key: cord-0943704-2ycf6qd8 authors: Harnett, Joanna; Oakes, Kerrie; Carè, Jenny; Leach, Matthew; Brown, Danielle; Cramer, Holger; Pinder, Tobey-Ann; Steel, Amie; Anheyer, Dennis title: The effects of Sambucus nigra berry on acute respiratory viral infections: a rapid review of clinical studies date: 2020-08-22 journal: Adv Integr Med DOI: 10.1016/j.aimed.2020.08.001 sha: 45941ed8f762dc103b0d583b7e4e349be1ef6341 doc_id: 943704 cord_uid: 2ycf6qd8 nan The evidence included in this review is mostly derived from clinical studies involving adult participants and examining short-term use of commercial formulations of S.nigra berry for up to 16 days. Findings from included studies suggest that mono-herbal preparations of S.nigra berry (in extract or lozenge formulation) may reduce influenza-type symptoms, including fever, headache, nasal congestion and nasal mucous discharge in adults, when taken within the first 48 hours of symptom onset. Within 2-4 days of S.nigra treatment, most adult participants experienced significant symptom reduction, by an average of 50%. Evidence regarding the effectiveness of S.nigra berry on the symptom of cough, and need for / use of medicines (including antibiotics) to treat acute respiratory infections, is currently unclear and inconsistent. Adverse events were rare with no serious events reported. Adverse events, reported in two studies, were more common in comparators than in treatments. There is currently no reliable or sufficient scientific evidence to support the use of S.nigra in pregnant or lactating women. The S. nigra plant belongs to the Adoxaceae family, which is indigenous to Europe, Asia and North Africa (1) . Historically, the flower and berry of the Elder plant have been used in herbal preparations for the treatment of common cold and flu (1) . Preclinical studies have shown elderberry extracts to have antimicrobial and antiviral effects, including activity against influenza viruses (2) . These antiviral effects have been attributed to the inhibition of viral replication by S.nigra. Additionally, elderberry extracts have been shown to increase cytokines that activate immunomodulation (3). S.nigra berries contain multiple constituents, including flavonoids, triterpenes, acyl spermidines, αlinolenic acid, linoleic acid (1), mucilage and hydroxycinnamic acid derivatives (4) . The rich anthocycanin flavonoid content is associated with antioxidant activity (5) . The unripe berries also contain toxic constituents, but these are lost during drying and heating processes; as such, these toxic constituents are not typically present in commercially available preparations (3). Research question Does S.nigra improve outcomes in humans with acute respiratory viral infections? Original prospective intervention studies involving adult participants with acute respiratory viral infections written in English that evaluated the effect of S.nigra (as a mono-or combination therapy) in any form, dose and route of administration. All comparators or controls were included. Studies involving children, or participants with bacterial, fungal or non-infectious respiratory disease and not meeting the inclusion criteria above were excluded from this review. Relevant studies were identified by searching MEDLINE (Ovid), EMBASE (Ovid), AMED (Ovid) and CINAHL (EBSCO) for articles published from inception to May 2020. One author (KO) scanned the title and abstract of each record retrieved. All articles that appeared to meet the selection criteria were accessed and evaluated in full text. For articles that met the inclusion criteria, two authors (KO and JMC) extracted the relevant population and intervention characteristics into an extraction template, with any disagreements resolved by discussion with AS. Where duplicate papers and papers reporting aspects of the primary study, the authors (JMC and AS) checked the data aligned before removing the secondary paper and the original publication (typically the older paper) was included. The risk of bias of each study was evaluated by KO and JMC, using the Cochrane Collaboration Risk of Bias tool (6) , and checked by AS. Any disagreements were resolved by consensus. The Cochrane Risk of Bias tool is comprised of seven domains including; random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessors; incomplete outcome data; selective outcome reporting; and other sources of bias. Reviewers designated a judgement related to the risk of bias for each item. 'Yes' indicated a low risk of bias, and 'No' a high risk of bias and 'Unclear' indicating unclear or unknown risk of bias. (see Table 3 ). Data were synthesised in narrative form. Due to the heterogeneity of the data, a meta-analysis was not conducted. The database search identified 40 studies. After the removal of duplicates (n=10), 30 studies were screened by title and abstract. This resulted in the exclusion of 15 studies. The remaining 15 studies were screened as full text. Ten studies were excluded as they reported the wrong study design (n=4), were a systematic review (n=4) or duplicated already included studies (n=2). Five studies were included for full review. The included studies involved a total of 936 participants (minimum 27, maximum 473, mean 187). The study population were primarily adults aged between 18 and 70 years, with two studies also including children aged from 5 years (7) or 12 years (8). The most common conditions studied were influenza (7-9) and influenza-like symptoms (10), followed by common cold (11) . All included studies used a proprietary herbal medicine product as the intervention. Four studies used mono-herbal preparations of S.nigra berry extract (7, (9) (10) (11) . One study used a poly-herbal preparation, which contained S.nigra berry plus Echinacea purpurea root (8) . The preparations were administered orally in the form of a syrup (7, 10), capsules (11), granules (8) or lozenges (9) . Doses ranged from 15mls four times per day (syrup), 3 capsules per day, 175mg lozenge four times per day or 5ml of the poly-herbal formula in 150ml of hot water using an initial dosage of 5 times per day for days 1-3 followed by a maintenance dose of twice per day (days 4-10). The risk of bias assessment for the first domain (randomisation process) resulted in all 5 studies being rated as having a low risk of bias (7) (8) (9) (10) (11) . For domain 2 (treatment assignment), two studies were considered to have some concerns (8, 9) , and three studies were rated as having low risk of bias (7, 10, 11) . Under domain 3 (missing outcome data), all five trials were judged as having low risk of bias (7) (8) (9) (10) (11) . For domain 4 (measure of outcomes), all five studies were rated as having low risk of bias (7) (8) (9) (10) (11) . In domain 5 (selective reporting), all trials were judged to be at low risk of bias (7) (8) (9) (10) (11) . Overall, two studies were identified as having some concerns (8, 9) and three studies were judged as having J o u r n a l P r e -p r o o f low risk of bias (7, 10, 11) . These judgements should be taken into consideration when interpreting the findings of this review. Treatment outcomes reported included overall reduction in symptoms; duration of illness/rate of recovery, and the use of rescue medication including analgesics, nasal spray, cold tablets, antibiotics. Four studies (7, (9) (10) (11) ) measured reduction of symptoms; fever reduction (7, (9) (10) (11) and one study (9) also reported reduction of headache, muscle ache, nasal congestion and mucus discharge and cough All studies reported (7-11) a reduction in overall symptom severity among participants receiving S.nigra berry (whether in mono-or poly-herbal formulation) when compared with controls. One study reported that participants receiving treatment reported significant improvement in symptom severity following 48 hours whereas the control group reported increased severity in the same time-period (8). Duration of illness and rate of recovery was reported in four studies (7, 8, 10, 11) . Three studies demonstrated that the duration of illness was almost 50% shorter for those receiving S.nigra berry compared with the control group (7, 10, 11) . In one study, the rate of recovery was similar between a S.nigra polyherbal preparation and an active control (Oseltamivir) (8) . In the two studies (10, 11) reporting the use of rescue medication including analgesics, antibiotics, nasal sprays, or cold tablets to manage participant symptoms, the need for such medication was found to be inconsistent. In one study, participants assigned to S.nigra berry treatment reported using rescue medication to manage influenza-like symptoms less frequently than control participants (10) . By contrast, a second study found no difference between groups in the reported use of rescue medication or prescribed antibiotics among participants with the common cold (11). Adverse events were rare with one study (11) reporting two adverse events (fatigue and cold-like symptoms) attributed to S.nigra berry compared to three (itchy throat, fatigue and kidney pain) attributed to placebo. A second study (8) Overall, the evidence obtained from the five studies included in this review involving 936 people suggests that mono-herbal preparations of S.nigra berry when taken close to the onset of symptoms and for up to two weeks, may assist in relieving the symptoms of the common cold and influenza. S.nigra berry may be effective in reducing the duration and severity of fever, headache, nasal J o u r n a l P r e -p r o o f congestion and nasal mucous discharge when associated with an acute viral respiratory infection. Some evidence suggests that S.nigra berry may relieve cough or help prevent the worsening of cough when attributed to such viral infections however this finding is inconsistent across studies. As the formulation, dose and duration of S.nigra berry treatment varied between studies, general recommendations regarding these clinically important factors cannot be made. Accordingly, TGAapproved monographs and pharmacopoeias (12) Phytopharmacy: An evidence-based guide to herbal medicinal products Anti-influenza virus effects of elderberry juice and its fractions. Bioscience, biotechnology, and biochemistry The effect of herbal remedies on the production of human inflammatory and anti-inflammatory cytokines Physico-chemical characteristics of some wild grown European elderberry (Sambucus nigra L.) genotypes. Pharmacognosy magazine Chapter 8: Assessing risk of bias in included studies. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1. 0 [updated Cochrane Handbook for Systematic Reviews of Interventions Version Inhibition of several strains of influenza virus in vitro and reduction of symptoms by an elderberry extract (Sambucus nigra L.) during an outbreak of influenza B Panama Echinaforce Hotdrink versus oseltamivir in influenza: a randomized, double-blind, double dummy, multicenter, noninferiority clinical trial Pilot clinical study on a proprietary elderberry extract: efficacy in addressing influenza symptoms Randomized study of the efficacy and safety of oral elderberry extract in the treatment of influenza A and B virus infections Elderberry supplementation reduces cold duration and symptoms in air-travellers: A randomized, double-blind placebo-controlled clinical trial Australia: Department of Health The effect of Sambucol, a black elderberry-based, natural product, on the production of human cytokines: I. Inflammatory cytokines