Complementary and alternative medicine in the treatment of acute bronchitis in children: A systematic review

Journal Pre-proof Complementary and alternative medicine in the treatment of acute bronchitis in children: A systematic review ¨ P.M. Wopker, M. Schwermer, S. Sommer, A. Langler, K. Fetz, T. Ostermann, T.J. Zuzak

PII:

S0965-2299(19)30535-7

DOI:

https://doi.org/10.1016/j.ctim.2019.102217

Reference:

YCTIM 102217

To appear in:

Complementary Therapies in Medicine

Received Date:

13 April 2019

Revised Date:

27 September 2019

Accepted Date:

11 October 2019

¨ Please cite this article as: Wopker PM, Schwermer M, Sommer S, Langler A, Fetz K, Ostermann T, Zuzak TJ, Complementary and alternative medicine in the treatment of acute bronchitis in children: A systematic review, Complementary Therapies in Medicine (2019), doi: https://doi.org/10.1016/j.ctim.2019.102217

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Complementary and alternative medicine in the treatment of acute bronchitis in children: A systematic review

P.M. Wopker1,2, Ph.D. M. Schwermer1,2, S. Sommer1,2, M.D. A. Längler1,2, K. Fetz3, Ph.D. T. Ostermann3, M.D. T.J. Zuzak 1,4 *

of Pediatrics, Gemeinschaftskrankenhaus Herdecke, Germany

2Professorship 3Department

for integrative Pediatrics, Witten/Herdecke University, Faculty of Health, Germany

of Psychology, Chair of Research Methodology and Statistics in Psychology,

Witten/Herdecke University, Germany Faculty of medicine, University of Duisburg-Essen, Germany

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1Department

Corresponding author

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PD Dr. med Tycho Zuzak

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Department of Pediatrics Gemeinschaftskrankenhaus Herdecke

Gerhard-Kienle-Weg 4, 58313 Herdecke

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Telefon: +49 2330 62-2183; Telefax: +49 2330 62-34744

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E-Mail: [email protected]

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Brief running title: Complementary and alternative medicine in the treatment of acute bronchitis in children Text word count: 4285

The project was financially supported by the Mahle Foundation and the Christophorus Foundation

Highlights    

Our review gives an overview of studies investigating complementary and alternative medicine therapies for infantile acute bronchitis Clinical studies for herbal medicine, anthroposophic medicine, Traditional Chinese medicine and homeopathy were identified by a comprehensive systematic literature search Study results indicate promising effects of several remedies Randomized controlled trials are rare

Abstract Objective: Our review summarizes published literature of complementary and alternative

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medicine (CAM) used for the treatment of acute bronchitis in children. Background: Acute bronchitis is one of the most frequent pediatric diseases and has high prevalence for in- and outpatient care. Acute bronchitis is mainly a viral-caused infection,

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but a high and inappropriate use of antibiotics has been demonstrated in many countries. As CAM therapies might reduce the use of antibiotics and can complement conventional

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therapies in children, they could be an appropriate treatment option. Methods: A systematic literature search was conducted using general and complementary

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and alternative medicine (CAM)-specific databases. A search term including 65 CAMassociated definitions was applied.

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Results: Literature search revealed 309 articles, whereby 18 articles hit search criteria. These clinical trials were subgrouped into the categories herbal medicine, anthroposophic

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medicine and homeopathy. The most often studied approaches are herbal remedies, in

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particular the Pelargonium sidoides extract, EPs® 7630. Its efficacy was demonstrated in three placebo-controlled trials and two observational studies. Anthroposophic approaches (mainly ribwort-containing remedies) were investigated in two controlled trials and three observational studies. Two studies were found investigating the homeopathic remedies, Monapax® and Droperteel®.

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Conclusion: Study results indicate a favorable effect of investigated CAM approaches. However, only three of 18 studies were randomized controlled trials (RCTs), so a reliable statement on effectiveness was not possible and further RCTs are indispensable.

Keywords: bronchitis; cough; child; complementary and alternative medicine

1. Background

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Acute bronchitis is one of the most common diseases in pediatrics and is one of the main reasons for a doctor’s consultation as well as admission to hospital 1. Due to its high frequency, acute bronchitis ranks among the most costly children’s conditions in western

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countries 2. The disease can range from mild to severe and is characterized by symptoms

symptoms

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such as coughing and respiratory rales. Fever and dyspnea can also be possible . Acute bronchitis is mostly a viral-caused inflammation of the mucous

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membrane of the bronchi 4. Bacterial infection may occur as a superinfection subsequent to the viral inflammation 3. Conventional treatment includes inhalation with sodium chloride

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(0.9 %), application of β2 agonists (e.g. salbutamol) in case of obstruction and, if indicated, the use of antibiotics to treat bacterial infection 3.

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Even though bronchitis is mostly a viral-caused (85-95 %) infection, antibiotic medication is applied frequently 5. In fact, about 75 % of all outpatient antibiotic prescriptions for children

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aim to treat respiratory infections, including bronchitis 6. In various studies, the use and effect of antibiotics was investigated and assessed to be inappropriate. An unnecessary prescription practice and overuse of antibiotics were identified

7-11

. Additionally, the

administration of antibiotic drugs may have numerous side effects such as gastrointestinal complaints

12

or allergic reactions

13

. Moreover, taking into consideration the drastically

growing resistance threatening the ability to effectively treat bacterial infections, antibiotics 3

have to be used carefully and scarcely in case of a bacterial cause 6,9,14. As antibiotics are not effective against viral-caused acute bronchitis, therapy is restricted to the treatment of symptoms. Here, CAM might provide a safe appropriate option. Furthermore, research indicates that physicians practicing both, CAM and conventional medicine, have lower prescription rates of antibiotics than physicians applying solely the conventional approach 15

.

CAM applies various non-conventional approaches, including drugs, external applications as well as creative and movement therapies, to restore health

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. These therapies can be

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applied in addition or as alternative to conventional medicine.

Concurrently, a growing interest in CAM can be observed and has been shown for Europe 17,18

and the United States 19.

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The interest in CAM is not unique to any specific illness or restricted to utilization in adult

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patients. There is, actually, a great and seemingly growing use of CAM therapies in pediatrics, as many parents state to adopt CAM in the treatment of their children

17,20-22

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More than 50 % of Canadian and European children from numerous countries receive CAM therapies supplemental to or instead of conventional medicine in case of sickness .

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16,17,20-22

One of the reasons for the increasing interest in CAM is the patients’ and parents’

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perception of it being “natural” and safer than conventional medicine as well as enabling the patient to take charge of his own health conditions 19.

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Parents in Germany, for example, state to rely on CAM therapies for their children to strengthen the immune system, improve chances of healing and to seek stabilization of physical and mental conditions 16. Given the increasing use of CAM therapies in pediatrics, it is important for physicians and health providers to be aware of the safety and efficacy of such therapies. Recently, a systematic review demonstrated that CAM therapies are considered for the treatment of 4

bronchiolitis, an acute lower respiratory tract infection of viral origin affecting mainly very young infants 23. This review also showed that the evidence of CAM therapies is yet poorly investigated as only 11 clinical trials of moderate quality were identified. No significant benefit was shown, however no serious adverse events were reported either. Therefore, the aim of this review is to provide an overview on published literature investigating CAM-based therapies for acute bronchitis in children.

2. Methods 24

. The PRISMA

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Research and writing was conducted according to the PRISMA protocol

checklist has been taken into account wherever possible (supplemental data 1.)

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2.1 Search strategy

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To obtain an overview on existing published literature on CAM-based therapies for acute bronchitis in children, a thorough database screening was performed. Here, general

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databases (PubMed, Cochrane Library, OVID) and CAM-specific databases (CAMbase, CAM-QUEST®, Anthromedics) were screened from their inception to May 2019. All English

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and German written articles were included.

To ensure a high coverage of search results, we developed a comprehensive search term

search

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including bronchitis-specific symptoms and 64 CAM-associated therapy approaches. The term

for

the

PubMed

screening,

for

example,

was

as

follows:

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„((bronchitis[title/abstract] OR (dyspnoea[title/abstract] OR dyspnea[title/abstract] AND cough[title/abstract])

OR

bronchiolitis[title/abstract])

AND

(child[title/abstract]

children[title/abstract] OR childhood[title/abstract] OR pediatric[title/abstract])) (acupressure[title/abstract] technique[title/abstract]

OR OR

acupunct*[title/abstract]

alternative

medicine[title/abstract]

OR OR

OR AND

alexander alternative

therapies[title/abstract] OR anthroposophic*[title/abstract] OR aromatherap*[title/abstract] 5

OR art therapy[title/abstract] OR auricul*[title/abstract] OR autogenic training[title/abstract] OR

Ayurvedic

medicine[title/abstract]

OR

balneotherapy[title/abstract]

OR

biofeedback[title/abstract] OR chiropractic*[title/abstract] OR clinical ecology[title/abstract] OR

colon

cleansing[title/abstract]

OR

colon

irrigation[title/abstract]

OR

colour

therapy[title/abstract] OR complementary medicine[title/abstract] OR complementary therapies[title/abstract]

OR

supplement*[title/abstract]

OR

dance dietary

therapy[title/abstract] therapy[title/abstract]

OR

OR

dietary

Doman

Delcato

patterning[title/abstract] OR electroacupunct*[title/abstract] OR essential oils[title/abstract]

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OR eurythm*[title/abstract] OR flower remedies[title/abstract] OR health food[title/abstract] OR herbal*[title/abstract] OR homeopath*[title/abstract] OR hydrotherapy[title/abstract] OR hypnosis[title/abstract] OR hypnotherapy[title/abstract] OR imagery[title/abstract] OR medicine[title/abstract]

OR

laser

therapy[title/abstract]

OR

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integrative

light

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therapy[title/abstract] OR magnetic therapy[title/abstract] OR massage[title/abstract] OR meditation[title/abstract] OR mindfulness[title/abstract] OR music therapy[title/abstract] OR OR

supplement*[title/abstract]

OR

naturopath*[title/abstract]

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naprapathy[title/abstract]

nutritional

OR

nutritional

therapy[title/abstract]

OR

oils

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volatile[title/abstract] OR osteopath*[title/abstract] OR phytotherap*[title/abstract] OR plant medic*[title/abstract] OR plants extract[title/abstract] OR Qi Gong[title/abstract] OR OR

relaxation

techniques[title/abstract]

OR

relaxation

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reflexolog*[title/abstract]

training[title/abstract] OR shiatsu[title/abstract] OR sound therapy[title/abstract] OR Tai

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Chi[title/abstract] OR traditional African medicine[title/abstract] OR Traditional Chinese medicine[title/abstract]

OR

traditional

remedies[title/abstract]

OR

unani

medicine[title/abstract] OR yoga[title/abstract] OR zone therapy[title/abstract]) NOT chronic*[title] NOT asthm*[title]” The list of CAM terms used for the search was adopted and modified from a publication of Böhm et al.

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. According to the requirements of each database, terms were adapted, 6

specified or translated.

2.2 Selection process First, all types of detected articles (clinical studies, reviews, experience reports, casuistries) were included. To identify relevant content, all articles were screened for title and abstract. Articles meeting the inclusion criteria were analyzed more closely. Selection was performed independently by two reviewers (PW, MS). In case of discrepancy, a third reviewer was sought out for consent (TZ).

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Inclusion criteria: - German or English written language

- Search terms child and bronchitis were obligatory

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- Case reports

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- Full text available

- Clinical studies

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Articles concerning chronic bronchitis, bronchiolitis and asthma were excluded.

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2.3 Data processing

Relevant articles were subsequently classified into clinical studies and case reports. The

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types of articles were further subgrouped into different CAM-categories regarding their therapeutic approach: Herbal Medicine, anthroposophic medicine and homeopathy. Their

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content was thoroughly analyzed in respect to year of publication, study design, therapeutic approach/remedy, number and age of participants, dosage and frequency of therapy as well as for the outcome.

3.

Results

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The online database screening revealed a variety of CAM-associated therapies for bronchitis in children. After removal of duplicates, 309 articles met search criteria; among these 19 clinical trials investigating CAM therapies were identified. The content of residual articles did not correlate to the research question and its terms. The most common reason for exclusion was investigation of therapies in an adult cohort, study of diseases other than bronchitis or studies dealing with conventional therapy approaches. Initially results for bronchiolitis were included in the search but were excluded from the evaluation in the further process (Fig. 1).

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Clinical trials investigating diverse CAM therapies for bronchitis in children could be subdivided into herbal medicine (11 articles), anthroposophic medicine (5 articles) and homeopathy (2 articles). An overview of all articles including the study type, therapeutic

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approach, outcome and other parameters is displayed below (Table 1-3).

Figure 1: Article selection (diagram modified from 24)

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3.1 Herbal medicine For the treatment of bronchitis in children, the prevailing results on CAM therapies, as found by the database screening, are based on herbal medicine. Three RCTs and eight observational studies investigating the effectiveness of herbal remedies applied against acute bronchitis in children were identified (Table 1).

3.1.1 RCTs EPs® 7630

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One of the most examined remedies in herbal treatment for bronchitis in children is the herbal drug EPs® 7630 containing pelargonium sidoides roots. There are several promising RCTs stating its effectiveness.

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Kamin et al. showed in a placebo-controlled trial (400 patients, 6-8 years) a significantly

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greater reduction in the complaint score for the EPs® 7630 group compared to the placebo group. Patients were randomized to receive either 30 mg, 60 mg, 90 mg EPs® 7630 or

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placebo medication. Marked improvement could equally be seen after seven days for the treatment with 60 mg and 90 mg per day (p = 0.0004 and p< 0.0001) 26.

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Another trial by the same author with the same study design was carried out on 220 patients aged 1-18 years.

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The intake of concomitant medication that could alter the

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outcome, such as antibiotics, bronchodilators and others, was an exclusion criterion. Paracetamol was permitted in case of fever above 38.5°C. A significant greater decrease

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of bronchitis-specific symptoms was revealed for the test group compared to the placebo group (p<0.0001).

The effect of EPs® 7630 was also illustrated by a similar randomized placebo-controlled study performed on 200 patients aged 1-18 years 28. Doses differed from 3x10 drops, 3x20 drops to 3x30 drops (solution containing 80 g EPs® 7630 in 100 ml) daily according to the

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patient´s age. From day one to seven the intervention group showed a markedly stronger reduction of bronchitis-associated symptoms than the placebo group (p <0.0001).

3.1.2 Non-RCTs EPs® 7630 In a large prospective observational study, comprising of a total of 2,099 patients (1,601 adults and 498 children) presenting symptoms of acute bronchitis, EPs® 7630 was applied in age-appropriate doses from 3x10-3x30 drops

29

. After a period of 14 days, the final

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evaluation of the subgroup of children showed a decrease in the score of bronchitisspecific symptoms from 6.3 (+/-2.8) to 0.9 (+/-1.8) points. Side effects in children were rare (14/498) and mainly gastrointestinal disorders. Authors assessed efficacy and safety as

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good.

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. Here, 742

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EPs® 7630 was also subjected to a post-marketing observational study

children aged between 0-12 years were treated with doses varying from 3x5, 3x10 to 3x20

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drops daily over a maximum duration of two weeks. At the end of treatment, complete remission or improvement of bronchitis-specific symptoms was stated for 90.2 % of the

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patients.

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Hedera helix extract (Ivy leaf extract)

In a large observational study about Hedera helix extract, 5,181 children, out of a total of

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9,657 patients including adults, received a median dosage of 10 ml/day for seven days. After seven days, in 95 % of all patients absence or improvement of symptoms was marked. A slightly better effect could be seen in adults. In 36.2 % of the young patients antibiotics were given as concomitant medication. This only slightly improved treatment and outcome, but there was a significant higher relative risk of side effects (26 %) 31.

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Herbal therapy with Hedelix® (ivy leaf extract as a syrup and as cough drops) was also investigated by two non-interventional studies on 136 children, respectively

32

. During a

medium duration of 10 days, children allocated to treatment with syrup received according to their age and weight 1x2.5-3x5 ml/day. The doses for drops varied from 3x5- 3x31 drops/day. The effect was measured via a verbal rating scale with a final visit on day 8-14. The outcome was comparable in both groups. A within-subject decrease of cough (51.4 % to 1.9 %), pain on coughing (14.4 % to 0.5 %) and rhinitis (45.9 % to 1.6 %)

Isothiocyanate

(Angocin®

mixture

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could be observed.

Anti-Infekt

N)

Another prospective cohort study renders direct comparison between the herbal drug

33

. Out of a total of 858 children suffering either from

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for the treatment of acute bronchitis

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preparation containing nasturtium herb and horseradish root and standardized antibiotics

acute bronchitis, sinusitis or urinary tract infections, 290 children suffering from acute

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bronchitis were treated with the herbal drug (test group) while 112 received antibiotic therapy (control group). At the end of treatment, the test and the control group of the entire

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target population showed a comparable reduction of complaints. Even though in the beginning the test group showed markedly less complaints than the control group, the

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result was interpreted as Angocin® Anti-Infekt N and antibiotics being an equivalent

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treatment for the diseases aforementioned.

Thyme and primrose The combination of thyme and primrose as treatment for cough and bronchitis was subject to an observational non-controlled study. The herbal combination was given as juice to 636 children. Improvement of cough as the major parameter was achieved after seven days for most patients 34. 11

The same combination (as Bronchicum® Elixir) was given to 200 toddlers in another observational study. The treatment with 6x1 ml/day also resulted in a within-subject improvement of the cardinal symptom cough in 71 % of the cases 35.

Thyme and ivy leave A thyme/ivy leave syrup (Bronchipret® Saft) was tested in a large post-marketing observational study carried out on 1,234 children

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. Pursuant to age, doses were

prescribed by the treating physician. The symptom-scoring evaluation on day ten showed

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a decrease of complaints from 8.8 to 1.3 points with tolerability judged as “good” or “very good” by 96.5 % of the doctors.

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3.2 Anthroposophic medicine

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Most studies found by the database screening examined both adults and children. Two controlled trials and three observational studies were identified (Table 2). One study

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referred exclusively to an anthroposophic treatment of children compared to conventional

3.2.1 Non-RCTs

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therapy 37.

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WALA® Plantago Bronchial Balm

The WALA® Plantago Bronchial Balm, a solution for chest embrocations to ease

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symptoms of bronchitis such as cough, was subject of two studies. In an observational study performed on a total of 103 patients (84 children and adolescents <20 years), the authors point out that embrocations with WALA® Plantago Bronchial Balm resulted in remission or marked improvement of symptoms in 92 % of participants

38

. Treatment was exerted one or two times daily for three to seven days. A

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reduction of symptoms occurred mostly within two or three days and good tolerance was stated. The other study was a subgroup analysis of an international controlled cohort study

39

.

Here, 93 children up to 11 years with cough due to acute bronchitis were treated with an average of two to three embrocations a day for five days. A complete remission was observed in 30 patients after seven days. In a final follow-up visit on day fourteen, 38 of the remaining 77 participants presented a complete remission of symptoms, 32 a marked improvement and seven a slight improvement. This corresponded to an overall high

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satisfaction in 95 % of all treated patients.

WALA® Bronchi Plantago coated pillules

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WALA® Bronchi Plantago in a different form of application, as coated pillules, was

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investigated in an observational study carried out on a total of 113 patients 40. The average age was 24.3 years and 48.7 % of patients were 14 years or younger. Average dosing was

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five to ten coated pillules, one to three times per day. Complete recovery from acute bronchitis-related symptoms (57.5 %) or at least improvement (38.1 %) was documented

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after an average of 7.2 days. In 2.7 % of the cases deterioration was observed. Efficacy

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was asserted to be higher for the subgroup of children <14 years than for adults.

WALA® Thymus Oleum aethereum 5 %

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A subgroup analysis of the aforementioned international controlled cohort study

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also

revealed data for a small group of 23 patients, of which 14 were children, treated with WALA® Thymus Oleum aethereum 5 % as embrocation. All participants suffered from cough while four patients were precisely diagnosed with bronchitis. Administration of treatment was two to three times daily for six to 14 days. The final evaluation, although of limited meaningfulness for the current research question due to the very small number of 13

comprised children participants, showed cure or marked improvement for 16 patients accompanied by high satisfaction of the entire target group.

WALA® Plantago cough linctus The international controlled cohort study

39

also yielded data for a third anthroposophic

remedy: WALA® Plantago cough linctus. It was tested on a small target group of 29 patients. Ten of them were children <11 years. The syrup was given four to five times daily over a period of 10-14 days. Within two weeks, 13 of the patients stated a complete cure

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of symptoms, 11 a marked improvement and three a slight improvement. Additionally, 25 out of 29 patients indicated high satisfaction.

41

. One out of two studies mentioned in the article was

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in another observational study

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In addition, Rinker et al. also pointed out WALA® Plantago cough syrup as being efficient

considered because the main target group was children. In this study, 111 patients were

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treated with WALA® Plantago cough syrup, whereby 90 % of patients were children or adolescents (5-20 years; ø 14 years). Infants were treated with one teaspoon of cough

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syrup in warm water or tea, three to four times a day. Dosage was increased for children and adolescents from one tablespoon three times daily up to every two hours. The within-

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subject evaluation after four to twelve days revealed complete remission of symptoms (44.1 %) or noticeable improvement (45.9 %) in all patients. Overall, physicians classified

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efficacy as good or very good in 84.3 % of the cases and absence of side effects was declared.

Further anthroposophic therapies Another prospective observational study investigated the effect of an anthroposophic therapy approach compared to conventional medicine in the treatment of acute respiratory 14

tract and ear infections in children

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. The cohort comprised 529 children aged one month

to 17 years. Herein, 443 patients were allocated to be treated by anthroposophic physicians and 88 patients received conventional treatment. The final evaluation showed a much lower use of antibiotics for the anthroposophic group (5.5 %) compared to the conventional group (25.6 %). Likewise, the use of analgesics was markedly lower for the anthroposophic group (3 % vs. 26 %). In addition, they observed a faster improvement of symptoms and a higher satisfaction of the caregivers in the anthroposophic group.

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3.3 Homeopathy

Despite the fact that homeopathy is one of the most commonly used CAM practices among children in Germany

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, only two studies based on this practice were found

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(Table 3).

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3.3.1 RCT

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In a placebo-controlled trial the effect of Monapax® syrup, a combination of the homoeopathic remedies Drosera, Coccus cacti, Cuprum Sulfuricum and Ipecacuanha, was 43

. In the test group

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examined on 180 children (test group N=89, placebo group N=91)

children from 7 months to 12 years received Monapax® syrup for acute dry cough.

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Treatment was given three times daily in age-appropriate doses for seven days. A significant (p<0.0001) greater improvement of the cough was shown for children treated

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with Monapax® syrup compared to placebo group.

3.3.2 Non-RCT

In an observational study, 201 children, 70 % of them suffering from mostly viral-caused bronchitis, were treated with Droperteel®, a homeopathic remedy consisting of different herbal components

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. For the mean duration of treatment, participants received one pill 15

three times daily. As 75 % of patients were showing complete or partial cure of symptoms within the first week, 90 % of the participating physicians rated the effectiveness at least as

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“good”.

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Table 1: Clinical trials investigating herbal medicine indicated for acute bronchitis in children Indication

Number and age Concomitant of participants medication

Randomized, double-blind, placebocontrolled clinical study

Acute bronchitis

N=400 (6–18 y). Not mentioned 4 groups: 30 mg EPs® 7630 N=101; 60 mg EPs® 7630 N=99 , 90 mg EPs® 7630, N=99; placebo N=101

Kamin EPs® 7630 (herbal drug preparation from Pelargonium sidoides roots)

Randomized, doubleblind, placebocontrolled study

Acute bronchitis

C. Nauert 2003 34

RCTs

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Kamin EPs® 7630 Randomized, Acute bronchitis (herbal drug placebopreparation from controlled study Pelargonium sidoides roots)

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W 2012 27

Herbal drug preparation EPs® 7630 (Pelargonium sidoides roots (1:8–10) extraction solvent ethanol 11%)

Herbal Clinical combinations of observational thyme and study primrose root

N=200 (1-18 y)

Pr

W. Kamin 2010 28

Dosage frequency

and Outcome

f

Study design

pr

W 2009 26

Remedy/ therapeutic approach

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Reference

Acute bronchitis

Paracetamol allowed in case of fever of 38.5°C and higher. Usage unknown

30 mg, 60 mg or Decrease in bronchitis-specific 90 mg/day symptoms from day 0-7: Placebo: 3.3 ± 2.6, EPs 7630 (30 mg): 3.6 ± 2.4, EPs 7630 (60 mg): 4.4 ± 2.4, EPs 7630 (90 mg): 5.0 ± 1.9. Better score for 60 mg and 90 mg compared to placebo (p = 0.0004 and p < 0.0001). Tolerability was comparable to placebo in all treatment groups 1-6 y: 3x10 Score of bronchitis-specific symptoms drops/day, comparing day 1 to day 7: 6-12 y: 3×20 EPs® 7630 group: 3.4±1.8, drops/day, control group: 1.2±1.8 (P <0.0001). 12-18 y: 3×30 Outcome and satisfaction significantly drops/day. better for EPs® 7630 group. Preferably 30 min Tolerability comparable in both groups before a meal. Duration 7 days 1-6 y: 3x10 Decrease of bronchitis-specific drops/day, symptoms from day 0-7: 6-12 y: 3x20 EPs® 7630 group compared to placebo drops/day, group: 4.4 +/- 1.6 vs 2.9 +/- 1.4 points. 12-18 y: 3x30 Decrease markedly higher for EPs® drops/day. 7630 (P < 0.0001). Preferably 30 min Tolerability comparable in both groups before a meal. Duration 7 days

In EPs® 7630 group: 6.3 %, in placebo group 10.1 %. Exclusion criteria: Antibiotics, bronchodilators, glucocorticoids, analgesics, secretolytics, mycolytics, antitussives or other bronchitis medication. Paracetamol allowed for fever >38.5°C. Infants(1-4 y) Not mentioned Infants 6x2.5 ml/day, Most patients: N=312, children 6x5 ml/day. Marked reduction of cough within 7days children (4-12 y) Duration 7-9 days N=324 N=220 (1-18 y) N=111 EPs® 7630, N= 109 placebo.

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2007 Herbal drug Prospective preparation controlled Angocin ® Anti- cohort study Infekt N

Indication

Number and age Concomitant of participants medication

Acute sinusitis, Children (4-18 y) acute bronchitis, N=858; acute cystitis Test group N=523. Antibiotic (control) group N=335. Only acute bronchitis N=290 (test group N=178, antibiotic group N=112)

Dosage frequency

and Outcome

Mainly expectorants: In test group 16.9 %, in antibiotic group 19.6 %. Inhalations: Test group 93.3 %, antibiotic group 94.6 %.

Dosage and duration determined by physician, average dosage for children (4-18 y): 12.8 pillules/day

Complaint score at start less severe in test group (mean score 1.67), antibiotic group (mean 2.00; p > 0.001). After 7-14 days: No significant differences in complaint score (test group 0.41, antibiotic group 0.49; p = 0.722). Adverse events: N=3 (0.6 %) in test group, N=14 (3.9 %) in antibiotic group (p =0.001). Average reduction complaint score: Test group 82.1 %, antibiotic group 77.7 %. Therapy with Angocin ® Anti-Infekt N judged to be as efficient as treatment with standard antibiotics

Antitussive agents and expectorants (26.5 %) rhinilogical agents (12.8 %), broncholytic agents (6.5 %). Supportive measures (compresses or inhalations) in 44.5% of the children

Infants (0-2 y): 3x5 drops/ day, children (2-6 y): 3x10 drops/ day, children (> 6 y): 3x20 drops/ day. To be taken with liquid before meals. Duration maximal 2 weeks

Day 7: Decrease of five bronchitis specific symptoms from baseline 6.0+/3.0 points to 2.7+/2.5. Day 14: Decrease to 1.4 +/- 2.1. Cure or partial remission of symptoms in 90.2 %. Physicians rated treatment as successful in 88.3 % of cases

Age-appropriate dosages prescribed by the doctor on a case-by-case basis

Decrease of bronchitis specific symptoms from day 0-4: 8.8 to 4.8 points. On day 10 to 1.3 points. Tolerability rated as “good” to “very good” by physicians in 96.5 % of cases

Acute bronchitis (83.4 %) or acute exacerbations of chronic bronchitis (14.3 %),

N=742 (0-12 y)

Acute bronchitis

N=1234 (2-17 y); Not mentioned <2 y N=12; 2-5 y N=372; 6-11 y N=438; 12-17 y N=412

O. 2007 36

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Non-RCTs

na l

M. Haidvogl et al Herbal drug: EPs® Clinical 2007 30 7630solution observational (liquid herbal study preparation from the roots of Pelargonium sidoides; 80g EPs® 7630 in 100 ml solution)

Pr

e-

pr

33

Study design

f

K.-H.Goos

Remedy/ therapeutic approach

oo

Reference

Marzian Bronchipret® Saft Clinical (extracts from observational thyme and ivy) study

18

Number and age Concomitant of participants medication

H. Matthys et al. EPs® 7630 Clinical 2007 29 (liquid herbal drug observational preparation from study the roots of Pelargonium sidoides; 80 g EPs® 7630 in 100 ml solution)

Acute bronchitis

N=2099 (0–93 y). Total subgroup of children (0-18 y) N=498; infants (>2 y) N= 420; toddler and school children (3-18 y) N=78

M. 2008 35

Acute cough, Infants N=200 Unknown bronchial and/or (6-12 months) mucous catarrh

Schmidt Bronchicum® Clinial Elixir observational (herbal extracts study from primula root and thyme herb) Hedera helix Clinical (syrup containing observational dried ivy leaf study extract)

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Non-RCTs

M. Schmidt 2012 Hedelix® Clinical 32 (ivy leaf extract as observational a syrup and as studies cough drops)

Concomitant medication N=465 out of 2099 (22.2%). Specific medication unknown

oo

Bronchitis All patients (acute or N=9657; chronic children N=5181. bronchial inflammatory disease)

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S. Fazio 2009 31

Dosage frequency

and Outcome

f

Indication

pr

Study design

Concomitant drugs: N=5.865 (60.7 % of the patients); antibiotics N=3.795 (39.2 %), antibiotics in children N=1874 (36.2 %).

Acute N=268 (0-12 y); Concomitant respiratory syrup N=136, medication catarrh and/or drops N=136. exclusion criteria chronic recidivating inflammatory bronchial disease

0-6 y : 3x10 drops, 6-12 y: 3x20 drops, >12 y: 3x30 drops. Average duration 14.6 +/- 7 (14) days. Preferably 30min prior to meal

6x1 Average 6.4 days

e-

Remedy/ therapeutic approach

Pr

Reference

Decrease in bronchitis specific symptoms for subgroup of children (N=498): 6.3 +/- 2.8 to 0.9 +/-1.8. Adverse events children (mostly gastrointestinal problems) N=14. Good efficacy and safety concluded

ml. Follow up N=199: Improvement of duration cough in 71 %, improvement of other symptoms 67-74 %

Average dosage 15 ml/day (10 ml in children and 22 ml in adults). Average duration 7 days

After 7 days 95 % of all patients and 53.7 % of children <14 y: Improvement or cure of symptoms. Adverse events (mainly gastrointestinal disorders): 2.1 % of patients, 1.2 % in children. Relative risk of adverse events H. helix monotherapy versus H. helix plus antibiotics/chemotherapy increased by 26 %, efficacy marginally increased by 0,3 %.

0-1 y: 1x 2.5 ml as syrup or 3x5 drops, 1-4 y: 3x2.5 ml syrup or 3x16 drops, 4-10 y: 4x 2.5 ml syrup or 3x21 drops, 10-12 y: 3x 5 ml syrup or 3x 31 drops. Average duration 10 days

Follow up N=257. Comparable results in both studies: Decrease of symptoms day 8-14: Rhinitis (N=257) from 45.9 % to 1.6 %, cough (N=257) from 51.4 % to 1.9 %, pain on coughing (N=201) from 14.4 % to 0.5 %.

19

Table 2: Clinical trials investigating anthroposophic medicine indicated for acute bronchitis in children Indication

Number and age of Concomitant medication participants

U. Meyer WALA® 38 2003 Plantago Bronchial Balm

Clinical observational study

Bronchitis

N=103; <10 y 10-20 y N=34

F. Rinker WALA® 2004 41 Plantago cough syrup

Clinical observational study. Acute 2 groups described. Focus bronchitis on the one including children

Dosage frequency

and Outcome

f

Study design

oo

Remedy/ therapeutic approach

Concomitant anthroposophic, 1-2 embrocations N=50; phytotherapeutic or daily, homeopathic remedies: duration 3-7 days. > 75 % of patients. Conventional medicine N=4; ACC N=3, Amoxicillin N=2

e-

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N=111; (average: 14 y) Concomitant anthroposophic medication 45 %. Conventional medicine 4.6 %; Salbutamol N=2; Oralcephalosporin N=1; Cromoglicic acid N=2

Infants: 1 teaspoon in warm water/tea 3-4x/day. Children/ adolescents: 1 tablespoon in warm water/tea 3x/day. Higher doses up to 1 tablespoon every 2 hours possible

Improvement or cure of symptoms (cough, crackles expectoration) noted in 92 % of patients. Reduction of symptoms for nearly all patients within 2-3 days. Tolerance judged as good for adults and children

After 4-12 days: 44.1 % of patients absence of symptoms, 45,9 % noticeable improvement, 4.5 % no improvement, 92.4 % good tolerance, no response in 3.3 %. Global outcome of both studies: Efficacy rated as „good" to „very good" by physicians in 84.3 % of the cases. Tolerance rated “good" to “very good" by all patients. No undesirable effects

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Non-RCTs

pr

Reference

20

Remedy/ therapeutic approach

Study design

Indication

Number and age of Concomitant medication participants

F.Wellhausen 2006 40

WALA® Bronchi Plantago coated pillules

Clinical observational study

Acute bronchitis

N=113 (average 24.3 y) < 3 y N=9 ; <14 y N=55,

f

Reference

and Outcome

Average doses: 5-10 coated pillules 1-3x/day. Medium duration 8.6 days

Final examination after a medium of 7.2 days: 57.5 % of patients complete cure, 38.1 % improvement of symptoms, 2.7 % deterioration. Physicians´ judgement on effectiveness: “Very good/good” 87.6 %, “mediocre“ 8 %, “bad” 3.5 %.

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Pr

e-

pr

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Concomitant medication in 46 %: Secretolytic agents 23 %, antitussive agents 8 %, nosedrops15.9 %, antipyretics 8.8 %, decongestant medication 8.8 %, inhalation 8 %, antibiotics 4.4 %, liquids to gargle 2.7 %.

Dosage frequency

21

WALA® Subgroup analysis Plantago controlled cohort Bronchial (IIPCOS-2) Balm, WALA® Plantago cough linctus, WALA® Thymus Oleum aethereum 5 %

of a Cough due study to acute bronchitis

Number and age of Concomitant medication participants

Dosage frequency

WALA® Plantago Bronchial Balm N=112; <11 y N=93; WALA® Plantago cough linctus N= 29; <11 y N=10; Thymus Oleum aethereum 5 % N= 23; <11 y N=14 number of patients receiving conventional treatment unknown

WALA® Plantago Bronchial Balm: 1-6x embrocations daily, medium 2-3x daily. Duration 3-10 days, medium 5 days. WALA® Plantago cough linctus: 4-5x/day. Average duration 10-14 days; Thymus Oleum aethereum 5 %: 2-3x/day. Duration 6-14 days.

Pr na l Jo ur Non-RCTs

WALA® Plantago Bronchial Balm: N=92 concomitant anthroposophic medication, N=9 conventional medicine; N=5 nosedrops; WALA® Plantago cough linctus: Concomitant anthroposophic medication N= 21. Conventional medication N=5; codeine N=2; Thymus Oleum aethereum 5 %: Concomitant anthroposophic medication N=21

f

A. Oppermann 2009 39

Indication

oo

Study design

pr

Remedy/ therapeutic approach

e-

Reference

and Outcome

All remedies: High patients´satisfaction and good tolerance in 95 %. Additional antibiotics in anthroposophic group N=1/164. Antibiotic prescription to anthroposophic group 0.8 %, to conventional group 26.6 %. WALA® Plantago Bronchial Balm: Follow up on day 7 (N=103): N= 30 absence of symptoms, N=59 improvement, N=10 slight improvement, N=1 no change, N=3 deterioration. After 14 days (N=77): N=38 absence of symptoms, N=32 improvement, N=7 slight improvement. Anthroposophic treatment judged to be as efficient as conventional treatment WALA® Plantago cough linctus Day 7: N=5 complete cure, N=13 marked improvement, N= 6 improvement. Day 14 (N=22): N=8 complete cure, N=11 marked improvement, N=3 slight improvement. High satisfaction N= 25/29 Thymus Oleum aethereum 5 %: Day 7: N=5 complete cure, N=13 marked improvement, N=6 improvement. Day 14 (N=22): N=8 complete cure, N=11 marked improvement, N=3 slight improvement. High satisfaction N= 25/29 Day 7 (N=23): 22 N=2 complete cure, N=14 marked improvement, N=7 improvement. High patients´ satisfaction

Acute respiratory or ear infections

N=596 (1 month-17 y). Anthroposophic treatment N=443, conventional treatment N=88.

f

Number and age of Concomitant medication participants

oo

Analgetics (day Anthroposophic 5 conventional 25.6 %.

0-28): group %, group

Dosage frequency

and Outcome

Follow up N=529. Antibiotics given from day 0-28: Anthroposophic group 5 %, conventional group 25.6 % (p<0.001). Additional factors in anthroposophic group: Significant lower use of analgesics, faster cure of symptoms, higher caregiver´s satisfaction. Rare and mild adverse drug reactions (2.3 % in both groups)

na l

Pr

H. J. Hamre Anthroposophic Prospective controlled study 2016 37 medication including nonmedication therapy (e.g. compresses, antibiotics if necessary) compared to conventional therapy including antibiotics

Indication

pr

Study design

e-

Remedy/ therapeutic approach

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Non-RCTs

Reference

23

Table 3: Clinical trials investigating homeopathy indicated for the treatment of acute bronchitis in children Remedy/ therapeutic approach

Study design

Indication

Number and age Concomitant of participants medication

Dosage frequency

and Outcome

Acute, cough

dry N=180 Not mentioned, (7 months-12 y) exclusion criteria: Test group N=89; antibiotic treatment Placebo group N=91

7 months-3 y: 8x2 ml/day, 4-7 y: 8x3 ml/day, 8-12y: 8x4 ml/day. Duration 7 days

RCT

Pr

e-

pr

H. Voß et al. Monapax® syrup Double-blind, 2017 43 (containing a combination of placebo-controlled Drosera, Coccus cacti, Cuprum trial Sulfuricum, Ipecacuanha)43

oo

f

Reference

na l

Bronchitis, Pertussis

N=201; bronchitis N=140

Not mentioned

Average dose 3x1/day (40 % of children received simply the average dose). Intensified doses at start possible: 1 pill/hour or 1 pill/15 min for 2 h

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Non-RCT

L.Gegenheimer Droperteel® Clinical 2000 42 (containing a combination of observational Drosera Lachesis, Carbo study vegetabilis, Dactylopius and Kalium carbonicum)

Significant (p < 0.0001) improvement of the Cough Assessment Score: Test group: 5.2 ± 2.6 points; placebo group: 3.2 ± 2.6 points Difference of the least square means of improvement: 1.9 ± 0.4. Effect size of Cohen´s: d = 0.77. Control group shows higher rates of improvement and remission in all secondary parameters. Mild or moderate adverse drug reactions in both groups (test group N=6, placebo N=9) Physicians judged “good to very good” in >90 %. No effect N=3. Day 0-7: Partial or complete cure of symptoms N=150. Day 14: Partial or complete cure N=198. Droperteel® judged to be save and without adverse effects

24

4. Discussion Acute bronchitis is one of the most common diseases in pediatrics in western countries. Conventional medicine offers hardly any therapeutic options to cure symptoms and remains mainly restricted to inhalation with sodium chloride (0.9 %) and application of β2 agonists (e.g. salbutamol) in case of obstruction. As a mostly viral-caused infection the treatment with antibiotics is not effective. Nevertheless, an overuse and unnecessary prescription practice has been stated

7-11

. Considering the growing threat of antimicrobial

resistance, the use of antibiotics must be restricted to bacterial infections.

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Reviews and observational studies suggest that CAM might help to lower the use of antibiotics and therefore contribute to solving the issue of growing antibiotic resistance

15,37,45,46

. Therefore, CAM might also be an option in the treatment of acute

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bronchitis in children. In general, we found 18 studies investigating CAM therapies

re

assigned to herbal medicine, anthroposophic medicine and homeopathy. All studies indicated efficacy and tolerability of CAM therapies. However, quality of studies varied

lP

from observational to placebo controlled studies. Herbal medicine, with 11 identified studies, seems to be the most and best investigated field. Here, three RCTs were

na

conducted to investigate the liquid herbal preparation from the roots of Pelargonium sidoides, EPs 7630®. These studies 26-28 as well as two observational studies 30,29 reported

ur

a good efficiency and tolerability of EPs7630®. A significantly better score of bronchitis specific symptoms in test group than in placebo group was shown 26-28. Unfortunately there

Jo

was sparse information on concomitant medication and if there was, patients taking antibiotics were excluded, so no comparison to antibiotic-treated patients could be made. Among all studies investigating herbal preparations, the issue of antibiotic use and reduction, respectively, were only addressed in two studies. A prospective controlled cohort study investigating the herbal preparation, Angocin ® Anti-Infekt N, demonstrated that the treatment was equally effective as antibiotics in the treatment of acute sinusitis, 25

acute bronchitis and urinary tract infection

33

. Since the indication for antibiotic use is

questionable though, as only urinary tract infections are a mainly bacterial-caused infection, the conclusion shows only limited significance. Another study investigating a novel preparation of an ivy leaf extract showed that additional use of antibiotics have no benefit on efficacy but a higher risk for side effects (26 %) 31. Other herbal extracts (Bronchipret®, Bronchicum® Elixir, Hedelix ®) were investigated in observational studies demonstrating good efficacy

31,32,34-36

. However, control groups were

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missing so no statement to the benefit to conventional treatment could be made.

Summarized, current studies demonstrated efficacy and safety of herbal preparations in the treatment of infantile bronchitis. High qualitative trials were conducted for EPs7630®

-p

but for other herbal preparations controlled trials are pending and urgently needed. 37,39,40,41,

were detected in

re

In the field of anthroposophic medicine four eligible articles

“Anthromedics”, a database searching in the archive of the German journal for

lP

anthroposophic medicine “Der Merkurstab”. In a prospective controlled study design comparing anthroposophic medicine to conventional medicine in the treatment of acute

na

respiratory or ear infection a significant (p < 0.001) reduction in the use of antibiotics as well as a high patient´s satisfaction was shown in the anthroposophic treated pediatric

ur

patients 37.

A subgroup analysis of a large controlled cohort study demonstrated a high patient´s

Jo

satisfaction and good tolerance of WALA® Plantago Bronchial Balm, WALA® Plantago cough linctus, WALA® Thymus Oleum aethereum 5 %

39

. Furthermore, a higher

prescription rate of antibiotic in the conventional-treated compared to anthroposophictreated patients was reported. Two further anthroposophic remedies, WALA® Plantago cough syrup

41

and WALA® Bronchi Plantago coated pillules

40

were investigated in

observational studies. More than 80 % of physicians assessed the efficacy of the remedies 26

as “good” or “very good”. The outcome would be regarded as of limited meaningfulness though, as no control groups were examined. All four studies revealed efficacy and safety of anthroposophic medicine. Anthroposophic medicine seems to be equally effective or more effective than conventional medicine and seems to reduce antibiotic use. However, controlled trials are missing to evaluate these promising results. Moreover, two studies investigating the homeopathic preparations, Droperteel® and Monapax® were identified

42,43

. The patients treated with the homeopathic cough syrup

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Monapax® in comparison to placebo group showed a significant improvement of the cough assessment score and showed better results in secondary parameters (cough specific, symptoms, parents' sleep quality, Integrative Medicine Outcomes Scale, Integrative 43

. Droperteel® was investigated in a non-controlled

-p

Medicine Patient Satisfaction Scale)

42

. The

re

observational study and judged by the physicians as efficient and safe

homeopathic approach remains therefore poorly investigated, even though both studies

lP

mentioned above suggest effectiveness.

In line with our results, a current review found only few (N=11) low quality studies

na

investigating CAM therapies for the treatment of bronchiolitis; another mainly viral caused respiratory tract infection affecting very young infants 23. In contrast to CAM therapies used

ur

for the treatment of bronchitis, no marked effect referring to the main outcome parameter, length of hospital stay, was shown. However, CAM approaches studied for the treatment

Jo

of bronchiolitis differ from that used for the treatment of bronchitis. Studies found for bronchiolitis additionally comprise Traditional Chinese Medicine and nutritional therapy approaches.

In summary, our review underlines that CAM therapies used in children are still a poor investigated field as shown by other authors

23,44,45,

. Only few studies mostly of low or

moderate quality are published. Due to the small number of identified trials and 27

inconsistent outcome parameters an evaluation of safety and efficiency is impossible. Furthermore, the issue of antibiotic use and reduction remains uncertain and and only high quality studies could provide evidence base for this hypothesis. Therefore, more randomized controlled trials are necessary.

4.1 Limitations CAM is not a universally defined term

46

and encompasses a plethora of therapy

approaches. In order to comprehensively gather data, broad search terms implying 65

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CAM-related therapy approaches were used. Nevertheless, it cannot be ensured that all CAM-associated therapy approaches have been registered. Predefined search criteria such as English and German language and the exclusion of some umbrella terms such as

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upper respiratory tract infection and respiratory tract infection could have also reduced

re

hits. Contrary to the PRISMA guideline all forms of clinical trials were deliberately included without predefined outcome parameters to present a thorough overview of used CAM

5. Conclusion

na

analysis could not be realized.

lP

approaches. Moreover, due to the variety of included study types and their quality a meta-

ur

Literature revealed promising results for several CAM-based therapy approaches indicated for acute bronchitis in children. Still, an evidence-based statement on effectiveness

Jo

remains limited to RCTs, which have only been found for the herbal preparation EPs® 7630 and the homeopathic remedy Monapax®.. Thus, further randomized placebocontrolled trials are required to estimate effectiveness and safety, as well as reduction in antibiotic use, of CAM therapies.

28

6. Disclosure Statement The authors declare that they have no conflict of interest.

7. Acknowledgement

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We thank the Mahle Foundation and Christophorus Foundation for their financial support.

29

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