rate of treatment failure (57% reduction in the risk of treatment failure). We found an estimated reduction of 4 days in hospital stay from SFJD with usual care. We also found low certainty evidence that SFJD as adjuvant therapy may offer benefits in physiological outcomes: PaO2, PaCO2, FEV1/FVC ratio, white cell counts and inflammatory markers (low to very low certainty).
We found no evidence of serious adverse events associated with use of SFJD.

Strengths and limitations
The review was registered in advance and followed rigorous methodology with pre-specified eligibility criteria, a comprehensive search with English and Chinese databases included without language restrictions, and assessment of eligibility and risk of bias in duplicate. We conducted some pre-defined plausible subgroup and sensitivity analyses and applied GRADE criteria to determine certainty of evidence. Twelve of the 13 trials we included focused on inpatients, and all trials combined SFJD with antibiotics and symptomatic treatment, which is in line with routine clinical practice. In addition, the daily dosing regimen of SFJD was the same in all trials.
There are several limitations: No trials included placebo. Usual care was not standardised across trials, the characteristics of patients varied and phenotyping was poor so it was difficult to identify a responder population. All trials had high risk of bias in the blinding domain, and most trials had unclear risk of bias in attrition. Additionally, inferences were also limited for some outcomes with a small number of patients and events. Most GRADE evidence certainty was low or very low which suggests that readers should be legitimately concerned with the evidence. However, our findings were robust to a variety of subgroup and sensitivity analyses.

Relation to prior research work
We identified one published systematic review [49] (in Chinese) of SFJD for AECOPD. This previous systematic review did not register their protocol, and GRADE was not utilised to evaluate the confidence of evidence. The nine trials identified in this previous systematic review were all included in our review. Our results are consistent with the prior systematic review. Inclusion of recent trials allowed us to address additional outcomes, including ICU admission, health related quality of life and time to resolution of clinical symptoms, as well as to provide assessment of included evidence certainty.

Implications
Our results support the need for a future blinded RCT of SFJD for AECOPD. All trials had a high risk of bias; and as very few trials included outpatients it is unclear whether our findings can be generalised to this setting. Similar effects across outcomes (treatment failure, length of hospital stay, PaO2and PaCO2, FEV1/FVC ratio, clinical symptoms and infection-related index) strengthened the credibility of the findings.
One trial [39] required that participants had to have pulmonary infection confirmed by guidelines for diagnosis and treatment of community-acquired pneumonia [50]. Although subgroup analyses showed that results from this trial were not significantly different from other trials, it remains possible that the effects of SFJD vary by underlying pulmonary infection.
The apparent benefits of SFJD combined with antibiotic and symptomatic treatment in AECOPD are considered importantan absolute reduction in risk of treatment failure (11.8% lower) and shortening of hospital stay (approximately 4 days fewer) without identifiable long-term or serious adverse events compared to antibiotic and symptomatic treatment.

Conclusion
Published trials suggested positive effects of SFJD in combination of antibiotics and symptomatic treatments on reducing treatment failure, duration of hospitalisation, symptoms. However, due to the high risk of bias and the limited number of trials, the findings were inconclusive. Further high-quality, rigorously conducted double-blind, placebo-controlled trials are warranted.
Additional file 1: Table 1. Herbal compositions of Shufeng Jiedu capsule. Table 2. Definitions of treatment failure in 11 trials. Table 3. Subgroup analyses and sensitivity analyses for treatment failure with Shufeng Jiedu for AECOPD patients. Figure 1. Impact of Shufeng Jiedu capsule on treatment failure in AECOPD patients stratified by mode of administration of antibiotics. Figure 2. Impact of Shufeng Jiedu on treatment failure in AECOPD patients stratified by complications. Figure  3. Impact of Shufeng Jiedu on treatment failure in AECOPD patients stratified by clear or unclear randomization concealment. Impact of Shufeng Jiedu on treatment failure in AECOPD patients stratified by reported loss to follow up or not reported. Figure 5. Impact of Shufeng Jiedu on treatment failure in AECOPD patients used worst plausible assumptions of patients lost to follow up or not used. Figure 6. Impact of Shufeng Jiedu on duration of hospital stay (days) in AECOPD patients. Table 4. Certainty in the estimates rated according to the GRADE.