Chinese Herbal Medicine for Postinfectious Cough: A Systematic Review of Randomized Controlled Trials

Chinese herbal medicine has been commonly used in the treatment of postinfectious cough. The aim of this review is to systematically evaluate the efficacy and safety of Chinese herbal medicine for postinfectious cough. An extensive search for RCTs was performed using multiple electronic databases, supplemented with a manual search. All studies included were confirmed with specific inclusion criteria. Methodological quality of each study was examined according to the Cochrane risk of bias assessment. Quality of evidence was evaluated using rating approach developed by GRADE working group. The literature search yielded 352 results, of which 12 RCTs satisfied the inclusion criteria, offering moderate-to-high levels of evidence. Methodological quality was considered high in three trials, while in the other nine studies the unclear risk of bias was in the majority. Findings suggested that, compared with western conventional medicine or placebo, Chinese herbal medicine could effectively improve core symptoms of postinfectious cough, act better and have earlier antitussive effect, and enhance patients' quality of life. No serious adverse event was reported.


Introduction
Patients who complain of a persistent cough lasting >3 weeks but not >8 weeks after experiencing the acute symptoms of an upper respiratory tract infection are considered to have a postinfectious cough (PIC) [1]. PIC is supposed to be the most common cause of subacute cough [2], which is distinguished from the chronic cough by the duration of coughing [3]. For adults, retrospective studies of unselected patients with a history of upper respiratory tract infection showed that the frequency of PIC ranged from 11 to 25% [4], which increased to the range from 25 to 50% during outbreaks of atypical pathogens infections [5,6]. Respiratory viruses, M. pneumoniae, Chlamydophila pneumonia, and some specific bacteria have been implicated in the cause of PIC [7,8]. The pathogenesis of the PIC has not been clearly recognized. It was frequently thought to be relevant to multiple factors involving disruption of epithelial integrity, widespread airway inflammation, and bronchial hyperresponsiveness [9][10][11][12].
Although PIC is self-limited and will usually resolve on its own in time, persistent cough always incurs much health troubles and economic miseries for patients and their surroundings. Thus, medication therapy is imperative sometimes. Up to now, optimal treatment of western conventional medication (WCM) for patients with PIC is not known [1]. Symptomatic therapeutic medications including antihistamine, decongestant, and ipratropium bromide are being commonly used. Besides, brief course of inhaled or oral corticosteroids [13] has sometimes been administered in view of airway inflammations. But corticosteroids were generally used just in patients with severe paroxysms of PIC for their remarkable side effects [1]. Central acting antitussive agent such as codeine or dextromethorphan would be considered, as a last resort, in those patients who are resistant to other treatment approaches; however, there have been no clinical trials conducted to support its effect [1]. In addition, antibiotics are usually abused in treatment of PIC. Therefore, research for optimal treatment of PIC is particularly needed [14,15].
TCM has unique understanding of PIC and has established its own diagnosis and treatment approach. In TCM theory system, PIC, equivalent to the category of exogenous 2 Evidence-Based Complementary and Alternative Medicine cough, is caused by invasion of external evil factors (windevil, cold-evil, summer-damp-evil, wet-evil, dryness-evil, and fire-evil). These factors disturb or suppress Qi activity in the lung, leading to acute cough. If things continue this way, the lung-Qi would be damaged and unable to drive evils out, leaving external evils lingering in the lung for a long time. In this case, patients would suffer a fairly long duration of cough. With thousands of years of experience, TCM clinicians summarized the most common pathomechanism of PIC as "disorder Qi activity in the lung" due to "wind-evil invading the lung. " The corresponding therapeutic method is "dispelling wind and dispersing the lung-Qi. " PIC is a disease with complex pathogenic conditions including phlegm turbidity and deficiency of the lung-Yin. So flexible treatment based on syndrome differentiation is important.
An increasing number of clinical trials on CHM for PIC have been performed. This current systematic review aims to collect the evidence from RCTs to evaluate the therapeutic effect and safety of CHM in the management of PIC.

Research Protocol.
All methods were performed according to a predefined, unpublished protocol, which consisted of the search databases, detailed research question, search strategies, and eligibility criteria. The detailed research question included study design, patient characteristics, interventions, and outcomes.

Database and Search
Strategies. Literature searches were conducted to identify reports of randomized controlled trials involving CHM for PIC in the following preliminary determined electronic databases: Chinese National Knowledge Infrastructure (CNKI), Wanfang Database, EMBASE, MED-LINE (PubMed), Cqvip Database, Google Scholar, Scholarly and Academic Information Navigator (CiNii), and Cochrane Library from inception to July 2013. Ongoing registered clinical trials were searched on the website of Chinese clinical trial registry (ChiCTR) (http://www.chictr.org/). Searches for relevant conference proceedings, unpublished literature, and studies (Table 1) included in previous relevant systematic reviews were performed. Moreover, manual searches for bibliographies of all retrieved literature sources were conducted for additional references. No language restriction was applied.
The following phrases and their derivatives or relevant terms were utilized singly or in combination: "post-infectious cough, " "subacute cough, " "cough post influenza, " "postviral cough, " "post-cold cough, " "whooping cough, " "Chinese herbal medicine, " "traditional Chinese medicine, " and "randomized controlled trial. " The search terms were modified to adapt to different databases with a highly sensitive search strategy developed by the Cochrane Collaboration [16]. We contacted authors for further information or clarification. Searching work was done by two reviewers (Wei Liu and Hong-Li Jiang) independently. Searching results were crosschecked for accuracy.

Types of Studies.
All relevant randomized controlled trials or quasirandomized controlled trials that were published before July 20, 2013 were considered, regardless of blinding.

Types of Participants.
Any patients with diagnosed and existing PIC, of either gender, any profession or ethnicity, and any ages ≥12, were included. Those without description of diagnostic criteria but stated patients with definite PIC were also considered.

Types of Interventions.
Studies involving a comparison between CHM alone or in combination with WCM and the same WCM or placebo as controls were included. CHM included herbal extracted product, Chinese patent medicine (CPM), and self-modified herbal formula. CHM could be of any dose, duration, dosage form, and route of administration. Studies involving cointerventions of traditional extrapulmonary therapies such as acupuncture, cupping, or point application were excluded.

Outcomes.
Primary outcomes measures were as follows: (1) cough symptom score, which consists of the daytime-score and the nighttime-score, ranging from 0 to 6 [17]; (2) cough relief time, defined as both the daytime-score and the nighttime-score ≤1, which lasted for 48 hours; (3) cough disappearance time, defined as both of the daytimescore and the nighttime-score = 0, which lasted for 48 hours. Secondary outcome measures were as follows: (1) Obvious effective rate, defined as reduced rate of symptoms score ≥70% according to the Guiding Principle of Clinical Research on New Drugs of TCM [18,19]; (2) quality-of-life (QoL) score, evaluated using Cough-Specific Quality-of-Life Questionnaire (CQLQ) [20] or Leicester Cough Questionnaire (LCQ) [21]; (3) adverse events.

Studies Selection and Data Extraction.
Two reviewers (Wei Liu and Hong-Li Jiang) independently screened the titles and abstracts of searching results against prespecified inclusion criteria to identify potential relevance that required full texts for further identification. Disagreements were resolved by consensus. All articles included were judged by the third reviewer (Bing Mao).
Two reviewers (Wei Liu and Hong-Li Jiang) systematically extracted data regarding study design, demographic characteristics, interventions, and outcome measures independently. Discrepancies were resolved by discussion between the two reviewers or by consultation with the third arbitration (Bing Mao).

Qualities Assessment.
We used risk of bias assessment tool recommended by the Cochrane Collaboration to address the following six domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and "other bias" [22]. The risk of bias for each item was summarized as three levels: low, Evidence-Based Complementary and Alternative Medicine 3 We also used GRADE approach to assess the quality of the evidence for each individual outcome. Besides withinstudy limitations of design and execution (methodological quality), the GRADE approach incorporates comprehensive considerations of the following four factors: directness of evidence, inconsistency of results, imprecision, and publication bias [23,24]. Accordingly, we graded the quality of evidence as very low, low, moderate, or high.
The first reviewer (Wei Liu) performed the quality assessments with supervision from the other two reviewers (Hong-Li Jiang and Bing Mao).

Data Analysis.
In this review, a formal meta-analysis would not be conducted for the predicted large heterogeneity across trials [25]. Therefore, a narrative synthesis approach was applied.

Description of Included Studies.
The search strategies came up with 352 potentially relevant citations. Twelve trials involving 1289 subjects satisfied all the inclusion criteria ( Figure 1). One unpublished study [35] searched on the website of ChiCTR was included (registration number ChiCTR-TRC-12002297). Patients included in all studies were explicitly diagnosed as having PIC according to the nationwide unified western medicine diagnostic criteria [17] or ACCP Evidence-Based Clinical Practice Guidelines. TCM syndrome differentiation was identified based on the recognized guiding principles [18,38]. TCM syndrome of each patient was specified in ten studies and it was defined as "syndrome of wind evil invading the lung" in seven studies. As to the interventions, two studies compared CHM with placebo [33,35], five studies compared CHM with WCM [26,29,31,34,37], and two studies compared CHM adjuvantly used with WCM to the same WCM alone [27,28], two studies compared two CPMs [30,32]. Three trials reported a followup period to evaluate the sustained or subsequent effect of interventions [31,33,35]. CHMs used in the studies included were totally different. But nine of them [28][29][30][31][32][33][35][36][37] were prescribed based on the same TCM therapeutic principle of "dispelling wind and dispersing the lung-Qi" ( Table 2).

Quality Assessment of Included Studies.
In general, the unclear risk of bias is in the majority. Very limited information was available in many studies to permit a judgment of whether the risk of bias existed (Table 3).
Appropriate random component in the sequence generation process was described in six trials [30-33, 35, 36]. One study [37] implemented a quasirandom method by allocating patients according to sequence number of visiting. In this situation, patients' assignments could possibly be foreseen, which would introduce high selection bias.
Allocation concealment was presented in three trials [32,33,35]. One study [27] only pointed "envelopes" but did not specify whether they were sequentially numbered, properly opaque, or sealed. Other studies failed to show any information of allocation concealment. Thus, whether the randomization was effectively conducted was doubtful, leading to an unclear risk of selection bias.
Blinding was not addressed in most studies. Only three studies [32,33,35] claimed to be double-blind and elaborated the blinding method that was unlikely to be broken, contributing to a sufficient protection against bias. One study [37] stated single blind just in broad terms, so the performance risk of bias was classified as "unclear. " Three studies [27,29,34] were open-label trials, and the patients' knowledge of interventions they received was likely to result in a high risk of detection bias.

Quality of Evidence of Included Studies.
The "GRADE profiler" of the Cochrane Collaboration Network was used to assess the individual outcome. The quality of evidence was labeled as moderate to high (Table 4).

Outcome Measures of Included Studies.
Forest plots were used to show the statistical results of some outcome measures. Two studies [35,36] divided patients into three groups, so each of them was regarded as two RCTs in the final analysis.

Cough Symptom Score.
Cough symptom score was reported in five studies. Two studies [26,27] showed no significant difference between bakumondo-to group and WCM group at the last visit of view, but both of them found that bakumondo-to group had a more quick antitussive effect. Three studies [30,31,35] concluded significant difference between the trial group and the control group ( Figure 2).

Cough Relief Time.
Seven trials selected cough relief time as an outcome measure. For this indicator, six studies demonstrated statistically significant difference between the trial group and the control group [29,30,[33][34][35]37], indicating a more rapid cough relief effect of CHM, of which two studies [33,35] estimated cough relief time for each group using Kaplan-Meier method (median cough relief time: T = 6 d, C = 7 d; log-rank test = 0.026 [33]; median cough relief time: H = 4 d, L = 4 d, C = 6 d; log-rank test < 0.001 [35]). In the other study [32], significant difference between two CPMs (Su-huang Zhi-ke capsule and Zhi-ke Ning-sou capsule) was not observed in statistical analysis (Figure 3).

Obvious Effective Rate.
Nine trials selected "effective rate" (ER) as an outcome measurement. In these studies, "rate ratio" (RR) was calculated as the ratio between the proportion Evidence-Based Complementary and Alternative Medicine 7     of responders in the trial group and the proportion of responders in the control group. Responders were defined as those patients with an improvement rate of symptoms score ≥70%. For this indicator, eight studies were statistically significant, showing that CHM can improve clinical core symptoms of PIC [28,30,[32][33][34][35][36][37]. The same effect of CHM and WCM was reported in one study [29] (Figure 4).

Quality-of-Life
Score. Quality-of-life (QoL) evaluation was conducted in two studies. Both of them showed that CHM possessed a better effect in improving patients' quality of life. One study [35] calculated CQLQ total score and demonstrated significant difference across groups ( < 0.00001, MD = −8.34, 95% [−11.63, −5.05]). The other study [30] recorded physical, psychological, and social domains

Adverse Events.
In general, CHM was claimed to have fewer side effects compared with WCM. Adverse events were mentioned in eleven studies. Four studies [25,28,29,33] reported that no adverse events were observed at the end of treatment. In seven studies [26,[30][31][32][34][35][36], various adverse events were reported for 49 patients in the control group and for 114 patients in the trial group. All the adverse reactions were mild and did not affect results estimation ( Figure 5).

Discussion
Broadly speaking, findings of this current review suggested that CHM may have potential positive clinical effect in the treatment of PIC, and the outcome evidence was relatively optimistic for us to make further research to draw a confirmative conclusion.
Three included studies [32,33,35] were well-designed, leading to favorable methodological quality and robustness of results. Besides, reporting form and content of these three articles were comprehensive and they basically met the international criteria of CONSORT statement [39]. In other studies, limitations commonly concerned the issue of allocation concealment and blinding. Just like most of the TCM clinical trials, allocation concealment was not reported or not appropriately put into effect in most studies in this review. Only two studies [33,35] were double-blind and placebocontrolled. Both of them explicitly claimed that outcome assessors and data analyzers were definitely unconscious of interventions that patients received. Placebo is considered as a welcome and reasonable control for effective estimation of CHM [40,41], because CHM is considered to possess a potential psychological positive effect which is similar to placebo. So if intervention other than placebo is applied as control, the placebo-like effect of CHM may bring out false or exaggerated positive results in favor of the trial group.
Imperfections of included studies also lie in the common absence of sample size calculation. Only three studies [32,33,35] estimated sample size. Two studies [26,27] recruited less than 30 cases in each group, so it was not ensured whether they could provide enough power to detect the difference between groups. In addition, a small sample also might cause   exaggerated difference between groups. Therefore, outcomes in this case should be regarded with caution. Although the formulas used in the trials included in this review were not completely equivalent, nine of them [28][29][30][31][32][33][35][36][37] were prescribed based on the same fundamental TCM therapeutic principle of "dispelling wind and dispersing the lung-Qi. " Ephedra, Platycodon grandiflorus, Folium perilla, Almond, and Schizonepeta tenuifolia were usually used in prescriptions with this function. The corresponding TCM syndrome of patients is "wind evil attacking the lung", which Evidence-Based Complementary and Alternative Medicine 13 is considered as the most common syndrome in patients with PIC. In addition, TCM therapeutic principles such as nourishing the lung-Yin, resolving phlegm, expelling cold, or eliminating heat were also commonly used for PIC.
Most studies implied good safety of CHM. However, some results should be treated with prudence because only three studies [27,33,35] judged the definite relevance between adverse events and corresponding interventions. As a significant complementary and alternative therapeutic method, TCM is traditionally regarded as natural with fewer side effects. Thus, some researchers tend to pay less attention to safety of CHM. But since the toxicological risks of CHM have been observed in many researches [42], more emphasis should be placed on this issue.
In this review, only four studies [26,27,33,35] declared ethical approval and only one study [35] completed clinical trial registration on a publicly accessible database before the trial was set about. Hence, compliance with ethical guideline and trial registration should be addressed in further researches to eventually strengthen the effectiveness and value of scientific evidence.
Although most of the studies in this review authoritatively recommended CHM for PIC, it is impossible to conduct a meaningful meta-analysis to prove the conclusion. Clinical investigators have to consider repeating studies with the same CHM for a powerfully statistical proved conclusion. Decoction, as a complex mixture, is usually prepared artificially. Therefore, the processes of decoction manufacturing and decoction administeration are unlikely to realize quality-andquantity control. Accordingly, the consistency of decoction throughout the whole treatment course is suspected. In addition, if decoction is used as intervention in a research, blinding method is difficult to be implemented for it seems impossible to produce a simulation. Thus, prepared drugs formulated as granules, tables, pills, or capsules are in need to reduce bias in TCM clinical trials.

Conclusion
Findings suggest that CHM may effectively improve core symptoms of PIC, act better and have earlier antitussive effect, and enhance patients' quality of life. CHM is relatively safe and well tolerated without serious side effects. The most common syndrome of patients with PIC is "syndrome of wind evil invading the lung"; correspondingly, "dispelling wind and dispersing the lung-Qi" is the commonest TCM therapeutic principle for PIC. Since some of the studies included in this review were well-designed and comprehensively reported, various limitations still existed. Therefore, confirmative conclusions are not allowed. But current evidence is promising for clinical investigators to do further in-depth researches. Larger-scale, multicentre, placebo-controlled studies for diverse populations are definitely welcomed. Action mechanism of CHM in treatment of PIC, which has been poorly known, needs to be researched to prove the effectiveness and safety of CHM in a more convincing and essential manner.