key: cord-0772273-8hd4f5xi
authors: Jeon, Sae-Rom; Kang, Jung Won; Ang, Lin; Lee, Hye Won; Lee, Myeong Soo; Kim, Tae-Hun
title: Complementary and alternative medicine (CAM) interventions for COVID-19: An overview of systematic reviews
date: 2022-03-13
journal: Integr Med Res
DOI: 10.1016/j.imr.2022.100842
sha: 0a577b82fd44c36d976132ea70bd99097950d53a
doc_id: 772273
cord_uid: 8hd4f5xi

BACKGROUND: Since the beginning of the Coronavirus disease 2019 (COVID-19) pandemic, various complementary and alternative medicines (CAMs) have been used in clinical practice. In this overview, we summarized the evidence for CAM interventions in the treatment of COVID-19 patients. METHODS: For this overview, PubMed, Embase and Cochrane Library were searched from inception to October 2021. Systematic reviews (SRs) on the effectiveness and safety of CAM interventions for COVID-19 patients were located, and the MeaSurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) was used to evaluate the reporting quality of the included SRs. Keywords including COVID-19 and CAM interventions were used for locating SRs. For evidence mapping, we created a two-dimensional bubble plot that included the width and strength of the evidence for each CAM intervention and specific outcome. RESULTS: In this overview, we identified 24 SRs (21 for traditional Chinese Medicine (TCM) medications, two for vitamin D and one for home-based activity). From the included SRs, TCM herbal medications were reported to show good results in decreasing the rate of disease progression (relative risk (RR) 0.30, 95% confidence intervals (CI) [0.20, 0.44]), time to the resolution of fever (standard mean difference (SMD) -0.98, 95% CI [-1.78, -0.17]) and rate of progression to severe COVID-19 cases (RR 0.34, 95% CI [0.18, 0.65]), but the evidence for other interventions did not show effectiveness with certainty. Gastric disturbance was a major adverse event of TCM medications. CONCLUSION: There is evidence that TCM medications are effective in the symptom management of COVID-19 patients. However, evidence for the effectiveness of most CAM interventions still needs evaluation.

Since the first patient was diagnosed in November 2019 with Coronavirus disease 2019 , the disease has spread worldwide, and the pandemic has still continued till 2022. Due to active implementation of newly developed vaccines and the establishment of acute treatment strategies globally, confusion at the beginning of the outbreak has settled, but prediction about how long this situation will go on seems unclear. 1 As the pandemic continues, in addition to the strategies that have focused only on the prevention of COVID infection and management of acute symptoms, there is a growing interest in long-term symptom management. In the case of underdeveloped countries, there is a possibility that internationally accepted treatment strategies may not be fully used due to insufficient medical resources. For these reasons, complementary and alternative medicine (CAM) interventions are being employed as alternative interventions for COVID-19 according to the medical situation of each country. 2 However, with these increases in CAM use, it is important to consider the clinical evidence of these interventions. In the midst of the flood of information about the pandemic and viable remedies, it is necessary to find appropriate CAM treatments for COVID-19 patients based on the current best evidence. CAM treatments cannot be incorporated into an appropriate strategy to combat COVID-19 when the CAM interventions are influenced by false beliefs or cultural habits. 3 Clinical trials involving COVID-19 patients have been planned and conducted actively, and a significant accumulation of information on the effectiveness and safety of CAM interventions has been achieved in a fairly short period of time. 4, 5 To establish the clinical evidence for individual CAM interventions is an important step; however, it is now time to summarize the evidence from different sources, to evaluate the level and quality of the evidence and to identify where a lack of evidence exists. The purpose of this study is to create an evidence map which includes information for the CAM interventions according to what those interventions have strong evidence and those that need further testing.

This study is an overview of SRs for assessing the current research status of CAM interventions for COVID-19 patients. In this overview, we summarize published systematic reviews (SRs) of CAM interventions, and suggest an evidence map. We searched published SRs and included studies for analysis based on the following selection criteria. The study population included patients with acute COVID-19 infection and long COVID symptoms. Long COVID-19 was defined as a variety of symptoms that continued after the clearance of acute COVID-19 infection, such as fatigue, cognitive impairment, dyspnea, cardiac problems, sleep disturbances, pain and posttraumatic stress disorder. 6 There is no confirmed definition but patients with recovered clinical symptoms, or no symptoms were diagnosed as clearance of acute COVID-19 infection when two consecutive reverse transcriptase polymerase chain reaction (RT-PCR) tests in a 24-hour interval for respiratory specimens were all negative.

Regarding interventions, we included any type of CAM intervention following the definitions provided by the United States National Institutes of Health. 7 Nutritional, psychological, physical, combinations of psychological and physical, combinations of psychological and nutritional and manipulative or traditional medicine interventions were included.

Combination therapy with conventional formal treatment for acute COVID-19 and long COVID were allowed if CAM interventions were offered to patients.

Outcomes were not limited. As the research purpose of this overview was to evaluate the current research on CAM interventions for COVID-19, we did not impose any restrictions on the outcomes in the included reviews. Clinical results and laboratory tests could be included.

Studies that offered comparisons of interventions were not limited in any way. Conventional treatment for COVID-19 or no treatment could be included in this review.

Regarding our study design, we only included SRs that assessed the clinical evidence of CAM interventions for COVID-19 patients.

PubMed, Embase and Cochrane Library were searched from inception to October 2021. Two authors (S-RJ and T-HK) conducted selection of the studies independently, and discussed the results until an agreement was reached. After selection of the studies, data extraction was conducted by two authors (S-RJ and T-HK) independently with a predefined extraction form, and disagreement was solved through discussion. Data including intervention types, review objectives, population, number of included studies, summary effect estimates and overall risk of bias were extracted from the original SRs. Search strategies were modified according to the specific features of the electronic databases (Supplementary file 1).

To assess the reporting quality of the included SRs, the MeaSurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) checklist was used for each included study. Sixteen items of the AMSRAR 2 checklist were assessed for each SR, and overall quality was also suggested, which we used as an item for evaluating the overall confidence of the included SRs. Overall quality was graded as "High" when no or noncritical weakness was present in all items, "Moderate" when one more noncritical weakness was present in the items, "Low" when one critical limitation was identified or "Critically low" when more than one critical limitation was observed. AMSTAR 2 was assessed by two authors (T-HK and S-RJ) and discussed if there was any disagreement. An arbiter (JWK) decided if the disagreement was not resolved. 8

A bubble plot, which included information about the effectiveness of interventions and the confidence level of the included SRs, was drawn based on Hempel et al.'s methodology. 9 In the bubble plot, each intervention had two-dimensional information, including the x-axis (overall risk of bias), y-axis (the number of included original studies in each SR) and bubble size (overall confidence level of the included SR assessed by AMSTAR 2 checklist). When an intervention had more than two SRs, we selected only one SR for the intervention, which was rated as the highest quality considering the number of included studies. The x-axis for each intervention was decided with the summary effect estimates with overall risk of bias in the selected SR, and it had three categories with "Effective" if statistically significant positive effect estimates with low overall risk of bias: "Potentially effective" if statistically significant positive with high risk of bias (or unclear risk of bias) or "Unidentified" if no significant positive effect with high risk of bias (or unclear risk of bias). The y-axis shows the number of included randomized controlled trials (RCTs) in the SR. The size of the bubble represents the confidence level for the evidence, which was decided with AMSTAR 2 assessment, and a larger circle suggests higher confidence. R software (ver 4.0.2) and the 'ggplot2' package were used for the evidence map.

For this study, a total of 24 SRs were included through the database search ( Figure 1 ). Among the included SRs, TCM medications were evaluated in 21 studies, 10-30 home-based activity (n=1) 31 and vitamin D (n=2) 32, 33 were assessed. Various types of TCM medications were included in most of the SRs, and LinghuaQingwen granules or capsules were tested in four SRs (Table 1) . 13 

The overall clinical effectiveness of TCM treatments in relative risk (RR) ranged from 1. 15 30 Most studies reported any types of AEs related to the usage of TCM herbal medication. However, six studies reported no information of AEs. 15, 22, [27] [28] 30 The reported main AEs of TCM medications were gastrointestinal reactions such as abdominal distention, abdominal pain, nausea, vomiting, diarrhea, belching, acid reflux or loss of appetite. In one study, overall RR of total adverse drug events was suggested to be RR = 1.13, 95% CI (0.45, 2.83), which represented that there was no significant difference in the overall risk of AEs between groups. 11 In addition, there was no significantly different risk for specific types of AEs between the TCM medication group and the control group. About the assessment of causality and severity of AEs, there was no information in the included SRs (Table 2 ).

Home-based activities, including exercise, yoga and muscle relaxation techniques, were reported to show improvement in mental wellness. 31 However, vitamin D supplements did not result in the improvement of major health outcomes in COVID-19 patients (RR of mortality 0.55, 95% CI [0.22, 1.39]). 33 However, there were no descriptions of AEs in the SRs for home-based activity 31 and vitamin D (Table 2 ). 32, 33

From this overview of SRs, we assessed the evidence status of CAM interventions for COVID-19 patients through evidence mapping methods. TCM medications seem to be effective in improving disease progression, reducing fever resolution time and reducing the rate of progression to severe cases, which was supported by evidence based on comparatively large numbers of RCTs. However, TCM medications did not seem to be related to the improvement of GI symptoms in COVID patients, as vitamin D was not effective in improving mortality. From the evidence map, there are still unclear areas of evidence for TCM medication, herbal medications and physical exercise in terms of symptom clearance time, overall clinical effectiveness, improvement in lung CT and mental wellness, which remain areas for future rigorous RCTs ( Figure 2 ).

From this study, we found that studies on TCM medications have been suggested actively for COVID-19 patients. Some medications appeared to be effective and safe for managing COVID-19 symptoms and disease progression, while others should be tested in future RCTs.

Some CAM interventions seem to stray far from the established evidence. Vitamin D supplements did not seem to improve major health outcomes in COVID-19 patients, although there were some controversial results on the causal relationship between low serum levels of vitamin D and severity (or mortality) induced by COVID-19 infection. 32, [34] [35] [36] Although the evidence for safety cannot be guaranteed due to the limitation of reporting in SRs, administration of TCM medications does not seem to increase the incidence of AEs in COVID-19 patients, other than digestive discomfort.

Evidence mapping is a novel methodology for synthesizing research evidence that identifies the quantity and quality of established evidence in specific areas and can present gaps between current research and needs for future research. 37 Although it has limitations due to the absence of a standardized methodology and the disadvantage of being unable to provide accurate and complete quantification, evidence mapping is an effective tool for integrating studies in a wide range of areas and presenting an overall picture of what evidence has accumulated. 37, 38 During the COVID-19 pandemic, various CAM interventions, including TCM, yoga, Ayurveda, homeopathy and dietary supplements, have been prescribed for COVID-19 patients and the general population with considerable usage prevalence. [39] [40] [41] [42] However, from this overview study, we found that most of these interventions need appropriate evidence regarding their clinical effectiveness and safety. Some countries published recommended guidelines on the usage of CAM interventions, 43, 44 and some underdeveloped countries adopted CAM interventions for the management of the COVID-19

pandemic. If CAM interventions are to be used appropriately in response to the COVID-19 pandemic and contribute to improving the health situation of each country, evidence for the effectiveness and safety of these interventions that are assumed to be effective or are already effective in clinical practice should be presented to support the medical decision process.

This study has limitations. Due to the absence of standardized methodology for evidence mapping, there could be ambiguities in the process of analysis or research data and interpretation of the results. We did not analyze detailed interventions for each type of CAM therapy, and heterogeneity should be critical in the synthesized results. We only included SRs, and some CAM interventions had RCTs assessing the effectiveness and safety of interventions that were not evaluated in SRs. All these limitations urge the readers to interpret these study results carefully. Future updated overviews and mapping of evidence will be requisite. In addition to this, there should be new RCTs on the effectiveness and safety of CAM interventions for long COVID, which is expected more frequently.

In conclusion, there is evidence that TCM medications reduce the fever resolution time and the rate of progression to severe cases. However, evidence of the effectiveness of most CAM interventions still needs to be evaluated. Clinical evidence of various CAM interventions for acute COVID 19 infection and long COVID needs to be evaluated through rigorous RCTs in future. In the bubble plot, each intervention had two-dimensional information including x-axis (overall risk of bias), y-axis (the number of included original studies in each systematic review (SR)) and bubble size (overall confidence level of the included SR assessed by AMSTAR 2 checklist). Bigger size represents more confidence of the assessed SR. The name of each bubble includes the name of intervention-symptom (or condition) of interests. *Overall confidence of the systematic review was assessed using AMSTAR 2 tool. **Overall risk of bias was quoted from the systematic review. *** The improvement of lung CT was decided based on change of the degree of lung filtration in the lung CT between before and after treatment. According to the included SR, basic absorption (decreased lesion in over 70% of lung field), improvement (over 30%), no change, and aggravation 11 . **** Flu-like symptoms were defined to be common symptoms of flu including cough, fever, sore throat, gastrointestinal symptoms (nausea, loss of appetite, diarrhea), bodily pain and fatigue according to the included SR 20 

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