The Effectiveness and Safety of Heat Sensitive Moxibustion for Anaphylactic Rhinitis: A PRISMA Compliance Systematic Review and Meta- Analysis of Randomized Clinical Trials

Jun Yang Jiangxi University of Traditional Chinese Medicine https://orcid.org/0000-0002-2804-2267 Jun Xiong (  xiongjun196071@163.com ) The A liated Hospital of Jiangxi University of TCM Ting Yuan Jiangxi University of TCM Xue Wang Jiangxi University of TCM Yun Feng Yunfeng The A liated Hospital of Jiangxi University of TCM Xiao hong Zhou The A liated Hospital of Jiangxi University of TCM Liao Kai The A liated Hospital of Jiangxi University of TCM Ling Ling Xu Jiangxia University

Almost one in six rhinitis patients is AR [4], a multicentric trial from 13 allergy centers in Central China had shown that 33.9% of the patients had intermittent moderate-severe AR and 53.3% persistent moderatesevere AR [5]. Those conditions not only brings a huge economic burden to the family of AR but also affects people's physical and mental health [6]. In the USA, direct health-related costs of AR are reported to increase by about 2~5 billion dollars and productivity losses by about 2~4 billion dollars a year [7]. Some studies have suggested that AR may increase the risk of anxiety, hypochondriasis or suicide [8.9].
Loratadine Tablets and inhaled budesonide are recommended for AR, while the long term use of the drug accompanied by the less effective and adverse effects such as nasal dryness and epistaxis [10.11].
Researchers found when patients accepted suspended moxibustion in clinically, they may feel one or more heat sensations (heat penetration, heat expansion, heat transmission, and nonthermal sensations) on their body [12]. Heat sensitive moxibustion (HSM), as a type of suspended moxibustion, refers to practitioners administer moxibustion on heat-sensitive acupuncture points, which are extremely sensitive to the heat stimulation of burning moxa [13].
The spectrum of disease on HSM showed that AR takes up a large proportion of respiratory system diseases [14]. On the basic theory of traditional Chinese medicine (TCM), professor Chen Rixin presents the thought of on "no allergy without any de ciency". HSM is a kind of external therapy for internal disorders, directly acting on the pathogenesis, strengthening the antipathogenic qi and removing the allergic factors [15]. It can increase blood volume, speed the blood ow, and regulate the immunologic function of the patients with AR [16]. Studies have shown that HSM could reduce the serum content of IgE and IL-4 in AR rat, and reduce allergic in ammation of nasal mucosa [17].
Some randomized controlled trials (RCTs) have reported that HSM could relieve uncomfortable symptoms and improve the life quality of AR. Review of the previous systematic review and metaanalysis, they did not provide the information about protocol and registration and without assessing the evidence quality and effect on follow-up [18]. Considering the weakness of the previous, we updated studies from seven databases and applied the scienti c method to provide reliable evidence about the effectiveness and safety of HSM for AR.

Protocol and registration
Our study has been registered on PROSPERO as CRD42019140723; the protocol was available from http://dx.doi.org/10.1097/MD.0000000000018557. This study reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [19].

Information sources and search
We searched through the database of PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), Wanfang, Chinese Science and Technology Periodical Database (VIP) and Chinese Biomedical Literature Database (CBM) from their inception to April 2020. We also manually searched the library of Jiangxi University of traditional Chinese medicine for supplementary. The terms "allergic rhinitis", "perennial allergic rhinitis", "seasonal allergic rhinitis", "allergic rhinoconjunctivitis", "allergic rhinitis", "hay fever", "nasal allergy", "pollenosis", "pollinosis" were searched in combination with each of the following: "Heat sensitive moxibustion", "Thermal moxibustion", "Heat-sensitive Point Moxibustion", "RCT" and "randomized controlled trial". The search was restricted to studies of human participants.
Search strategy can refer to Table 1, taking PubMed as an example.

Types of Studies
We collected RCTs of HSM for AR published in Chinese and English up to April 2020.

Types of Participants
The included participants were diagnosed under clear criteria of AR, patients with asthma, nasosinusitis, vasomotor rhinitis, infectious rhinitis, hormonal rhinitis were excluded.

Types of Interventions and Comparisons
We selected the intervention group that used HSM or HSM combined with other active therapies (e.g. conventional drugs and needling acupuncture), and the control group that chose other therapies (e.g. placebo, needling acupuncture, western drug) or the same active therapies as the intervention.

Types of Outcome Measures
The primary outcome was the total nasal symptom and sign score [20], which was measured after cessation of treatment and on three months follow time. The secondary outcomes include total effective rate (which was assessed by the total nasal symptom and sign score) [21], rhinoconjunctivitis quality of life questionnaire (RQLQ) [22] and adverse events.

Study Selection
All of the retrieved studies were managed by NoteExpress 3.0 to delete the duplicated. According to the inclusion criteria, reviewers selected the eligible through titles and abstracts, then full-text of the potential were assessed further. A researcher (JY) contacted the author to obtain information about the study as for the incomplete of the relevant data. Any divergences were settled by discussion or consulting the third one (YFJ), more than two authors independently conducted the process of study selection.

Data Extraction
Related characteristics of the included about the rst author, publication year, sample, mean age/ age range, intervention, comparison, follow time were independently extracted by two reviewers (XHZ and LLX). The data were recorded by WPS 2019; disagreements were resolved by discussion or consulting with a third review (KL) until the agreement was accordant.

Assessment of risk of bias
We evaluated the methodological quality of the included trials by the Cochrane risk of bias tool [23]. Two reviewers (TY and XW) independently assessed the included studies; disagreements were settled by consulting with a third review (YFJ) during the process.

Statistical Analysis
Statistical analyses were performed by Review Manager (Version 5.3). Risk indices (RRs) with 95% con dence interval (CI) were standardized for dichotomous outcomes; the standard mean difference (SMD) with 95% con dence interval (CI) was used for continuous outcomes. Heterogeneity was assessed by applying a chi-squared test. I 2 was considered to indicate a substantial level of heterogeneity. According to the heterogeneity levels of the included systematic reviews and meta-analyses, the randomeffects model (I 2 ≥ 50%) or xed-effects model (I 2 <50%) was properly selected. Subgroup analysis was conducted to identify and explain the heterogeneity. Funnel plot was used to assess publication bias.

Quality of Evidence
The GRADE approach was used to assess the quality of evidence for the main outcomes [24]. The rating included four levels: high, moderate, low, and very low, according to the quality of the evidence from ve domains (limitations, inconsistency, indirectness, imprecision, and publication bias) [25]. Two reviewers (TY, XW) separately conducted the assessment process; any disagreement was resolved through discussion and consultation with a third author (JX).

Study Selection and Characteristics
We obtained 93 relevant citations from seven electronic databases and manual searches. After 58 duplicate records were removed, we screened the remaining 35 records for eligibility and excluded eight records based on titles and abstracts. Full texts of the remaining 24 citations were retrieved for further assessment, and 12 records were eliminated. Finally, we included 15 RCTs and 1088 patients of AR, which were published from 2008 to 2020. The owchart of literature selection is represented in Figure 1.
We found two studies used HSM with needling acupuncture as the intervention [27.40], and seven studies used the western drug as the comparison [ Table 2.

Risk of Bias Assessments
For the selection bias, 7(46.67%) studies speci cally reported the method of random sequence generation, 4(26.67%) studies explained proper allocation concealment by light-tight envelope [28.29.31.39]. Most articles only mentioned that they "randomly divided the participants", while they failed to provide the details of random sequence generation and allocation concealment. For blinding of participants and personnel, one research adopted moxibustion compared with the intervention [35]. Two RCTs reported blinding of outcome assessment, and the data was managed by intentional analysis [30.32]. There were no studies with selective reporting. The risk of bias of the included was shown in

After 3 months follow time
Six RCTs of 535 participants reported the total effective rate after 3 months follow time [28.33.35-37.39].
The overall meta-analysis demonstrated that HSM alone or combination of HSM with needling acupuncture and were superior in AR after 3 months follow time, and there was no signi cant heterogeneity among the included studies (OR = 5.31, 95%CI (3.66, 7.72); P < 0.00001, I 2 = 0%; Figure 7). The xed-effect model and subgroup meta-analysis was conducted, the result showed that HSM was more effective for AR than the western drug (OR = 5.63, 95%CI

Adverse Effects
There were two studies referred to the adverse effects [35.39]. Xu reported one case of rash which relieved after one week on the HSM group. Zhang reported that there were no adverse effects on his research.

Publication Bias
Funnel plot based on studies on total nasal symptom and sign score and total effective rate was performed to detect the potential publication bias by RevMan5.3.0 software. The results showed that 10 studies were distributed beyond the funnel, illustrating that there may be publication bias in the total nasal symptom and sign score of HSM for AR (Figure 9). Funnel plot of 15 studies about total effective rate manifested that there was no signi cant asymmetry ( Figure 10).

Level of Evidence
The level of evidence for three outcomes (total nasal symptom and sign score, total effective rate and RQLQ) were assessed by GRADE, which was displayed in Table 3. The results showed that the overall quality of the evidence was low, and all the outcomes were biased in allocation concealment or inadequate blinding. The outcomes of the total nasal symptom and sign score and RQLQ were imprecision which was caused by small sample sizes. The outcome of the total nasal symptom and sign score and RQLQ displayed high heterogeneity for course, treatment of the patient or different control groups. The funnel plot of the total nasal symptom and sign score and RQLQ were dissymmetrical.

Summary of Main Findings
Our studies included 15 RCTs of 1088 patients for meta-analysis, the result showed that HSM, which was more effective than the control group. It could relive uncomfortable symptom and improve the life quality of the patients of AR. We found that it also plays a great advantage during the follow-up period. There were two studies mentioned adverse reactions, one case of rash on the treatment, which was relieved after one week. We can not draw a conclusion on the safety of HSM for the insu cient number of researches included.
The quality of the evidence was low; the outcome of the total nasal symptom and sign score and RQLQ displayed high heterogeneity. Although subgroup analysis was conducted to explore the heterogeneity of treatment effects in RCTs, heterogeneity still existed in these comparisons. Variability of duration from six to thirty and different acupoints selected might be the possible source of bias. Majority of the RCTs was limited to low methodology quality; most studies failed to provide the details of random sequence generation and allocation concealment. The lack of blinding may exaggerate the results of the outcome measures. The conclusion of the composite outcome was not very reliable.

Strengths and Limitation
Following is the summary of the present research: (1) Comprehensive search strategies were applied to relative databases to ensure that all RCTs were identi ed; (2) Compared to the previous studies, we provided registration and considered the level of the evidence on our study; (3) Subgroup analysis was performed based on variable comparisons, and we considered the follow-up effect of the HSM, which could ensure the credibility of our results.
There are some limitation in the present study: (1) The low quality of the included studies with a high risk of selection bias and performance bias for without providing the details of random sequence generation and allocation concealment, losing of blinding, so the results should be interpreted with caution. (2) considering the small number of studies reported the side effects; we could not assess the overall side effects of HSM for AR. (3) Due to the treatment mode and the duration of each trial were not equivalent, we could not con rm how long HSM treatment is required to achieve the best effect for AR. (4) The outcome of total nasal symptom and sign score consisted of four symptoms and one sign; we did not record the score of each part separately in our study, so we could not tell the symptom difference of HSM treatment.

Opportunities for Future Research
Through this review, we found that current evidence is of low quality. Thus further research is needed: (1) The primary RCTs should give more attention to allocation concealment and blinding, which could reduce the risk basis of the evidence. (2) Although there were some RCTs research to explore the e cacy of HSM, few studies concentrated on the adverse effects and laboratory examination such as IgE, IgM, IgG and so on. (3) More researches could pay more attention to the speci c symptom improvement (sneezing, rhinorrhea, nasal itching and nasal obstruction) of AR for HSM, to explore the best effect of HSM on symptom improvement.

Conclusion
In conclusion, the results of this meta-analysis suggest that HSM alone or combination of HSM with needling acupuncture is more effective to relieve the symptoms and improve the life quality than the western drug, suspended moxibustion, or needling acupuncture in the treatment of AR. On the period of follow-up, the effect of HSM took more advantages over the control group. The results should be interpreted cautiously for the low quality of the evidence. There is no enough evidence to support that HSM is a safe method for AR; future studies should place more emphasis on the safety of HSM for AR. More efforts are required to improve the study quality of RCTs, and researchers should strictly adhere to the relative methodology and reporting guidelines. Availability of data and materials All data generated or analyzed during this study are included in this published article.

Competing interests
The authors declare that they have no competing interests. [36]. Yang shurong, Chen huan, "Clinical observation of 68 cases of perennial rhinitis treated by "heat sensitive point" moxibustion," Research on ent of traditional Chinese medicine, 2008.