Background
Influenza is a common viral infection worldwide, occurring in seasonal epidemics. According to the World Health Organization (WHO), 5–15% of the population is affected by annual epidemics of influenza infection in the upper respiratory tract [
1], and 290,000–650,000 people die from influenza-related diseases annually [
2].
Three types of antiviral drugs have been approved by the Japanese national health insurance system for the symptomatic treatment of influenza infection, namely neuraminidase inhibitors (NAIs), adamantanes, and cap-dependent endonuclease inhibitors. Four NAIs—oral oseltamivir, inhaled zanamivir, inhaled laninamivir, and intravenous peramivir—are available and widely prescribed in Japan because they act against both types of the influenza virus, A and B. In contrast, amantadine and rimantadine (known as adamantanes) are less widely prescribed because they only act against the influenza A virus, which shows marked resistance to adamantanes [
3]. Baloxavir marboxil is a newly approved cap-dependent endonuclease inhibitor, and as such, little is known about its post-marketing safety. The resistance of influenza to baloxavir marboxil has been reported in 2.2 and 9.7% of the phase 2 and 3 clinical trials, respectively [
4].
A recent systematic review of oseltamivir revealed that it can shorten the duration of symptoms by 16.8 h in adults but does not reduce hospital admissions due to complications from influenza. The review also pointed out that the drug conferred an increased risk of nausea and vomiting in adults [
5]. The WHO has recommended that patients in low-risk groups should be managed with symptomatic treatments and advised to stay home to avoid spreading the infection. However, patients at high risk of developing severe or complicated illness should be administered antiviral agents [
1]. Currently, few influenza strains are resistant to NAIs [
6], but antiviral resistance may increase if the widespread use of NAIs is continued, as was observed for oseltamivir-resistant seasonal H1N1 influenza A viruses between 2007 and 2009 [
3].
Recently, the efficacies of several traditional Chinese medicine formulas as symptomatic treatments for influenza have been evaluated. For instance, a systematic review of the Cochrane library reported that
Ganmao capsules were more effective than amantadine at shortening the duration of influenza symptoms [
7]. A randomised controlled trial (RCT) showed that
maxingshigan-yinqiaosan, alone or in combination with oseltamivir, reduced the duration of fever in patients infected with the 2009 H1N1 influenza virus [
8].
Maoto (Ma-Huang-Tang in Chinese) has been widely prescribed as a symptomatic treatment for the common cold and flu according to claims in the Japanese national health insurance system. It can be prescribed to both children and adults. Traditionally, the symptoms that indicate maoto are headache, chill, fever, arthralgia, and cough, without sweating. Maoto can also be applied for rheumatoid arthritis, bronchial asthma, infant nasal obstruction, and difficulties in sucking milk.
Maoto is a multicomponent formulation, originally extracted from four crude drugs, as follows: 5 g of ephedra herb, 5 g of apricot kernel, 4 g of cinnamon bark, and 1.5 g of glycyrrhiza root. It is currently prepared for prescription use in Japan as granules (7.5 g daily, produced by Tsumura & Co., Teikoku Pharma, and Honzo Co.; no official paediatric dosage available) or powder (6.0 g daily, produced by Kracie Pharma and Kotaro Pharm. Co.; no official paediatric dosage available) through the process of decoction, concentration, drying, and the addition of an excipient. The maoto preparation is orally administered, usually after dissolution in warm water.
Some studies have demonstrated that
maoto and its component ingredients are active. For instance, ephedra herb and its tannins inhibit endosome acidification and influenza A virus fusion to the cell membrane [
9,
10]. Glycyrrhizin, an active component of glycyrrhiza, reduces the number of cells infected with influenza A and inhibits virus uptake through the cell membrane during the early phase of infection [
11]. Cinnamaldehyde, which is derived from cinnamon bark, inhibits protein synthesis by the influenza A virus at the post-transcriptional level. In one study carried out in mice, inhalation and nasal inoculation of cinnamaldehyde increased the survival rate after virus infection [
12]. Masui et al. [
10] reported that
maoto acts against influenza A in vitro, while laninamivir and amantadine do not. In addition, using multiple subtypes of the influenza virus (A/PR8, A/H3N2, A/H1N1pdm, and B), the authors found that
maoto reduced the intracellular virus titre, as well as the levels of matrix protein 2 and nucleoprotein present in the experimental system. Nagai et al. [
13] showed that
maoto (0.8 g/kg/day and 1.3 g/kg/day) had an antipyretic effect in the early phase of influenza A infection in mice and that the levels of anti-influenza immunoglobulin M, immunoglobulin A, and immunoglobulin G1 antibodies increased in nasal fluid, bronchoalveolar lavage, and serum. Thus,
maoto, as a multicomponent formulation, has multiple effects on the life cycle of the influenza virus and broad influence on host metabolism [
14].
Maoto is a prescription drug that has been covered by the Japanese national health insurance system for over 40 years. The cost of
maoto is much less than that of NAIs. Specifically, the officially set drug cost of
maoto is 150 JPY (1.4 USD) per person, whereas the standard prescription of oseltamivir and acetaminophen costs 3260 JPY (29.6 USD). We previously calculated that, if half a prescription of oseltamivir was replaced with
maoto, the annual saving in medical costs in Japan would be 9 billion yen (82 million USD) [
15]. Nowadays,
maoto is also available in the pharmacy as an over-the-counter drug, although its concentration is half that of the prescribed medication.
The efficacy and safety of maoto in alleviating flu symptoms have been evaluated in clinical studies. These studies compared maoto with NAIs, or maoto plus NAIs with NAIs alone. However, the results have been inconsistent, and no meta-analysis has yet analysed the efficacy and safety of maoto in alleviating flu symptoms.
Thus, the objective of this review and meta-analysis was to evaluate the efficacy and safety of maoto in alleviating flu symptoms.
Methods
Criteria for inclusion in the present review
We included both RCTs and comparative non-randomised studies (NRSs) of prescription
maoto extract. The NRSs included quasi-RCTs, non-RCTs, prospective or retrospective cohort studies, historically controlled trials, and (nested) case-control studies [
16].
We included studies that enrolled patients who had uncomplicated influenza diagnosed using a rapid antigen detection test (RADT) and/or genetic detection with polymerase chain reaction. Studies were included regardless of the patients’ age.
We included studies assessing the efficacy of maoto. The possible comparisons were as follows: (1) maoto vs. placebo, (2) combination of maoto plus NAIs vs. NAIs alone, and (3) maoto vs. NAIs. Co-interventions were allowed if they were offered to both arms of the study. We excluded studies that included other herbal formulas.
The primary outcome measure (efficacy) was the length of time from the start of medication to resolution of influenza symptoms (fever, headache, malaise, myalgia, and chills) and virus isolation.
The secondary outcome measures (safety) were as follows: (1) side effects and adverse reactions, such as nausea, abnormal behaviour, or discontinuation of symptomatic treatment; (2) morbidity (complications caused by influenza infection) or mortality; and (3) hospitalisation for any reason.
Search methods for identification of studies
We searched the following databases for studies published in or before October 2017: MEDLINE/PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, a Japanese database (
Ichushi), two Chinese databases (China National Knowledge Infrastructure [CNKI] and VIP), and two Korean databases (Korean Medical database [KMbase] and Korean Association of Medical Journal Editors [KAMJE]). In this search, we used the key words ‘maoto/mao-to/ma-huang-tang’, and ‘flu/influenza’. Our search strategies are supplied in Additional file
1: Search Strategies and Results. We did not use any publication or language restrictions. All reference lists were checked to identify additional studies.
Data collection and analysis
The first two authors (TY and RA) scanned the titles, abstracts, and keywords of every record retrieved. We located the full articles for further assessment when the information given suggested that the study (1) included patients with uncomplicated influenza and (2) assessed the efficacy of maoto using one or more relevant clinical outcome measures.
Two authors (TY and RA) independently extracted, checked, and made a review table of the articles. The extracted data comprised the (1) authors and title of the study, (2) year of publication, (3) study size, (4) age and sex of participants, (5) detailed methodological information, (6) dose and duration of the intervention, (7) details of control interventions, (8) outcomes, and (9) side effects or adverse reactions. TY entered these data into the Review Manager software.
We assessed the reporting quality of each study, basing the assessment largely on the quality criteria specified by the Cochrane Handbook for Systematic Reviews of Interventions [
16] for RCTs and the Risk of Bias in Non-randomized Studies of Interventions [
17] for NRSs. The authors resolved any differences of opinion by discussion. Funnel plots were inspected visually to assess the possibility of publication bias.
We performed a quantitative meta-analysis when data for a given outcome were available in more than two of the included studies, regardless of the daily dosage or duration of maoto. To evaluate symptom duration, we ignored differences in the definition of symptom, as well as differences in the viral type (A or B) or surface antigen (e.g. H1N1 or H3N2). The unit of analysis was the individual participants. We tried to obtain any relevant missing data from the study authors by e-mail or telephone.
We examined heterogeneity through visual inspections of forest plots, a standard χ2 test with a significance level of α = 0.1, and the I2 statistic (an I2 statistic ≥75% indicated considerable heterogeneity). This analysis quantified inconsistency across studies and allowed us to assess the effects of study heterogeneity on the meta-analysis. To combine studies, we used the fixed-effects model when the studies in a given subgroup were significantly similar (P > 0.10; I2 statistic < 75%). We included RCTs and NRSs in this meta-analysis, and RCTs and NRSs were always analysed separately. The overall effect was tested using the Z score, with P < 0.05 being considered statistically significant.
When heterogeneity was suggested by the χ2 test and I2 statistic, we used a random-effects model to analyse whether heterogeneity may have led to the different effects among studies. In this model, data should be continuous, thus we used the weighted mean difference and 95% confidence intervals to analyse data that had been measured using the same scale, and then combined the weighted mean differences (e.g. duration of fever). We attempted to determine the potential causes of heterogeneity by examining the individual study and subgroup characteristics.
Discussion
Although we could not reach a definitive conclusion because the included studies had a high risk of bias, the findings of this meta-analysis suggest that maoto may shorten the duration of fever when used alone or in combination with NAIs and that maoto may be a well-tolerated approach for alleviating flu symptoms. However, it should be noted that the quality of evidence for this conclusion was low. In the future, better-designed trials will be required to elucidate the efficacy of maoto.
We rated the quality of the evidence from the included studies as very low to low for a variety of reasons. First, only two RCTs were included, and the participants in the RCTs were assigned to each arm using open allocation. Second, we could not obtain enough information regarding the participants’ demographic backgrounds, including possible confounders such as vaccination history. Third, no blinded studies were identified via the database search conducted in the present review, although it would be difficult to perform a double-blinded study of
maoto because it has a strong odour and taste [
7]. Indeed, it would be difficult to design a perfect placebo for clinical trials, because the evaporating chemicals generate a characteristic odour, and this odour might affect the outcome [
31]. Finally, none of the studies we employed in our analysis included a sample size calculation. Rather, the number of participants seemed to be based on the number of patients in the study season. Thus, we cannot exclude the possibility that β error occurred in the comparison between
maoto and NAIs, where no significant difference was found according to the present analysis. To fully understand whether
maoto is as effective as NAIs, an ‘equal efficacy’ or ‘non-inferiority’ study should be performed. It is worth performing such studies because
maoto is much less expensive than are NAIs (approximately 20-fold in Japan) [
15].
In the present study, we did not note any severe side effects or adverse reactions. Usually,
maoto is consumed for several days, and we believe that the safety of this drug is high. However, it does contain ephedra, and clinicians should be cautious when prescribing it to patients who have thyroid, cardiovascular, or prostate dysfunction, or to elderly patients [
32]. We acknowledge, however, that it may have been difficult for the researchers to collect comprehensive information regarding adverse events or complications, especially after the intervention period, because all of the studies we evaluated were performed in an outpatient setting. For example, the incidence of secondary bacterial pneumonia is common after the temporary resolution of influenza symptoms [
33].
In future studies,
maoto should ideally be used according to the traditional diagnosis of influenza, as mentioned in the introduction, and the inclusion or exclusion criteria should contain traditional concepts or diagnoses. However, what constitutes a traditional diagnosis may differ among researchers and clinicians, and it is difficult to utilise strictly defined criteria in clinical trials. In our previous study, none of the symptoms, such as chill and absence of sweating, were themselves obligate indicators for
maoto in the alleviation of influenza symptoms, suggesting that
maoto can be used to treat probable influenza infection regardless of whether traditional concepts or diagnoses are used [
34].
Our search did not reveal any other reviews on
maoto. However, the Cochrane collaboration did perform a systematic review of studies using traditional Chinese medicines, reporting that traditional Chinese medicines have clinical efficacy in alleviating influenza infection symptoms, similar to NAIs [
7]. The systematic review by the Cochrane collaboration did not ultimately include one RCT by Kubo et al. [
20] that was included in this review, because the intervention used in that RCT was
maoto, a Japanese traditional medicine, not a traditional Chinese medicine.