Ivy leaf dry extract EA 575 for the treatment of acute and chronic cough in pediatric patients: review and expert survey

Abstract

Objectives

EA 575 (Prospan) is a herbal medicine containing a dried extract of ivy leaves (drug extract ratio 5–7.5:1; extraction solvent, 30% ethanol). Although widely used for the treatment of cough, there remains a lack of clarity on the effects of EA 575 in children. This study aimed to evaluate the efficacy and tolerability of EA 575 in pediatric patients with cough, via a literature review and expert survey.

Methods

A MEDLINE/PubMed database search was performed to identify articles evaluating the efficacy and tolerability of EA 575 in pediatric patients with cough. An online survey of international pediatric cough experts was conducted to gather expert opinion regarding the use of EA 575 for pediatric cough.

Results

Ten controlled clinical trials and nine observational studies were identified. Controlled trials reported improvements in lung function and subjective cough symptoms with EA 575, while observational studies indicated overall favorable efficacy. EA 575 was generally well tolerated, with a low incidence of adverse events in children of all ages, including those aged <1 year. Survey responses from ten experts aligned with findings from the reviewed studies. Most experts agreed that EA 575 may improve quality of life, and highlighted its potential benefits on sleep.

Conclusions

EA 575 has minimal side effects in pediatric patients with cough, as demonstrated by large, real-world studies. EA 575 may provide clinical benefits in pediatric patients; however, more robust clinical trials are needed to confirm its efficacy.

PLAIN LANGUAGE SUMMARY

EA 575 (Prospan) is a medicine containing a dried extract of ivy leaves that is used to treat coughs. The aim of this review was to evaluate the available published information on the health benefits and side effects of EA 575 in children with coughs. We also conducted a survey of doctors who treat children with coughs. We found information from ten research trials that compared EA 575 with another cough medicine or a “dummy medicine”. Although these studies included only a small number of children, the results suggested that children’s breathing and cough symptoms may improve with EA 575 treatment. We also found nine studies that included children being treated in normal clinical situations and not in a research setting. Most of the children included in these studies and their doctors thought that EA 575 treatment was beneficial. A low number of side effects was reported in children of all ages, including in infants aged <1 year. Survey responses from ten doctors generally agreed with the findings from the research studies. Most of the doctors thought that EA 575 may improve quality of life. Improved sleep was commonly mentioned by doctors. Overall, our findings indicate that EA 575 has minimal side effects in children; we call for more research on the benefits of EA 575 on cough symptoms in children.

Keywords:

• Prospan
• plant extracts
• cough
• child
• pediatrics
• surveys and questionnaires
• review

Introduction

Dried leaf extracts of common ivy (Hedera helix L.) are well established in the treatment of certain respiratory diseases – particularly when cough is a symptom¹. EA 575 (Prospan) is a herbal medicinal product containing a dried extract of ivy leaves (drug extract ratio [DER] 5–7.5:1; extraction solvent, 30% ethanol)^2,3, which is manufactured in a range of dosage forms including syrup, drops, and effervescent tablets. Ivy leaf dry extracts with different DERs are also available, but are not considered therapeutically equivalent⁴.

Ivy leaf dry extracts contain triterpene saponins, flavonoids, phenolic acids and polyacetylenes⁵. In vitro studies indicate that the saponin, α-hederin, is one of the main active compounds in ivy leaf extracts^6–8. α-hederin is thought to inhibit the internalization of β₂-adrenergic receptors on alveolar type II cells and human airway smooth muscle cells, resulting in increased β-adrenergic responsiveness in the respiratory tract^6,7. Ivy leaf dry extract EA 575 is also the first phytomedicine for which biased β₂-adrenergic receptor activation has been demonstrated⁹. G protein-biased signaling results in elevated cyclic adenosine monophosphate (cAMP) levels, leading to surfactant secretion (which may reduce the viscosity of mucus and aid mucociliary clearance) and bronchodilation (which reduces airway resistance), thought to manifest clinically as secretolytic and bronchospasmolytic effects^6,8–14. Furthermore, in vitro studies indicate that EA 575 may have anti-inflammatory properties^9,15,16. Taken together, the actions of EA 575 on multiple cough triggers – mucus, bronchoconstriction, and inflammation – may account for the overall cough-relieving effect observed in clinical practice.

Accumulated data from clinical trials of EA 575 in mixed populations of adults and children support its efficacy on cough symptoms and its favorable tolerability profile^3,17. However, no comprehensive overview of the clinical benefits and possible side effects of EA 575 in the pediatric population, specifically, is available. The aim of this review was to evaluate published EA 575 studies in order to summarize the efficacy and tolerability of EA 575 in pediatric patients with acute or chronic cough. Additional insights regarding the potential clinical benefits of EA 575 in pediatric patients treated in real-world clinical practice were sought from international experts using an online survey.

Methods

Literature review search strategy

A literature review was conducted to identify published studies evaluating the efficacy and tolerability of EA 575 in pediatric patients with cough due to various causes. Any comparator, outcome measure, and study design was eligible. The review comprised a search of the MEDLINE/PubMed database, supported by additional articles known to the authors. The following search terms were used: (“EA 575” or “Prospan” or “ivy leaf” or “ivy leaves”) AND (pediatric or children). No limits on article language were applied. Early (before 1992) non-controlled studies were excluded as the European Medicines Agency (EMA) considers their methodology to be inadequate to show the efficacy of currently marketed products¹. The search was performed on 19 May 2020.

Questionnaire

Expert opinion on EA 575 was collected as part of a 30-minute online questionnaire that was designed by the authors (and reviewed by the sponsor) to answer the following research question: “According to international experts, what are the therapeutic principles for, and unmet needs in, the treatment of cough in pediatric patients?” Full details of the questionnaire and the target audience (healthcare professionals with expertise in the area of pediatric cough) have been published¹⁸. Briefly, the questionnaire comprised an introductory section to assess eligibility and obtain informed consent; sections on general therapeutic principles and unmet needs (previously reported¹⁸); and a section on the use of EA 575 for pediatric cough (reported here). A mix of open and closed questions were used. The questionnaire is provided as Supplementary file 1.

The questionnaire was designed and distributed in accordance with the Market Research Society (MRS) Code of Conduct; formal ethics approval is not required for market research. Participating experts gave digital written informed consent prior to starting the questionnaire. Questionnaire responses were anonymous, and no information was requested that would allow individuals to be identified.

Data were analyzed using Excel (Microsoft Corporation, Redmond, WA). For quantitative questions, means and numbers/percentages were calculated, as appropriate. No statistical comparisons were conducted due to the descriptive nature of the study and the small sample size.

Results

Literature review

A total of 19 articles, published between 1996 and 2020, and reporting the results of controlled clinical trials (n = 10) or observational studies (n = 9) with EA 575 were identified in the literature review. The trials/studies were conducted across six different countries/regions (Czech Republic, Germany, Slovenia, Switzerland, Ukraine, and Latin America).

Efficacy of EA 575 in controlled clinical trials

The designs of the controlled clinical trials (a mixture of randomized double-blind and open-label) and their results are summarized in Table 1. The trials assessed the efficacy of EA 575 in children with acute or chronic respiratory diseases including acute bronchitis, chronic obstructive respiratory disease, and bronchial asthma^1,19–26,28. Most trials enrolled 20–70 children, although Cwientzek et al. enrolled 201 children²⁶. Typically, EA 575 was administered as a syrup, and the most common treatment duration was 7–10 days (full range, 3–30 days). The effects of EA 575 on cough were assessed through subjective measures including patient/parent- or clinician-rated global assessments of efficacy, and changes in specific symptoms, such as cough frequency, shortness of breath, expectoration, and respiratory pain. Most trials also used spirometry to assess the effects of EA 575 on lung function, often accompanied by body plethysmography.

Table 1. Summary of controlled clinical trials of EA 575 in pediatric patients.

Reference	Design	EA 575 dosage form(s)	Comparator	EA 575 dose^a	Treatment duration	Disease area	Number of children (age range)	Concomitant medication usage	Setting	Efficacy/tolerability outcomes
Gulyas et al. (1997)^19	Randomized, double-blind, crossover	Syrup, drops	Different dosage forms	Syrup: 630 mg/day Drops: 252 mg/day	10 days	COPD	27 (10–16 years)	Not specified	Germany, inpatients	Spirometry: improvements in FEV1, FVC, VC, and PEF with syrup and drops Body plethysmography: clinically relevant improvements in RAW, ITGV, and sRAW with syrup and drops
Mansfeld et al. (1997)^1^,^20	Randomized, open-label, crossover	Suppositories, drops	Different dosage forms	Suppositories: 1,000 mg/day Drops: 218 mg/day	3 days with each dosage form	Bronchial asthma	26 (5–11 years)	Not specified	Switzerland, inpatients	Patient/parent-rated assessment of cough symptoms: no clinically relevant changes or differences between groups in the intensity/frequency of cough and shortness of breath Spirometry: clinically relevant improvements in FEV1 and FVC with suppositories and drops Body plethysmography: clinically relevant decreases in RAW with suppositories and drops Patient/parent- and clinician-rated global assessment of tolerability: “very good” in 25 children in both groups
Mansfeld et al. (1998)^21	Randomized, double-blind, crossover	Drops	Placebo	210 mg/day	3 days with drops and 3 days with placebo	Bronchial asthma	28 (4–12 years)	Not specified	Switzerland	Patient/parent-rated assessment of cough symptoms: no differences between EA 575 and placebo in frequency of dose-metered aerosol use, in intensity of shortness of breath, and in description of cough Spirometry: clinically relevant, numerically greater improvements in FEV1, FVC, and VC with EA 575 vs placebo Body plethysmography: significant improvements in RAW and ITGV with EA 575 vs placebo Patient/parent- and clinician-rated global assessment of tolerability: “very good” in all children in both groups
Gulyas (1999)^1^,^22	Controlled, pilot	Syrup	Acetylcysteine	630 mg/day	14–20 days	Chronic obstructive bronchitis	20 (9–15 years)	Not specified	Germany, inpatients	Spirometry: similar improvements in VC with EA 575 and acetylcysteine; greater improvements in FEV1 and PEF with EA 575 vs acetylcysteine Body plethysmography: greater improvement in RAW with EA 575 vs acetylcysteine
Unkauf and Friederich (2000)^1^,^23	Randomized, open-label	Syrup	Valverde (ivy leaf dry extract DER 3–6:1, 60% ethanol)^b	Age <4 years: 350–490 mg/day Age 4–10 years: 525–735 mg/day Age 10–12 years: 700–980 mg/day	10 days	Bronchitis	52 (≤12 years)	Not specified	Germany	Clinician-rated assessment of cough symptoms: no relevant between-group differences in bronchitis, expectoration, or cough Clinician-rated assessment of bronchitis-related impairment: bronchitis severity decreased, with non-inferiority of EA 575 vs DER 3–6:1 Clinician-rated disease severity: similar decreases in bronchitis severity with EA 575 and DER 3–6:1 AEs: no AEs were reported
Maidannik et al. (2003)^1^,^24	Open-label, interventional	Syrup	Ambroxol	Age 1–6 years: 1 tsp t.i.d. Age 7–14 years: 2 tsp t.i.d.	Acute disease: 7–10 days Chronic disease: 10–14 days	Acute and chronic respiratory diseases	72 (7 months–15 years)	Not specified	Ukraine, inpatients	Clinician-rated assessment of cough symptoms: frequency of shortness of breath resolved in both treatment groups, and productive cough decreased with EA 575 and ambroxol with no significant between-group differences Patient/parent- and clinician-rated assessment of efficacy: “excellent” or “good” by 86.8% of patients/parents and 90.1% of clinicians Spirometry: abnormal respiratory velocity parameters in 7.2% with EA 575 and 68.6% with ambroxol
Bolbot et al. (2004)^1^,^25	Open-label, interventional	Syrup	Acetylcysteine	Age 2–6 years: 630 mg/day Age 7–10 years: 1,260 mg/day	7–10 days	Acute bronchitis	50 (2–10 years)	26 children (antibiotics, antihistamines, etc.)	Ukraine	Clinician-rated assessment of cough symptoms: cough frequency, sputum viscosity, shortness of breath, and respiratory pain normalized in a similar timeframe with EA 575 acetylcysteine Spirometry: FEV1, FVC, PEF, MEF25, MEF50, MEF75, and AWSV25–75 showed significantly greater improvements with EA 575 vs acetylcysteine after treatment Clinician-rated global assessments of efficacy and tolerability: “very good” or “good” efficacy in 96% with EA 575 and in 79.2% with acetylcysteine; “very good” or “good” tolerability in 100% with EA 575 and in 76% with acetylcysteine
Brattström et al. (2006)^1	Open-label	Syrup	Ivy leaf dry extract (DER 3–6:1)	Age <4 years: 5 ml b.i.d. Age 4–10 years: 7.5 ml b.i.d. Age >10 years: 10 ml b.i.d.	10 days	Acute bronchitis	52	Not specified	Not specified	Assessment of bronchitis symptoms: therapeutically equivalent improvement with EA 575 and DER 3–6.1
Cwientzek et al. (2011)^1^,^26^,^27	Randomized, double-blind	Drops^b	Hedelix (ivy leaf soft extract DER 2.2–2.9:1, 50% ethanol/propylene glycol)	Age 2–4 years: 12 drops t.i.d. Age 4–10 years: 16 drops t.i.d.	7 days	Acute bronchitis	201 (2–10 years)^c	8 children received an inadmissible medication (most antibiotics)	Czech Republic	BSS and BSS subscales: similar improvements in both groups, confirming non-inferiority of EA 575 vs DER 2.2–2.9:1 Patient- and clinician-rated global assessments of efficacy and tolerability: high and comparable between the groups AEs: 2.7% reported an AE; most AEs were gastrointestinal, and all were non-serious
Zeil et al. (2014)^28	Randomized, double-blind, crossover	Syrup	Placebo	5 ml b.i.d.	28–30 days with syrup and 28–30 days with placebo	Bronchial asthma	30 (6–12 years)	All received 400 μg/day budesonide equivalent	Germany	Spirometry: no significant differences in relative change in FEV1 and MEF75–25 before bronchodilation with EA 575 vs placebo Body plethysmography (RAW), FeNO, EBC pH, PAQLQ: no changes with EA 575 or placebo ACQ: decreased with placebo (p < 0.05) but not with EA 575

^aDose given as mg herbal substance, where provided; ^bEA 575 was the comparator drug in this study; ^cthe study also included adults (data not shown).

Early (before 1992) non-controlled studies are not presented as the EMA considers their methodology to be inadequate to show the efficacy of currently marketed formulations of EA 575¹.

Abbreviations. ACQ, Asthma Control Questionnaire; ADR, adverse drug reaction; AE, adverse event; AWSV_25–75, average inhalation weight hour space velocity at 25–75% of the vital capacity; b.i.d., two times per day; BSS, Bronchitis Severity Score; COPD, chronic obstructive pulmonary disease; DER, drug extract ratio; EBC pH, exhaled breath condensate pH; EMA, European Medicines Agency; FeNO, fractional exhaled nitric oxide; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; ITGV, intrathoracic gas volume; MEF_25/50/75, maximal expiratory flow at 25/50/75% of the vital capacity; MEF_75–25, maximal expiratory flow at 75–25% of the vital capacity; PAQLQ, Pediatric Asthma Quality of Life Questionnaire; PEF, peak expiratory flow; RAW, airway resistance; sRAW, specific airway resistance; t.i.d., three times per day; tsp, teaspoon; VC, vital capacity.

Two publications described double-blind, placebo-controlled trials in children with bronchial asthma^21,28. Mansfeld et al.²¹ found no differences in the occurrence or intensity of patient/parent-reported shortness of breath, or in the description of cough, between EA 575 and placebo. However, a clinically relevant and statistically significant reduction in the primary outcome – change in airway resistance (RAW) from baseline to Day 3 – was reported in children who received EA 575 (p < 0.01 versus baseline; p < 0.05 versus placebo)²¹. In contrast, Zeil et al.²⁸ reported a lack of statistically significant improvement with EA 575 versus placebo in forced expiratory volume in 1 s (FEV₁) and maximal expiratory flow at 75–25% of the vital capacity (MEF_75–25) before bronchodilation from baseline to Day 28–30 (primary outcomes). Significant improvements from baseline to Day 28–30 with EA 575 were reported for some secondary endpoints (e.g. absolute change in MEF_75–25 before bronchodilation) but not for RAW measured before or after bronchodilation²⁸.

Three publications described active-controlled trials in children with acute respiratory diseases^24,25 and chronic respiratory diseases^22,24. In children with acute respiratory diseases, reduction in productive cough and subjective improvement of cough symptoms (assessed by clinicians and/or documented by patients) were similar following treatment with EA 575 syrup and with the mucolytic drugs ambroxol and acetylcysteine^24,25. Statistically significantly greater improvements in respiratory parameters were observed with EA 575 versus acetylcysteine in children with acute bronchitis²⁵. In children with chronic obstructive bronchitis, respiratory parameters improved with EA 575 and acetylcysteine, with changes in FEV₁ and peak expiratory flow (PEF) favoring EA 575²². In another study, respiratory velocity parameters normalized in most children with obstructive respiratory diseases who received EA 575 for 7 days, but worsened with ambroxol²⁴. With EA 575 treatment, respiratory parameters normalized within 6–7 days for children with acute bronchitis, and within 9–11 days for children with bronchopneumonia or exacerbation of bronchial asthma²⁴.

In three trials comparing the efficacy of different ivy leaf extracts, EA 575 decreased the severity of bronchitis (assessed by the Clinical Global Impression scale, the Bronchitis Severity Score, or a Visual Analogue Scale) to a similar extent to other ivy leaf extracts, including Valverde (DER 3–6:1) and Hedelix (DER 2.2–2.9:1)^1,23,26.

Finally, two trials compared the efficacy of different EA 575 dosage forms^19,20. In children with chronic obstructive pulmonary disease (COPD), EA 575 syrup and drops were considered efficacious and therapeutically equivalent based on assessments of lung function¹⁹. Treatment with EA 575 suppositories or drops also resulted in similar, clinically relevant improvements in FEV₁, FVC and RAW in children with bronchial asthma, but no clinically relevant changes or differences were observed in the incidence or intensity of cough and shortness of breath²⁰.

Efficacy of EA 575 in observational studies

The designs of the observational studies are summarized in Table 2. Eight of the studies were prospective (typically described as post-marketing surveillance studies)^{29–31,33–37}, and one was a retrospective review of patient files³². The studies generally considered children with acute and chronic bronchitis, or inflammatory or obstructive respiratory diseases (Table 2). The studies were of moderate size (30–200 children), with the exception of two larger prospective studies (>1,000 children) and the retrospective study (>52,000 children – safety outcomes only). Five of the studies also included adults and did not present outcomes separately for different age groups^{30,31,33,35,37}. The efficacy of EA 575 was evaluated in seven studies by documenting changes in specific patient symptoms (such as cough, expectoration, and shortness of breath) and using patient- and/or clinician-rated global assessments of efficacy.

Table 2. Summary of observational studies of EA 575 in pediatric patients.

Reference	Design	EA 575 dosage form(s)	EA 575 dose and treatment duration	Disease area	Number of children (age range)	Concomitant medication usage	Setting	Efficacy/tolerability outcomes
Lässig et al. (1996)^1^,^29	Prospective, surveillance	Syrup	At discretion of clinician	Recurrent obstructive respiratory diseases	113 (6–15 years)	73%; mostly inhaled combination cromolyn sodium/sympathomimetic	Germany	Clinician-rated assessment of cough symptoms: significant improvements in frequency of cough and expectoration Spirometry: significant improvements in FEV1, FVC, PEF, MEF25 and MEF50 Clinician-rated assessments of improvement and tolerability: 85.7% of children were “cured” or “significantly improved”; tolerability was “very good” or “good” in 98.2% AEs: no AEs reported
Hecker (1999)^30	Prospective, post-marketing surveillance	Syrup (age 0–9 years) or effervescent tablets (age ≥4 years)	According to manufacturer recommendations	Inflammatory and/or obstructive respiratory diseases	176 (≤15 years)^a	Not specified	Germany	[Adults and children combined] Clinician-rated assessment of cough symptoms: “cured” or improved cough and expectoration in ∼90%, and shortness of breath and respiratory pain in ∼60% Clinician-rated global assessments of efficacy and tolerability: “very good” or “good” efficacy in 86%; “very good” or “good” tolerability in 98% AEs: 1 AE reported (allergic exanthema)
Hecker et al. (2002)^31	Prospective, post-marketing surveillance	Effervescent tablets	At discretion of clinician	Chronic bronchitis	165 (4–12 years)^a	52.0%; an airway- relevant product in 14.8%	Germany	[Adults and children combined] Clinician-rated assessment of cough symptoms: “cured” or improved cough and expectoration in >90%, and shortness of breath and respiratory pain in >80% Clinician-rated global assessment of efficacy: “very good” or “good” in 91% AEs: 6 patients (0.4%); 4 discontinued treatment
Kraft (2004)^32	Retrospective	Syrup	At discretion of clinician	Symptomatic respiratory diseases	52,478 (0–12 years)	Not specified	Germany	ADRs: 0.22% in children (diarrhea, 0.1%; enteritis, 0.04%; allergic exanthema/urticaria, 0.04%; vomiting, 0.02%); incidence was age-dependent (0.4% aged <1 year, 0.13% aged >9 years)
Fazio et al. (2009)^33	Prospective, post-marketing surveillance	Syrup	According to manufacturer recommendations: 2.5–7.5 ml t.i.d. (depending on age) for 7 days	Acute or chronic bronchitis	5,181 (0–14 years)^a	59.1%; 36.2% received antibiotics	Latin America, outpatients	[Adults and children combined, except AEs] Clinician-rated assessment of cough symptoms: improvement/healing of cough, expectoration, dyspnea, and pain in >90% Clinician-rated global assessment of tolerability: “very good” or “good” in 96.6% Discontinuation: 4.0%; 1.9% due to improvement/healing AEs: 112 in children; mostly gastrointestinal
Beden et al. (2011)^34	Prospective, non-interventional	Syrup	At discretion of clinician for 7 days	Acute respiratory tract infection	193^b (2–14 years)	33.7%; 36 received systemic antibiotics	Slovenia	Clinician-rated assessment of cough symptoms: complete or partial improvement in coughing (95.3%) and expectoration (94.7%); most children with difficulty breathing and pain experienced complete improvement Patient-rated assessments of improvement and tolerability: 93.7% had “complete” or “partial” improvement; 97.9% had “very good” or “good” tolerability AEs: 1 AE (hives) was reported; 3 children discontinued treatment
Stauss-Grabo et al. (2011)^35	Prospective, non-interventional, post-marketing surveillance	Tablets	≥2 tablets b.i.d. for ≥7 days	Colds with cough, chronic inflammatory bronchial diseases	36 (11–20 years)^a	Not specified	Germany	[Adults and children combined] Patient- and clinician-rated global assessment of tolerability: “very good” or “good” by 96.4% of patients and by 98.5% of clinicians ADRs: 1 ADR (nausea)
Lang et al. (2015)^36	Prospective, non-interventional, post-marketing surveillance	Syrup, drops, liquid, effervescent tablets, and lozenges	At discretion of clinician for 7 days	Acute bronchitis	1,066 (6–12 years)	27.0% for respiratory conditions, mostly nasal sprays/drops (n = 95) and antibiotics (n = 28) 47 received antibiotics for a co-infection	Germany, outpatients	Patient/parent- and clinician-rated assessment of cough symptoms: patients/parents reported 42.1–58.1% decreases in cough intensity, chest pain, shortness of breath, sleep problems, expectoration, and cough attacks; clinicians reported ∼50% decreases in intensity of cough attacks, expectoration/sputum, dyspnea, and breath sounds BSS: 79.3% improvement Patient/parent- and clinician-rated global assessments of efficacy and tolerability: “very good” or “good” efficacy by 91.2% of patients/parents and 93.2% of clinicians; “very good” or “good” tolerability by 95.4% of patients/parents and 96.7% of clinicians ADRs: 10 (0.9%); 7 gastrointestinal, 2 allergic, 1 other
Kruttschnitt et al. (2020)^37	Prospective, non-interventional, post-marketing surveillance^c	Syrup	At discretion of clinician	Acute bronchitis	30 (6–17 years)^a	18.0% of children and adults received antibiotics; 22.3% received other medication	Switzerland	[Adults and children combined] Patient/parent-rated assessment of cough symptoms: reductions in cough intensity, chest pain, cough-related sleep disturbance, and expectoration BSS: continuous reduction in score Patient- and clinician-rated global assessment of tolerability: EA 575 rated “very good” or “good” by 98.3% of patients/parents and by 99.1% of clinicians AEs: 2 AEs

^aThe study also included adults; ^bthis study enrolled 18 children aged <2 years who were excluded from the analyses; ^cthis study also enrolled children who were treated with acetylcysteine; the decision to treat with acetylcysteine or EA 575 was made by the clinician before study enrolment, and only two children received acetylcysteine.

Abbreviations. ADR, adverse drug reaction; AE, adverse event; b.i.d., two times per day; BSS, Bronchitis Severity Score; FEV₁, forced expiratory volume in 1 s; FVC, forced vital capacity; MEF_25/50, maximal expiratory flow at 25/50% of the vital capacity; PEF, peak expiratory flow; t.i.d., three times per day.

Across the observational studies, a high proportion of patients (91%) and clinicians (≥86%) rated the global efficacy of EA 575 as good or very good^30,31,36. Regarding specific aspects of cough, patients treated with EA 575 showed improvements on cough frequency, shortness of breath, expectoration, and respiratory pain^{29–31,33,34,36,37}. Furthermore, one of the large studies in >1,000 school children with acute bronchitis documented a 58.1% reduction from baseline in patient- or parent-reported sleep problems after 7 days of EA 575 treatment³⁶. Overall, the number of episodes of wakefulness decreased from approximately 7 times per night to 2 times per night³⁶.

Safety and tolerability of EA 575 in pediatric patients

Safety and tolerability data for EA 575 were primarily obtained from the observational studies. Overall, studies documented a low incidence of adverse events (AEs) among pediatric patients who received EA 575^29–37. In the large, retrospective review of >52,000 pediatric patient files (15% aged <1 year, equating to >7,000 infants), the incidence of adverse drug reactions (ADRs) was 0.2%³².

The most common AEs affected the gastrointestinal tract (e.g. diarrhea, enteritis, and nausea) but still occurred at a low incidence (<2% of patients)^{31–33,35,36}. When analyzed according to age, the incidence of gastrointestinal ADRs was highest among children <1 year of age (0.35% of >7,000 infants) and decreased with increasing age³². Dermatological AEs (e.g. allergic exanthema/urticaria) were documented in a minority (typically, ≤0.6%) of patients^30,32–34.

Across all studies (clinical trials and observational), a high proportion of patients (≥95%) and clinicians (≥96%) rated the tolerability of EA 575 as good or very good^{20,21,25,29,30,33–37}. In one active-controlled trial, all clinicians rated the tolerability of EA 575 as good or very good, whereas 76% of clinicians rated the tolerability of acetylcysteine as good or very good²⁵. In another active-controlled trial, the mean clinician- and patient-rated global assessment of tolerability was good (scores of 4.2 and 4.0, respectively, out of 5), and comparable between EA 575 and ivy leaf DER 2.2–2.9:1²⁶. Similarly, a double-blind, placebo-controlled trial did not reveal any relevant differences in patient- or clinician-rated tolerability between EA 575 and placebo²¹.

Expert survey

In total, 322 email invitations to the expert survey were sent out. Thirty healthcare professionals gave consent to participate in the survey, of whom 18 met eligibility criteria, and 14 answered at least one question in the EA 575 section.

Participant characteristics

The 14 participants represented 9 countries: Croatia (n = 3), Germany (n = 2), the United Kingdom (n = 2), the United States (n = 2), Italy (n = 1), Malaysia (n = 1), Qatar (n = 1), Slovenia (n = 1), and the United Arab Emirates (n = 1). All participants had treated pediatric cough for >10 years and had managed >30 pediatric patients with cough in the past 6 months. Regarding the expertise of the healthcare professionals, 13 (93%) spent >50% of their professional time in clinical practice, 12 (86%) had participated in a specialist pediatric cough congress or session within a pediatric respiratory conference, 7 (50%) had been an author on an article relating to pediatric cough published in a peer-reviewed journal, and 8 (57%) had worked on national or international pediatric cough guidelines.

Four of the 14 participants (29%) had not prescribed or recommended EA 575 for pediatric patients and, therefore, were ineligible to continue with the survey. Reasons given for not prescribing or recommending EA 575 were not knowing about the product (n = 3) and a perceived lack of evidence of its efficacy (n = 1).

EA 575 for pediatric cough

In the past 6 months, all ten participants had recommended EA 575 to pediatric patients with acute cough. A small number of participants had also recommended EA 575 for chronic cough (n = 2) or chronic respiratory conditions such as asthma or chronic obstructive bronchitis (n = 2). EA 575 was recommended to children aged <1 year (n = 2), 1–2 years (n = 7), 3–6 years (n = 7), 7–12 years (n = 8), and >12 years (n = 6).

On a 5-point scale from “very good” to “very poor”, participants rated the overall effectiveness of EA 575 for pediatric cough as moderate (n = 1), good (n = 7), or very good (n = 2). Regarding specific symptoms, EA 575 was considered most effective (≥6 participants rated it good or very good) at reducing cough frequency, viscous mucus, cough intensity, and cough-related sleep disruption (Figure 1).

Figure 1. Clinician-rated effectiveness of EA 575 on reducing symptoms in pediatric patients with cough (n = 10).

Effectiveness was rated on a 5-point scale: very good, good, moderate, poor, or very poor. No clinicians rated the effectiveness of EA 575 as very poor at reducing symptoms.

Most participants (n = 8) were of the opinion that EA 575 improved overall quality of life in pediatric patients with cough. Five participants mentioned sleep as an aspect of quality of life that improved with EA 575 (Figure 2). Specific changes in sleep that were reported included longer duration and fewer awakenings.

Figure 2. Clinician-reported aspects of quality of life that improve with EA 575 (n = 8).

This was an open question.

On a 5-point scale, the overall tolerability of EA 575 in pediatric patients was rated as moderate (n = 1), good (n = 2), or very good (n = 7).

Discussion

Whereas previous reviews have addressed the efficacy and tolerability of EA 575 in adults and children combined, and often grouped with inequivalent ivy leaf extracts^3,38,39, the present review specifically and comprehensively evaluated the efficacy and tolerability of ivy leaf dry extract EA 575 in the treatment of pediatric patients with acute or chronic cough, via a literature review and an international expert survey. Nineteen published studies were identified – a mixture of controlled clinical trials and observational studies in pediatric patients with respiratory tract infection, bronchitis, bronchial asthma, and inflammatory or obstructive respiratory diseases. Considering this body of evidence, the findings suggest that EA 575 may provide a variety of clinical benefits in pediatric patients with cough, with minimal side effects. The safety data were mostly derived from real-world studies including a retrospective analysis of >52,000 pediatric patient records, of which >7,000 records were for children aged <1 year³². Given the large sample sizes across the real-world studies, the low incidence of AEs convincingly demonstrates the favorable safety and tolerability profile of EA 575 in pediatric patients. However, while the safety data were derived from large samples, the efficacy data must be interpreted with caution due to lack of replication, low quality of reporting, and small sample sizes.

Considering cough-related symptoms, the observational studies highlighted a broad range of subjective improvements with EA 575 treatment, including cough frequency, the production of viscous mucus, respiratory pain, and disrupted sleep^{29–31,33,34,36,37}, although results from controlled trials were mixed^{1,20,21,23–25}. One of the observational studies documented a more than three-fold reduction in the number of episodes of wakefulness in a large population of children with acute bronchitis³⁶. In the survey, several clinicians highlighted sleep as a key aspect of quality of life that improved with EA 575 – particularly sleep duration and continuity. Cough is known to have a considerable detrimental impact on sleep for children and their parents^40,41 and, therefore, improved sleep could be a welcome, indirect benefit of EA 575.

Controlled trials of EA 575 were generally positive with regard to changes in objective spirometry and body plethysmography parameters indicative of improved lung function. Active-controlled trials consistently reported improved FEV₁ in children with acute or chronic respiratory conditions treated with EA 575, with changes favoring EA 575 over acetylcysteine^22,24,25. Trials also demonstrated the equivalent efficacy of different formulations of EA 575 (i.e. syrup, drops, and suppositories) based on objective assessment of lung function in asthma and COPD^19,20, and minimal differences were observed between EA 575 and other ivy leaf extracts based on subjective severity rating scales in bronchitis^1,23,26. Findings from the placebo-controlled trials were less consistent, with one trial documenting a greater reduction in RAW and increase in FEV₁ with EA 575 versus placebo²¹, and the other reporting no notable changes in these parameters²⁸. Although randomized controlled trials are widely considered to provide the strongest evidence for therapeutic effect⁴², the placebo-controlled trials of EA 575 were small (≤30 patients), which could potentially account for the contrasting observations.

There is increasing recognition of the value provided by studies conducted in real-world clinical practice⁴³. Such studies can demonstrate the utility of medical interventions in a broader population than clinical trials, which may be more representative of the patients encountered by clinicians⁴³. In this review, real-world observational studies of EA 575 were generally larger than the clinical trials – most enrolled >100 children and three studies enrolled >1,000 children – providing greater confidence in the results. As expected with real-world data, the studies focused on safety and tolerability, and efficacy was generally assessed using simplistic subjective measures, such as patient- or clinician-rated global assessment of efficacy. Across the studies, these assessments hinted at clinical benefits with EA 575, which were corroborated by responses to the survey. While these findings suggest a favorable opinion of EA 575 efficacy, real-world evidence of efficacy can, generally, only complement evidence from clinical trials⁴⁴.

Overall, studies indicated that EA 575 is generally well tolerated by children with acute or chronic cough, and responses to the survey supported this conclusion. Of the side effects reported with EA 575, gastrointestinal symptoms were most common but still occurred at a low incidence (<2% of patients)^{31–33,35,36}. One large study suggested that side effects with EA 575 may be more frequent in younger children (<1 year of age); however, the incidence was still low (0.35% for gastrointestinal ADRs, versus 0.17% in 0–12-year-olds)³². In general, young children represent a vulnerable patient group, and some regulatory authorities, such as the US Food and Drug Administration, discourage the use of over-the-counter cough medicines in children <2 years of age due to safety concerns⁴⁵. While the recommended age range for EA 575 treatment varies worldwide depending on local regulatory authorities, it is reassuring that this review did not identify any significant safety concerns in the youngest age groups. Indeed, EA 575 has accumulated more than five decades of post-marketing experience across numerous countries, with some regulators authorizing its use in more vulnerable age groups (i.e. children aged <1 year). Together with the findings from observational studies, there is substantial support for the safety and tolerability of EA 575 in pediatric patients of all ages.

Several aspects of this review may limit the ability to make strong conclusions as to the efficacy of EA 575 in pediatric patients with cough. As discussed above, although the controlled clinical trials provided the highest quality evidence in the literature review, they tended to enroll small numbers of patients, and many did not include a placebo group. This is, perhaps, unsurprising considering the challenges associated with conducting controlled clinical trials in pediatric cough, such as the difficulty in recruiting children, the usually self-limiting nature of acute cough⁴⁶, and the considerable placebo-effect encountered in trials of cough therapies⁴⁷. Furthermore, the age of the clinical trials must be mentioned, as half of the controlled trials were >20 years old. Since the 1990s, the field has advanced, with considerable changes in the diagnosis and treatment of pediatric cough. For example, a diagnosis of COPD in childhood – used in one of the controlled trials¹⁹ – is inconsistent with current understanding of the causes and development of COPD⁴⁸. Although events in early life may increase the risk of developing COPD in adulthood⁴⁹, in current clinical practice, children are not diagnosed with COPD or other chronic obstructive respiratory diseases. Preferred diagnoses may include recurrent wheezy bronchitis, protracted bacterial bronchitis, bronchopulmonary dysplasia, and bronchiolitis obliterans.

The review was also limited by the quality of reporting. Many publications omitted key details of study design, and descriptions of the type, duration, and severity of AEs were not always available. Furthermore, clinical trials often differed in terms of the dose and duration of treatment with EA 575, and the endpoints evaluated. None of the trials included objective assessments of cough improvement; validated methods for measuring cough frequency are required for future research in this field¹⁸, especially for young children who have limited ability to describe their symptoms. While spirometry provided a quantitative assessment of lung function in a number of studies, performing spirometry in young children (aged <5 years) can be challenging⁵⁰ and, therefore, some trials excluded these children from testing. Consequently, findings relating to the effects of EA 575 on pediatric lung function must be interpreted with caution. Variation in study design has previously been cited as a barrier to evaluating the overall effectiveness of over-the-counter cough medicines⁵¹. Encouragingly, responses to the survey tended to agree with the findings from the literature. However, while expert opinion is valuable, it may not be representative of day-to-day clinical practice and, as purely subjective assessment of treatment effectiveness, it is not a substitute for clinical evidence. Also, interpretation of the survey responses was limited by the low response rate, which may be due to the strict entry criteria used to identify experts in the field of pediatric cough¹⁸. Furthermore, the survey coincided with the COVID-19 pandemic, which is a likely contributor to the low response rate, considering that the target audience consisted of respiratory experts.

Conclusions

Overall, the findings of this review suggest that EA 575 has minimal side effects in pediatric patients with cough, as demonstrated by large real-world studies that convincingly show a favorable safety profile in children, including infants aged <1 year. EA 575 may provide clinical benefits in pediatric patients with acute or chronic cough. However, caution is needed when interpreting the efficacy results due to small sample sizes, subjective outcome measures, and a lack of placebo control groups. To provide more robust evidence for the efficacy of EA 575 in pediatric patients with cough, larger controlled clinical trials would be welcomed, though the challenges associated with such research must be acknowledged. Further evaluation of the impact of EA 575 on aspects of quality of life, such as sleep, would also be valuable for clinicians and patients.

Transparency

 

Author contributions

GS and CV contributed to the design of the study and the interpretation of data. LU and CPW contributed to the design of the study, acquired the data, and contributed to the interpretation of data. All authors participated in the drafting or the critical review of the article; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Acknowledgements

Editorial support was provided by Cambridge – a Prime Global Agency, funded by Engelhard Arzneimittel GmbH & Co. KG. The authors thank Dr. Jasmine Fokkens and Dr. Christoph Strehl for the conceptualization of the review paper, and the participants for their time completing the questionnaire.

Declaration of financial/other relationships

GS has received honoraria from Dr. Willmar Schwabe GmbH & Co. KG for scientific services. LU and CPW are employees of Cambridge – a Prime Global Agency, which received funding from Engelhard Arzneimittel GmbH & Co. KG for this work. CV has received study, lecture or consulting fees from AstraZeneca, Boehringer Ingelheim, Engelhard Arzneimittel GmbH & Co. KG, Novartis Pharma, and Sanofi Aventis. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Data availability statement

The dataset supporting the conclusions of this article is included within the article and its supplementary files (see Supplementary file 2).

Additional information

Funding

This work was supported by Engelhard Arzneimittel GmbH & Co. KG (Niederdorfelden, Germany). The sponsors were involved in the design of the study and reviewed the content of the article but had no role in the analysis and interpretation of data.