Ivy leaf ( Hedera helix ) for acute upper respiratory tract infections: an updated systematic review

European Journal of Clinical Pharmacology https://doi.org/10.1007/s00228-021-03090-4 REVIEW Ivy leaf (Hedera helix) for acute upper respiratory tract infections: an updated systematic review Elizabeth Sierocinski 1 & Felix Holzinger 2 & Jean-François Chenot 1 Received: 30 July 2020 / Accepted: 13 January 2021 # The Author(s) 2021 Abstract Purpose Acute cough due to viral upper respiratory tract infections (URTIs) and bronchitis is a common reason for patients to seek medical care. Non-antibiotic over-the-counter cough medications such as ivy leaf extract are frequently used but their efficacy is uncertain. Our purpose was to update our previous systematic review and evaluate the effectiveness and tolerability of ivy leaf in the treatment of acute URTIs in adult and pediatric populations. Methods We searched MEDLINE, EMBASE, the Cochrane Library, and clinical trial registries from December 2009 to January 2020. Randomized controlled trials (RCTs), controlled clinical trials (CCTs), and observational studies (OSs) investigating ivy leaf mono- or combination preparations were included. Two independent reviewers assessed records for eligibility and risk of bias and performed data extraction. Results Six RCTs, 1 CCT, and 4 OSs were identified. Since the publication of our previous review, the number of RCTs has increased. All studies concluded that ivy leaf extract is an effective and safe option for the treatment of cough due to URTIs and bronchitis. Three RCTs reported a more rapid reduction in cough severity and/or frequency under ivy leaf treatment. The clinical significance of these effects appears to be minimal. No serious adverse effects were reported. The overall quality of reporting was low and the risk of bias was high. Conclusions Ivy leaf preparations are safe for use in cough due to acute URTIs and bronchitis. However, effects are minimal at best and of uncertain clinical importance. Keywords Acute cough . Bronchitis . Ivy leaf extract . Hedera helix Introduction Acute cough is one of the most common reasons for an individual to seek physician care and to require sick leave from work or school [1, 2]. Viral upper respiratory tract infections (URTIs) and acute bronchitis are the most common cause of acute cough [1] and are hallmarked by general malaise, low or no fever, sore throat, rhinitis, congestion, headache, muscle aches, and cough. Systemic symptoms * Elizabeth Sierocinski 1 Department of General Practice, Institute for Community Medicine, Universitätsmedizin Greifswald, Greifswald, Germany 2 Department of General Practice, Charité – Universitätsmedizin Berlin, Berlin, Germany typically recede after 2–3 days but cough may persist for several weeks [3]. Antibiotics for viral URTIs and bronchitis are ineffective and even harmful due to potential side effects as well as the contribution to the development of bacterial resistance [4]. Despite widespread knowledge of the associated risks, antibiotics are frequently prescribed to patients with URTIs and bronchitis [5]. To combat this issue and to assist physicians in the challenge of alleviating acute cough caused by viral illnesses, a strong evidence base regarding the efficacy and safety of non-antibiotic cough remedies in adults and children is needed. Ivy leaf (Hedera helix) extract preparations are widely used over-the-counter, non-antibiotic cough remedies authorized by the European Medicines Agency [6–8]. Ivy leaf extract contains saponins which are believed to have expectorant properties [9]. In vitro studies of ivy mono-preparations show evidence of potential antispasmodic and bronchodilating activity, anti-inflammatory effects, and antitussive properties Eur J Clin Pharmacol [9]. This review is an update of our systematic review published in 2011 which found that evidence for the efficacy of ivy leaf extract in acute cough was inconclusive due to lack of methodologically robust data [10]. The objective of this review was to identify and evaluate new data regarding the effectiveness and tolerability of ivy leaf in the symptomatic treatment of acute bronchitis associated with acute URTIs in children and adults. Methods Search methods We conducted a systematic literature search of MEDLINE, EMBASE, and the Cochrane Library from December 2009 until January 2020. Search strategies are available as supplementary material. We hand-searched the bibliographies of retrieved publications and manufacturer websites. Additionally, we searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTR), ClinicalTrials.gov, the European Union Clinical Trials Register (EU CTR), and European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) for ongoing and completed trials and observational studies. We included records in English, German, French, Spanish, and Polish. Study selection Randomized controlled trials (RCTs), controlled clinical trials (CCTs), and non-controlled observational studies (OSs) were included. Participants The target participants were adults and children with upper respiratory tract infections (URTIs) and bronchitis. Studies including other acute diseases such as chronic obstructive pulmonary disease (COPD) and asthma were only included if the majority of subjects had URTIs or bronchitis. Interventions Herbal expectorants in any dosage containing ivy leaf extract either as a single agent or in combination with other herbal agents were targeted. Outcomes We targeted clinical outcomes (e.g., morbidity, health-related quality of life); surrogate values (spirometric parameters); physical findings (auscultation); symptom (cough); and tolerability assessment by physicians or patients. Data extraction and management Two independent reviewers (JFC and ES) screened records for inclusion and extracted data using a predesigned template. Disagreements were resolved by consensus. Risk of bias assessment Two independent reviewers used the Cochrane Risk-of-Bias tools for Randomized Trials (RoB-2) and Non-randomized Studies of Interventions (ROBINS-I) to assess the outcome- and study-level level risk of bias of RCTs and CCTs/OSs, respectively [11, 12]. Disagreements were resolved by consensus. Financial conflicts of interest and publication bias were also assessed [13]. Data synthesis and subgroup analysis Included studies were categorized by study design. For controlled studies, the following subgroup comparisons were planned: ivy leaf extract vs. placebo; ivy leaf extract vs. conventional therapy; comparison of different formulations of ivy leaf extract. ROB figures were generated using robvis software [14]. All other figures were generated using drawi.io. The review protocol is published on PROSPERO (CRD42019141405). Results Description of studies We identified 387 potentially relevant records, including 11 trial protocols (Online Resource 1). Four protocols corresponded to studies included in our review and 7 lacked published results. O (...truncated)