key: cord-0827049-2i80gydr authors: Barnes, Larisa AJ; Leach, Matthew; Anheyer, Dennis; Brown, Danielle; Carè, Jenny; Lauche, Romy; N Medina, Daen; Pinder, Tobey-Ann; Bugarcic, Andrea; Steel, Amie title: The effects of Hedera helix on viral respiratory infections in humans: A rapid review date: 2020-08-13 journal: Adv Integr Med DOI: 10.1016/j.aimed.2020.07.012 sha: 40ef3f8c90341e20ae64e8dc142d85abf64b5fe7 doc_id: 827049 cord_uid: 2i80gydr nan treatment or prevention of COVID-19. However, the current evidence justifies further research to better understand its applicability in coronavirus infections. #EvidenceCOVID Verdict Current evidence suggests H. helix may improve the frequency and intensity of cough associated with viral respiratory infection. The overall applicability of additional findings is limited by the poorly defined outcome measures employed. However, studies focused explicitly on expectoration did report an increased conversion from dry to productive cough, and an improvement in expectoration amount, consistency and colour. These effects may be explained by a related finding of reduced oropharyngeal congestion and improved inflammatory markers (erythrocyte sedimentation rate and c-reactive protein). A decrease in frequency of night cough and respiratory pain was also reported, as was improved sleep quality and reduced cough-related sleep disturbance. Some studies also measured general respiratory tract infection symptoms and identified clinical improvement or resolution of fever, fatigue, sore throat, sneezing, wheezing, nasal congestion, postnasal drip and body-ache. A reduced need for antibiotic prescriptions was also identified. While not respiratory infections, were included. Studies that focused on monotherapy using H. helix products, as well as studies where H. helix was used in conjunction with other herbal or pharmaceutical medications were included. Populations with chronic respiratory conditions were included where their condition explicitly started as an acute viral respiratory infection. There were no language exclusions. The searches were date limited after scoping searches on systematic reviews investigating the role of H. helix in the treatment of respiratory viral infections was performed. A systematic review of clinical trials investigating H. helix in acute upper respiratory tract infections was published in 2011 [2] . Therefore, studies investigating the use of H. helix in acute respiratory viral infections were limited to trials from 2010-2020. A systematic review investigating the use of H. helix in chronic bronchial asthma was published in 2003 [5] . Therefore, studies looking at the use of H. helix in chronic respiratory conditions were limited to trials from 2002-2020. In vitro trials, in vivo animal studies, and studies that investigated bacterial or fungal based respiratory diseases were excluded. Studies were also excluded where the population presented with a chronic respiratory condition that was not explicitly described as originating from an acute respiratory infection (e.g. chronic asthma, COPD [Chronic Obstructive Pulmonary Disease]). Medline (Ovid); EMBASE (Ovid); AMED (Ovid); CINAHL (EBSCO); Web of Science; Scopus Search strategy for papers investigating Hedera helix and acute viral respiratory disease: The thirteen included studies comprised a total pool of 210,481 participants, with sample sizes ranging between 36 and 173,226. Five studies recruited children only (with ages ranging between one month and 18 years [3, 6, 7, 20, 24] , three studies recruited adults only (aged ≥18 years) [22, 23, 26] , and four studies recruited both adults and children (aged ≥2 years) [4, 9, 13, 21] ; one study [25] did not describe the sample. Conditions under investigation varied from bronchitis (n=3) [3, 4, 9] , to non-specific respiratory tract infection symptoms (i.e. cough n=2) [21, 22] , respiratory tract infection (n=4) [7, 13, 24, 26] , non-specific inflammatory airway disease (n=2) [6, 23] and bronchial obstruction-syndrome (n=1) [20] ; one study [25] did not describe the presenting condition. One study included both acute bronchitis and chronic bronchitis, as well as other chronic respiratory diseases with intense formation of viscous mucous [23] . Hedera helix was administered in oral form in all thirteen studies, with seven studies [3, 4, 6, 7, 9, 20, 22 ] using a single-herbal formulation and six studies [13, 21, 23 -26] using a multi-herbal formulation. The intervention was administered most frequently in syrup form (n=4) [4, 7, 21, 24] , followed by tablet (n=1) [25] , ethanolic extract (n=1) [22] , drop [9] and granulated [13] forms. Four studies [3, 6, 20 , 26] used multiple forms of administration (i.e. syrup, drops, liquid, effervescent tablet, lozenges, powder, inhalant), and one study [23] did not describe the product form. Treatment duration ranged from 7 days to 20 days, with a median duration of 8.5 days. Dosage of H. helix was difficult to quantify in most studies due to inadequate or incomplete reporting of product composition. Of the eight studies reporting a control/comparator, three used a placebo control [13, 21, 22] , two used an active control [4, 9] , one used standard treatment [24] , and one used case controls [26] ; in one study [25] , the type of control/comparator was not described. Prospective Intervention Studies (n=8) For Domain 1 (randomisation process), two studies were rated as having a high risk of bias [24, 25] , one was rated as having some concerns [23] and the remaining four studies were rated as low [9, 13, 21, 22] . For Domain 2 (treatment assignment), one trial was identified as high risk of bias [24] , two trials were rated as having some concerns [23, 25] , and four trials rated as low risk of bias [9, 13, 21, 22 ]. Under Domain 3 (missing outcome data), one trial was considered to have high risk of bias [24] , with six trials rated as low [9, 13, [21] [22] [23] 25] . For Domain 4 (measure of outcomes), one study was rated as high risk [25] , one was rated as having some concerns [24] , and five were rated as low risk of bias [9, 13, [21] [22] [23] . In Domain 5 (selective reporting), three trials were rated as having some concerns [13, 21, 25] , with the remaining four trials rated as having low risk of bias [9, [22] [23] [24] . Overall, two studies were judged as having high risk of bias [24, 25] , three were rated as having some concerns [13, 21, 23] and two were judged as low risk of bias [9, 22] . Retrospective and Cross-sectional Observation Studies (n=6) For Domain 1 (representative target population), one study was identified as high risk of bias [3] , the remainder were rated as low risk of bias [4, 6, 7, 20, 26] . For Domain 2 (representative sampling frame) one study was identified as high risk of bias [3] , five studies were rated as low bias [4, 6, 7, 20, 26] . Under Domain 3 (random selection/census taken), four trials were rated as high risk of bias [3, 7, 20, 26] , one was rated as having some concerns [6] and one was rated as low [4] . For domain 4 (non-response bias), one trial was identified as high risk of bias [20] , five trials were rated as low risk of bias [3, 4, 6, 7, 26] . Under Domain 5 (direct data collection), one trial was considered to have high risk of bias [26] , with five trials rated as low [3, 4, 6, 7, 20] . For Domain 6 (acceptable case definition), all studies were judged to be low risk of bias [3, 4, 6, 7, 20, 26] . Under Domain 7 (instrument reliability/validity), one trial was identified as high risk of bias [6] , one was rated as having some concerns [20], the remaining four trials were rated as having low risk of bias [3, 4, 7, 26] . In Domain 8 (data collection) and Domain 9 (prevalence period) all trials were judged to be at low risk of bias [3, 4, 6, 7, 20, 26] . For Domain 10 (appropriate numerators/denominators) one trial was considered to have high risk of bias [3] , one was identified as moderate risk of bias [20] and four were found to be at low risk of bias [4, 6, 7, 26 ]. Overall, one study was identified as high risk of bias [3] , two were rated as having some concerns [6, 20] and three were judged to have a low risk of bias [4, 7, 26] . These judgements should be taken into consideration when interpreting the findings of this review. The thirteen included studies reported on twelve distinct outcomes, including frequency/intensity of cough, characteristics of expectoration, severity/resolution of respiratory tract infection (RTI) symptoms, mucosal congestion, inflammatory biomarker activity, need for antibiotic therapy, global severity of disease, duration of sick leave, wellbeing, sleep quality, tolerability of intervention, and adverse events. Global severity of disease was assessed in five studies, using either the Bronchitis Severity Score (BSS) [3, 4, 9, 22] or the Clinical Global Impression (CGI) scale [3] . Two studies [3, 22] reported improvements in BSS and/or CGI among participants receiving H. helix preparations, with one study [22] demonstrating comparative improvement against placebo. Cwientzek et al. [9] found the J o u r n a l P r e -p r o o f intervention to be noninferior to active control (i.e. another H. helix preparation). Outcome data could not be extracted from one study [4] . Four studies assessed changes in the characteristics of expectoration using either a four-point scale [6, 23] or an undefined measure [7, 24] . Two studies reported an improvement in expectoration in the intervention group, including expectoration amount [6, 23] , consistency, ease and colour [23]. One study found a higher rate of conversion from dry cough to productive cough in the intervention group relative to standard treatment [24] . The fourth study [7] also reported an improvement in expectoration, decrease in night cough frequency and decrease in respiratory pain in children aged 2 to 14 years with acute respiratory infection, but did not articulate how this outcome was measured. Changes in general RTI symptoms were measured in two studies, using either an undefined questionnaire [21], or a four-point clinical improvement scale [13] . For both studies, a greater proportion of participants in the intervention group (i.e. multi-herbal formulations containing H. helix) reported clinical improvement or resolution of fever, fatigue, sore throat, sneezing, wheezing, nasal congestion, post-nasal drip and/or body ache relative to participants receiving placebo. Differences between groups were found to be statistically significant for all symptoms in Khan et al.'s 2018 study [13] . The treatment group in Ali et al.'s 2017 study [21] showed statistically significant levels of improvement in cough, fever, sore throat, wheezing, postnasal drip and body ache after treatment with the H. helix formulation compared with the placebo group. Mucosal congestion and inflammatory biomarker activity (i.e. erythrocyte sedimentation rate [ESR] and serum C-reactive protein [CRP]) were assessed in one study [24] . When compared with standard treatment, administration of a multi-herbal formulation containing H. helix for 7-17 days was associated with a statistically significant improvement in oropharyngeal mucosal congestion, ESR and CRP concentration in children with acute viral RTI. Change in wellbeing was assessed in one study using a five-point rating scale [6] . This study reported an improvement in wellbeing in participants receiving H. helix syrup/cough drops. Changes in sleep quality were evaluated in two studies, using either an undefined measure [3] , or a five-point rating scale [6] . The studies reported an improvement in sleep quality [6] or cough-related J o u r n a l P r e -p r o o f sleep disorder/disturbance [3] over an average period of 7-11 days among participants receiving H. helix preparations. Five studies examined the tolerability of the intervention using either an undefined method [20, 22, 24] or a five-point scale [6, 9] . Tolerability/compliance was rated as either good [9, 22, 24] , good to very good [6] , or high [20]. Adverse events were specifically assessed in twelve studies [3, 4, 6, 7, 9, 13, [20] [21] [22] [23] [24] [25] ; only one study did not explicitly report on adverse events [26] . Four papers reported that no cases of adverse events occurred among participants receiving H. helix preparations [13, 20, 21, 24] . Only one adverse event, a case of diarrhoea, was reported in Kruttschnitt et al.'s study [4] ; data on this participant were not included in the final study sample as authors were not able to obtain complete data from this subject [4] . One four year old boy developed a skin rash after being administered H. helix in Beden et al.'s paediatric study [7] . Schaefer et al. reported fewer cases of adverse events in the H. helix group versus control group (i.e. 9 vs. 12 cases), with all events stated to be "non-serious, of mild or moderate severity and not drug-related" [22, p507]. Cwientzek et al. [9] reported an adverse event rate of 2.7% in each group (n=7 in the treatment group; n=7 in the control group), of which all events were non-serious and primarily gastrointestinal in nature. Schmidt et al. [6] reported five cases of non-serious adverse effects among participants receiving H. helix preparations, including four gastrointestinal complaints (diarrhoea, nausea or vomiting), and one dermatitis event. Based on the evidence identified in this rapid review, Hedera helix preparations and herbal complex preparations including Hedera helix may be a therapeutic option for treating early symptoms of respiratory tract infections in adults and children. The best effectiveness for H. helix preparations has been proven for coughing. There is limited evidence suggesting H. helix's possible value in night coughing and cough-related sleep disturbance. Weak evidence also suggests H. helix may improve cough expectoration and other global virus-related symptoms (e.g. fever, fatigue, sore throat, bodyache, etc.). Currently, there is insufficient evidence to recommend the use of this supplement in the treatment or prevention of COVID-19. 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