Acute upper respiratory tract infections (AURTIs) are the illnesses caused by an acute infection with various viruses and bacteria involving the upper respiratory tract. Shuanghuanglian (SHL) injection, a Chinese medicine intravenous preparation extracted from honeysuckle, Scutellaria baicalensis, and fructus forsythiae, is commonly used to treat AURTIs. Although it is used largely in Chinese hospitals, there is no substantial evidence to demonstrate its clinical effect on AURTIs. We conducted a systematic review to evaluate the effectiveness and safety of Shuanghuanglian injection for the treatment of acute upper respiratory tract infections.
Acute upper respiratory tract infections (AURTIs) are the illnesses caused by an acute infection with various viruses and bacteria involving the upper respiratory tract. They include the common cold, laryngitis, pharyngitis/tonsillitis, acute rhinitis, acute rhinosinusitis, and acute otitis media, which are the commonest acute problem dealt with in primary care [1, 2]. Symptoms of AURTIs commonly include cough, sore throat, runny nose, nasal congestion, headache, low grade fever, facial pressure, and sneezing. Although the available evidence has shown that antibiotics probably provide little benefit for a large proportion of respiratory tract infections, antibiotics are still largely inappropriately used in clinic [3–5]. Antibiotic treatment to prevent suppurative and nonsuppurative complications may be inappropriate nowadays with generally low rates of major complications . More effective approaches to control infections and relieve symptoms in AURTIs are in a great need.
Shuanghuanglian (SHL) injection, a Chinese medicine intravenous preparation extracted from honeysuckle, Scutellaria baicalensis, and fructus forsythiae , is commonly used to treat various kinds of infectius diseases caused by bacterium or viruses in respiratory traction . The main chemical components of SHL injection are chlorogenic acid, baicalin, and forsythia glycosides , which have been found to have the ability of anti-inflammation, improving immunity, and inhibiting the growth of various viruses [9–11]. It has been reported that SHL injection could inhibit the respiratory syncytial viruse, parainfluenza I–IV , and 23 kinds of pathogenic bacteria such as Staphylococcus aureus  and Pseudomonas aeruginosa . SHLI can also enhance the NK cell activity, promote the production of alpha-interferon, raise the rate of lymphocyte transformation , and decrease the level of CD4+ cells and the ratio of CD4+/CD8+ while increasing CD8+ .
SHL injection has been approved for treatment of acute respiratory tract infection since 1973 in China . Although it is used largely in Chinese hospitals, there is no substantial evidence to demonstrate its clinical effect on AURTIs. We conducted a systematic review to evaluate the effectiveness and safety of Shuanghuanglian injection for the treatment of acute upper respiratory tract infection.
2.1. Inclusion Criteria
We included randomized controlled trials evaluating SHL injection for the treatment of AURTIs without language or publication status restriction. Any patients with AURTIs, including common cold, laryngitis, pharyngitis/tonsillitis, acute rhinitis, acute rhinosinusitis, and acute otitis media, without limitation on gender and age were included in the review. We defined the interventions as Shuanghuanglian injection in the form of liquid or power in the intravenous route of administration. The control group may have a placebo, nontreatment, or conventional treatment. Cointerventions such as supportive or symptomatic treatment were allowed as long as all arms of the randomized trial received the same cointervention(s). We excluded studies on other administration routes of Shuanghuanglian, comparing SHL injection with other Chinese herbal medicine, or SHL injection combined with other antibiotics or antivirus medication.
For trials to be eligible for this review, their results need to be extracted on at least one of the following primary outcomes: (1) severity of symptoms; (2) time to resolution of some common acute URTI-related symptoms (e.g., fever, cough, nasal discharge, cough, congestion, sneezing, and headache) and (3) one of the secondary outcomes: resolution of fever in five days, time off from school or work, antibiotic use, and adverse events associated with treatment.
2.2. Databases and Search Strategies
We searched the following electronic databases: Medline (1950 to 2012), Embase (1980 to 2012), the Cochrane Central Register of Controlled Trials (Issue 10, 2012), AMED (Allied and Complementary Medicine Database; 1985 to 2012), CMCC (Chinese Medical Current Contents, 1994 to 2012), China National Knowledge Infrastructure (CNKI) (1979 to 2012), VIP Database for Chinese Technical Periodicals (VIP) (1989 to 2012), and Wanfang Med Database (1994 to 2012). We employed highly sensitive strategies in which adapted subject headings and text words were developed around Shuanghuanglian and upper respiratory infection. Within these text words they were combined with “or,” and then the two kinds of searching terms were combined with “and.” For Chinese databases searching, additional limit on the study type of randomized controlled trial was added. Reference lists of included studies and significant reviews were also checked.
2.3. Data Extraction and Quality Assessment
Two authors (W. Zhou and S. Gao) independently screened the titles and abstracts of the search results to identify potential relevant studies. If necessary, their full texts were obtained for further evaluation on inclusion criteria. These two authors independently used self-developed data extraction form to extract data regarding study methods, participants, interventions, outcomes, and results. Any discrepancies were resolved by discussion between the two reviewers.
To assess the study quality, we used risk of bias assessment tool recommended by the Cochrane Collaboration to address the following six domains: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and “other issues” . The baseline comparability was considered in the “other issues.” The risk of bias for each outcome within and across the included studies was summarized into three levels: low, unclear, and high risk of bias. We used GRADE system to further assess the quality of the evidence for each individual outcome across included studies. Besides within-study risk of bias (methodological quality), the GRADE approach incorporates considerations of directness of evidence, inconsistency or heterogeneity, precision of effect estimates, and risk of publication bias [18, 19].
2.4. Data Analysis and Synthesis
We used risk ratio (RR) with 95% confidence intervals (CI) to summarize dichotomous outcome data of individual studies and used Mantel-Haenszel random-effects model to pool the results across all included studies. We used the mean difference (MD) to summarize continuous outcome data at the end of treatment or followup within studies and used the inverse-variance random-effects model to pool the results across studies. For meta-analysis, we used random-effects model because of the expected heterogeneity of the interventions. We examined forest plot visually first to detect heterogeneity and then used chi-squared test with an alpha of 0.1 for statistical significance and