Pelargonium sidoides extract for treating acute respiratory tract infections

  • Review
  • Intervention

Authors


Abstract

Background

Pelargonium sidoides (P. sidoides), also known as Umckaloabo, is a herbal remedy thought to be effective in the treatment of acute respiratory infections (ARIs).

Objectives

To assess the efficacy and safety of P. sidoides for the treatment of ARIs in children and adults.

Search methods

In April 2013 we searched MEDLINE, Journals@Ovid, The Cochrane Library, Biosis Previews, Web of Science, CINAHL, CCMed, XToxline, Global Health, AMED, Derwent Drug File and Backfile, IPA, ISTPB + ISTP/ISSHP, EMBASE, Cambase, LILACS, PubMed component “Supplied by Publisher”, TRIPdatabase, the publisher databases: Deutsches Ärzteblatt, Thieme, Springer, ScienceDirect from Elsevier. We conducted a cited reference search (forward) in Web of Science of relevant papers for inclusion. In addition we searched the study registries ClinicalTrials.gov, Deutsches Register klinischer Studien DRKS (German Clinical Trials Register), International Clinical Trials Registry Platform (ICTRP) – WHO ICTRP, Current Controlled Trials and EU Clinical Trials Register.

Selection criteria

Double-blind, randomized controlled trials (RCTs) examining the efficacy of P. sidoides preparations in ARIs compared to placebo or any other treatment. Complete resolution of all symptoms was defined as the primary outcome; in addition, we examined resolution of predefined key symptoms.

Data collection and analysis

At least two review authors (AT, JG, WK) independently extracted and quality scored the data. We performed separate analyses by age group and disease entity. Subanalysis considered type of preparation (liquid, tablets). We examined heterogeneity using the I2 statistic. We calculated pooled risk ratios (RR) using a fixed-effect model if heterogeneity was absent (I2 < 5%; P > 0.1), or a random-effects model in the presence of heterogeneity. If heterogeneity was substantial (I2 > 50%; P < 0.10), a pooled effect was not calculated.

Main results

Of 10 eligible studies eight were included in the analyses; two were of insufficient quality. Three trials (746 patients, low quality of evidence) of efficacy in acute bronchitis in adults showed effectiveness for most outcomes in the liquid preparation but not for tablets. Three other trials (819 children, low quality of evidence) showed similar results for acute bronchitis in children. For both meta-analyses, we did not pool subtotals due to relevant heterogeneity induced by type of preparation.

One study in patients with sinusitis (n = 103 adults, very low quality of evidence) showed significant treatment effects (complete resolution at day 21; RR 0.43, 95% confidence interval (CI) 0.30 to 0.62). One study in the common cold demonstrated efficacy after 10 days, but not five days (very low quality of evidence). We rated the study quality as moderate for all studies (unvalidated outcome assessment, minor attrition problems, investigator-initiated trials only). Based on the funnel plot there was suspicion of publication bias.

There were no valid data for the treatment of other acute respiratory tract infections. Adverse events were more common with P. sidoides, but none were serious.

Authors' conclusions

P. sidoides may be effective in alleviating symptoms of acute rhinosinusitis and the common cold in adults, but doubt exists. It may be effective in relieving symptoms in acute bronchitis in adults and children, and sinusitis in adults. The overall quality of the evidence was considered low for main outcomes in acute bronchitis in children and adults, and very low for acute sinusitis and the common cold. Reliable data on treatment for other ARIs were not identified.

Résumé scientifique

Extrait de Pelargonium sidoides pour traiter les infections aiguës des voies respiratoires

Contexte

Pelargonium sidoides ( P. Sidoides ), également connue comme Umckaloabo, est un remède à base de plantes supposé être efficace dans le traitement des infections respiratoires aiguës (IRA).

Objectifs

Évaluer l'efficacité et l'innocuité de P. Sidoides pour le traitement des IRA chez les enfants et les adultes.

Stratégie de recherche documentaire

En avril 2013 nous avons effectué des recherches dans MEDLINE, Journals@Ovid, La Bibliothèque Cochrane , Aperçus Biosis, Web de la Science, CINAHL, CCMed, XToxline, Santé Globale, AMED, les dossiers et archives de drogues Derwent, IPA, ISTPB + ISTP/ISSHP, EMBASE, PubMed, LILACS, la composante de Cambase « Apporté par l'éditeur », la base de donnés TRIP, les bases de données suivantes: Deutsches Ärzteblatt, Thieme, Springer ScienceDirect à partir d'Elsevier. Nous avons effectué une recherche de références bibliographiques (retrospective) dans le Web des Sciences pour l'incusion d'articles pertinents. En outre, nous avons consulté les registres d'études ClinicalTrials.gov, le Deutsches klinischer Studien (DRKS registre allemand d'essais cliniques), la plateforme du registre international d'essais cliniques (ICTRP) - OMS ICTRP, essais controlés en cours CCT et les Registres d'essais cliniques de l'UE.

Critères de sélection

Des essais contrôlés randomisés en double aveugle (ECR) examinant l'efficacité des P. Sidoides, préparations à base d'IRA par rapport à un placebo ou tout autre traitement. La disparition complète de tous les symptômes était définie comme le critère de jugement principal; en outre, nous avons examiné la disparition des symptômes principaux prédéfinis.

Recueil et analyse des données

Au moins deux auteurs de la revue (AT, JG, WK) ont indépendamment extrait et noté la qualité des données. Nous avons effectué des analyses séparées par groupe d'âge et de maladie. La sous-analyse prenait en compte le type de préparation (liquide, comprimés). Nous avons examiné l'hétérogénéité à l'aide du I 2 Statistique. Nous avons calculé les risques relatifs (RR) combinés en utilisant un modèle à effets fixes si l'hétérogénéité était absente (I 2 < 5%; P > 0,1), ou un modèle à effets aléatoires en cas d'hétérogénéité. En cas d'hétérogénéité substantielle (I 2 > 50%; P < 0,10), l'effet global n'a pas été calculé.

Résultats principaux

De 10 études éligibles huit ont été inclus dans les analyses; deux étaient de qualité insuffisante. Trois essais d'efficacité en cas de bronchite aiguë chez l'adulte (746 patients, preuve de faible qualité) ont montré une efficacité pour la plupart des critères de jugement pour la forme liquide mais pas pour les comprimés. Trois autres essais (819 enfants, preuve de faible qualité) ont montré des résultats similaires pour le traitement de la bronchite aiguë dans cette population. Pour les deux méta-analyses, nous n'avons pas regroupé les sous totaux en raison d'une importante hétérogénéité due au type de préparation.

Une étude chez les patients souffrant de sinusite (n =103 les adultes, très faible qualité des preuves) avait montré des effets du traitement (résolution complète à 21 jours; RR 0,43, intervalle de confiance (IC) à 95%, de 0,30 à 0,62). Une étude dans le traitement du rhume banal a démontré une efficacité au bout de 10 jours, mais pas à cinq jours (très faible qualité des preuve). Nous avons évalué la qualité comme modérée pour toutes les études (pas de validation d'évaluation des résultats, des problèmes mineurs d'attrition, essais engagés par un seul chercheur). D'après le graphique en entonnoir il y avait une suspicion de biais de publication.

Il n'y avait pas de données valides pour le traitement d'autres infections aiguës des voies respiratoires. Les événements indésirables étaient plus fréquents avec P. Sidoides , mais aucun n'était grave.

Conclusions des auteurs

Le P. Sidoides pourrait être efficace pour soulager les symptômes de la rhinosinusite aiguë et le traitement du rhume banal chez les adultes, mais il y a des doutes. Il pourrait être efficace pour soulager les symptômes de la bronchite aiguë chez l'adulte et l'enfant, et la sinusite chez l'adulte. La qualité globale des preuves a été considérée comme faible pour les principaux critères de jugement pour la bronchite aiguë chez les enfants et les adultes, et très faible pour la sinusite aiguë et le traitement du rhume banal. Aucune donnée fiable sur le traitement pour les autres IRA n'a été identifiée.

Plain language summary

Pelargonium sidoides (Umckaloabo), a herbal remedy, for treating acute respiratory tract infections

Umckaloabo is a herbal extract derived from the plantPelargonium sidoides (P. sidoides) and is available in both tablet and liquid forms. The extract is used for the treatment of acute respiratory tract infections (ARIs) where antibiotic use is unnecessary. In the light of inappropriate antibiotic use and increasing drug resistance rates worldwide, the need for an alternative, effective remedy for these medical conditions is crucial. On the other hand, there are concerns as to the safety of Umckaloabo.

We reviewed 10 randomized clinical trials of which eight were of sufficient quality for inclusion into the analyses. Three trials dealt with acute bronchitis in adults and showed inconsistent but overall positive results for resolution of symptoms (all symptoms, cough and sputum production). For acute bronchitis in children, there were also three studies showing an inconsistent but overall positive combined effect. The available data indicate that the tablet form may be less effective compared to the alcoholic extract. However, the number of trials is not sufficient to prove this. One study each was available for the treatment of acute sinusitis and the common cold in adults. Both showed that the drug was effective in resolving all symptoms including headaches and nasal discharge when taken for an extended time period. Adverse events were more common with P. sidoides, but none were severe.

Overall we considered the quality of the evidence low or very low for all major outcomes as there were few studies per disease entity, and all were from the same investigator (the manufacturer) and performed in the same region (Ukraine and Russia). Thus, in summary, there is limited evidence for the effectiveness of P. sidoides in the treatment of ARIs. The evidence is up to date as of April 2013.

Résumé simplifié

Pelargonium sidoides (Umckaloabo), un remède à base de plantes, pour traiter les infections aiguës des voies respiratoires

Umckaloabo est un extrait médicinal dérivé de la plante Pelargonium sidoides ( P. Sidoides ) qui est disponible dans deux formes, comprimés et liquide. L'extrait est utilisé pour le traitement des infections aiguës des voies respiratoires (IRA) pour lesquelles les antibiotiques ne sont pas nécessaires. Au vu de l'utilisation inappropriée d'antibiotiques et de l'augmentation des taux de résistance aux médicaments dans le monde, la nécessité de traitements efficaces pour ces pathologies médicales est cruciale. D'autre part, il existe des inquiétudes quant à l'innocuité de l'Umckaloabo.

Nous avons évalué 10 essais cliniques randomisés, dont huit étaient de qualité suffisante pour être inclus dans les analyses. Trois essais étudiaient la bronchite aiguë chez l'adulte et ont montré des résultats contradictoires, mais dans l'ensemble les résultats étaient positifs pour la résolution des symptômes (tous les symptômes, la toux et la production d'expectorations). Pour le traitement de la bronchite aiguë chez l'enfant, il y avait également trois études montrant des résultats inconsistants mais globalement positifs d’effets combinés. Les données disponibles indiquaient que les comprimés oraux pourraient être moins efficaces par rapport à l'extrait alcoolique. Cependant, le nombre d'essais n’est pas suffisant pour le démontrer. Une étude était disponible pour le traitement de la sinusite aiguë et une pour le traitement du rhume banal chez les adultes. Les deux ont montré que le médicament était efficace pour résoudre tous les symptômes, y compris des céphalées et écoulement nasal lorsqu' ils sont administrés pendant une période étendue. Les événements indésirables étaient plus fréquents avec P. Sidoides. , mais aucun n'était grave.

Globalement, nous avons considéré que la qualité des preuves était faible ou très faible pour tous les principaux critères de jugement puisqu’il y avait peu d'études par maladie et toutes les études étaient du même investigateur (le fabricant) et réalisées dans le même région (Ukraine et en Russie). En conséquence, il existe des preuves limitées sur l'efficacité des P. Sidoides dans le traitement d'IRA. Les preuves sont actualisées jusqu’en avril 2013.

Notes de traduction

Traduit par: French Cochrane Centre 9th January, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux; pour la France : Minist�re en charge de la Sant�

Summary of findings(Explanation)

Summary of findings for the main comparison. P. sidoides for the treatment of acute bronchitis in adults
  1. 1Outcome on request only, investigator-initiated studies only, minor attrition problems, success of blinding not assessed.
    2Relevant statistical heterogeneity, not completely solved by subgroup analyses, but both studies and all outcomes clearly in same direction.
    3Insufficient number of studies to perform statistical testing, but funnel plot across all conditions strongly suggests small study bias.
    41 study only.

P. sidoides for the treatment of acute bronchitis in adults
Patient or population: adults with acute bronchitis
Settings: in- and outpatient departments, GP practices; Ukraine and Russia
Intervention: P. sidoides versus placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control P. sidoides
Failure to recover by day 7 (complete resolution of all symptoms) - liquid preparation Study population RR 0.66
(0.52 to 0.83)
341
(2 studies)
⊕⊕⊝⊝
low 1,2,3
 
953 per 1000 629 per 1000
(495 to 791)
Moderate
960 per 1000 634 per 1000
(499 to 797)
Failure to recover by day 7 (complete resolution of all symptoms) - tablet preparation Study population RR 0.95
(0.91 to 0.99)
405
(1 study)
⊕⊕⊝⊝
low 1,3,4
 
990 per 1000 941 per 1000
(901 to 980)
Moderate
1000 per 1000 950 per 1000
(910 to 990)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 P. sidoides for treating acute bronchitis in children

Summary of findings 2. P. sidoides for treating acute bronchitis in children
  1. 1Outcome on request only, investigator-initiated studies only, minor attrition problems, success of blinding not assessed.
    2Insufficient number of studies to perform statistical testing, but funnel plot across all conditions strongly suggests small study bias.

P. sidoides for treating acute bronchitis in children
Patient or population: children with acute bronchitis
Settings: in- and outpatient departments, GP practices; Ukraine and Russia
Intervention: P. sidoides versus placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control P. sidoides
Failure to recover by day 7 (complete resolution of all symptoms) - liquid preparation Study population RR 0.82
(0.77 to 0.88)
420
(2 studies)
⊕⊕⊝⊝
low 1,2
 
971 per 1000 796 per 1000
(748 to 854)
Moderate
971 per 1000 796 per 1000
(748 to 854)
Failure to recover by day 7 (complete resolution of all symptoms) - tablet preparation Study population RR 0.96
(0.89 to 1.03)
399
(1 study)
⊕⊕⊝⊝
low 1
 
911 per 1000 874 per 1000
(811 to 938)
Moderate
912 per 1000 876 per 1000
(812 to 939)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 3 P. sidoides versus placebo for treating acute sinusitis in adults

Summary of findings 3. P. sidoides versus placebo for treating acute sinusitis in adults
  1. 1Outcome on request only, investigator-initiated studies only, minor attrition problems, success of blinding not assessed.
    21 small study only, very wide confidence interval.
    3Insufficient number of studies to perform statistical testing, but funnel plot across all conditions strongly suggests small study bias.

P. sidoides for treating acute sinusitis in adults
Patient or population: adults with acute sinusitis
Settings: in- and outpatient departments, ENT practices; Ukraine
Intervention: P. sidoides versus placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control P. sidoides
Failure to recover by day 21 (complete resolution of all symptoms) Study population RR 0.43
(0.3 to 0.62)
103
(1 study)
⊕⊝⊝⊝
very low 1,2,3
 
904 per 1000 389 per 1000
(271 to 560)
Moderate
904 per 1000 389 per 1000
(271 to 560)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 4 P. sidoides for common cold in adults

Summary of findings 4. P. sidoides for common cold in adults
  1. 1Outcome on request only, investigator-initiated studies only, minor attrition problems, success of blinding not assessed.
    21 small study only.
    3Insufficient number of studies to perform statistical testing, but funnel plot across all conditions strongly suggests small study bias.

P. sidoides for common cold in adults
Patient or population: adults with common cold
Settings: in- and outpatient departments, GP practices; Ukraine
Intervention: P. sidoides versus placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control P. sidoides
Failure to recover by day 5 (complete resolution of all symptoms) Study population RR 0.96
(0.9 to 1.03)
103
(1 study)
⊕⊝⊝⊝
very low 1,2,3
 
1000 per 1000 960 per 1000
(900 to 1000)
Moderate
1000 per 1000 960 per 1000
(900 to 1000)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Acute respiratory infections (ARIs) are divided into two types: those of the upper respiratory tract, such as tonsillopharyngitis, sinusitis, otitis media or common cold, and those of the lower respiratory tract, such as acute bronchitis. These infections are characterized by an acute inflammation of the mucosa associated with edema and increased mucus production. Typical symptoms are congestion and increased secretions and discharge, sore throat, cough and localized pain. The majority of acute respiratory tract infections are caused by viruses and are self limited. Generally in adults and older children, a common cold tends to last about one week, but coughs may persist for up to three weeks. In younger children symptoms tend to last 10 to 14 days (CKS Guideline 2011). Acute bronchitis may take up to three weeks to resolve (CKS Guideline 2010). Based on observations in general practice, the median time for symptoms associated with acute bronchitis to resolve following consultation varies between five days (for dyspnea) and 11 days for cough (Moore 2008). Subjective complaints may persist for four weeks or more in a minority of patients (Moore 2008).

Patients with acute sinusitis usually have symptoms for a median duration of seven days (Williamson 2007), and 50 (based on absence of restrictions) to 80 per cent (based on symptom resolution) of patients are considered cured after two weeks (Bucher 2003; Williamson 2007) although complete resolution may take up to 12 weeks in a minority of patients (CKS Guideline 2009).

ARIs are the major cause of sick certificates and days of loss of work (Gonzales 2000; Wenzel 2006) and a reduction of the duration of illness is, therefore, desirable.

Description of the intervention

Umckaloabo is a herbal remedy derived from the roots of Pelargonium sidoides (P. sidoides), which is native to South Africa. It is also sold as Umckabo, Umcka, Kaloba or Zucol. The medication was first marketed in Britain in 1897 for its supposed anti-tuberculotic properties but lost popularity with the advent of antibacterial therapy (Schulz 2003; Taylor 2005). Since the early 2000s it has again attracted attention from primary care physicians, infectious diseases specialists and public health bodies. A liquid alcohol containing preparation of P. sidoides (drops) was approved for the treatment of acute bronchitis in Germany in December 2005, where it is now one of the most frequently prescribed childhood medications, and subsequently in other countries. Other preparations like tablets (approved in May 2009), syrups for children (approved in October 2010) and quick dissolving lozenges (US - market) are also available.

How the intervention might work

Bench research has found weak antibacterial effects of P. sidoides ethanolic extract (EPs 7630) (Kayser 1997; Kayser 2001; Kolodziej 2003), which are unlikely to be relevant in vivo. P. sidoides extract EPs 7630 may interfere with the invasion and adherence of Streptococcus pyogenes (S. pyogenes) to human cells, potentially preventing bacterial superinfection (Conrad 2007a). Other hypotheses include similar effects on viral adherence and immunomodulation by the extract (Conrad 2007b; Kolodziej 2003; Kolodziej 2007; Luna 2011). The drug may also have mucolytic properties (it improves cilia function in vitro) (Neugebauer 2005). It is currently regarded as a cough expectorant.

Claims of effectiveness in various ARIs, such as acute bronchitis, sinusitis and non-streptococcal tonsillopharyngitis, have been based on a number of clinical studies, including several randomized controlled trials (RCTs) (Conrad 2007c; Schulz 2003). Specifically, trials have been performed in acute bronchitis, sinusitis and non-streptococcal tonsillopharyngitis, in both children and in adults. Almost all trials published so far have been manufacturer-initiated.

There is potential for serious side effects. Concerns relate to the presence of natural coumarins in P. sidoides extract which could lead to hemorrhagic complications (Latte 2000; Zimmermann 1965). Hypersensitivity reactions and hepatotoxic reactions have also been described (de Boer 2007; Teschke 2012a; Teschke 2012b)

Why it is important to do this review

ARIs are among the most common acute diseases in the community and are often the cause for a consultation of a general practitioner (Wenzel 2006). After seeing their doctor both children and adults often receive an empiric antibiotic prescription, although the limited effectiveness of this approach in a predominantly viral disease is well known. The increasing prevalence of community-acquired, drug-resistant infections is stimulating strategies to reduce antibiotic prescribing (Gonzales 2001). Beneficial treatment effects of P. sidoides in acute bronchitis or other self limiting respiratory tract infections could therefore lead to a decrease in unnecessary antibiotic prescriptions.

As concerns have been raised as to a potential for serious side effects of this frequently used herbal remedy, a critical review of the evidence is important.

Objectives

To assess the efficacy and safety of P. sidoides for the treatment of ARIs in children and adults.

Methods

Criteria for considering studies for this review

Types of studies

Double-blind, randomized controlled trials (RCTs).

Types of participants

We included participants of any age, and planned separate analyses for adults (≥ 18 years of ages) and children (≤ 14 years of age). Those aged 15 to 17 years were considered as either adults or children, depending on the definitions used in the respective studies. Participants were to have one or more ARI not necessitating antibiotic therapy; that is, sore throat (pharyngitis, retropharyngitis, laryngitis), bronchitis, tracheitis, sinusitis, rhinitis, otitis media, non-streptococcal tonsillitis and non-specific respiratory tract infection (common cold).

We excluded any condition for which an antibiotic or other specific therapy was recommended, such as streptococcal infections, pneumonia, diphtheria, tuberculosis, infections in immunocompromised or elderly persons, or any life-threatening condition. Also, studies restricted to patients with underlying chronic disease, such as asthma or chronic obstructive airways disease (COPD), or any other condition potentially impacting on the management and outcome of ARI were not included.

All identified studies used a threshold of < 48 hours from disease onset for defining acute disease.

Types of interventions

Included studies had to compare P. sidoides ethanol extract (Umckaloabo) or other P. sidoides preparations to placebo or any active comparator. Active comparators could include, for example, physical therapy, mucolytics/expectorants or prophylactic antibiotic therapy.

Types of outcome measures

Only studies providing information on improvement or resolution of symptoms were eligible.

Primary outcomes
  1. Time to complete resolution of all symptoms (in days), or number of patients not resolved at a predefined time.

  2. Time to complete resolution of key symptoms (in days), or number of patients with key symptoms not resolved at a predefined time.

The following symptoms were expected to be of primary interest (key symptoms).

  • Bronchitis: cough, productive cough, sputum production.

  • Tonsillitis or pharyngitis: pain on swallowing, sore throat.

  • Laryngitis: hoarseness.

  • Rhinitis and sinusitis: nasal discharge, purulent nasal discharge, headache.

  • Common cold: sore throat, nasal congestion, nasal discharge.

  • All: fever, malaise, absence of general well-being.

We considered time to complete recovery from key symptoms the most appropriate endpoint. However, this was not available for any of the studies. We had defined an alternative main outcome as the proportion of participants with continuing symptoms at predefined days of follow-up. Day seven was identified as a commonly reported time point of reference in most ARIs (Agbabiaka 2008). Day 21 was considered relevant in the subset of sinusitis studies. We considered data on individual symptoms more appropriate than symptom scores and sought these from the trial authors if not reported.

Secondary outcomes
  1. Reduction in severity of symptoms on a prespecified day (that is, improvement).

  2. Need for antibiotics at follow-up.

  3. Quality of life measures.

  4. Days off work or days off school, number of return visits, hospitalization.

  5. Side effects (any, and side effects leading to withdrawal from the trial).

Search methods for identification of studies

We performed all searches without language and time restrictions.

Electronic searches

The most recent searches were performed from 24 April to 3 May 2013 in all electronic databases as listed in Appendix 1, complemented by a Cited Reference Search (forward) of relevant articles in Web of Science up to 26 April 2013. Terms searched varied by the database used. As an example, the search strategy in MEDLINE (via Ovid SP) is shown in Appendix 2. For details of the search strategies in all databases, see Appendix 3.

In addition we searched relevant clinical study registries (Appendix 4).

Searching other resources

We contacted the manufacturer, drug approval authorities (for Germany: Federal Institute for Drugs and Medical Devices (BfArM, Bonn), 2009 version only) and authors of relevant articles to identify any unpublished material. We checked references of relevant articles and performed a cited reference search.

Data collection and analysis

Selection of studies

At least two review authors (AT, JG or MD) screened all studies by title and abstract (if available). All controlled clinical trials and all prospective cohort studies on the therapeutic effect of P. sidoides were made available to all review authors in full text. Three review authors (AT, JG, WK) selected relevant RCTs. We resolved any disagreement on the inclusion of studies by discussion with all review authors.

Data extraction and management

Three review authors (AT, JG, WK) extracted data using standardized extraction forms. We extracted information on data source; participants (age range, exclusion criteria, pre-treatment, disease type); details of intervention (dosing, duration of treatment) and comparison treatment; outcomes studied and duration of follow-up; study design features (including method of randomization, allocation concealment, intention-to-treat (ITT) analysis); and results, including adverse events and loss to follow-up. We resolved discrepancies in the data extractions by consensus. If an agreement was not reached, we consulted a fourth review author who served as the final arbiter (GA). For unclear or non-reported data, we approached the manufacturing company. Missing data were supplied by the statistician in charge at the manufacturing company (2008 version).

Assessment of risk of bias in included studies

We assessed the studies for internal validity using criteria based on the Cochrane Handbook for Systematic Reviews of Interventions (domain-based evaluation) (Higgins 2011). This included an assessment of the likelihood for selection bias (sequence generation, allocation concealment), performance bias (blinding of patients and caregivers, co-interventions), detection bias (blinding of outcome assessment, robustness of endpoint), attrition bias (completeness of follow-up, ITT analysis) and reporting bias. For missing information on details of study conduct we sought clarification from investigators wherever possible.

Individual domains are presented using the 'Risk of bias' tool provided by RevMan 2012, including summaries of risk of bias for major outcomes within a study and across studies (see Summary of findings for the main comparison; Summary of findings 2; Summary of findings 3; Summary of findings 4).

In accordance with the review protocol of 2007, we graded within-study quality as follows:

Grade A trials: Low risk of bias (plausible bias unlikely to seriously alter the results, all quality criteria met).
Grade B trials: Moderate risk of bias (plausible bias that raises some doubt about the results, one or more criteria partially met).
Grade C trials: High risk of bias (plausible bias that seriously weakens confidence in the results, one or more criteria not met).

Analyses were restricted to studies at low or moderate (or unclear) overall risk of bias (see chapter 8.8.3.1 (Higgins 2011).

We considered randomization adequate if allocation occurred by chance. Adequate measures included the use of random number tables or computer-based random number generation. We considered allocation concealment adequate if measures were taken to ensure allocation was unknown before inclusion into the study. Methods include the use of sealed envelopes, central randomization or distribution of coded bottles by the pharmacy. If this information was unavailable from the reports, we requested it from the manufacturer or trial author.

Three review authors (AT, JG, WK) independently graded the studies. Disagreements were discussed by these three review authors. If a consensus was not reached, a fourth review author (GA) acted as arbiter. Preceding the final analysis, a statistician (GR) checked all data and quality scorings for potential errors, based on the study reports. For the 2013 update, two review authors (AT, JG) reassessed all studies to complete the 'Risk of bias' assessment.

Measures of treatment effect

We calculated treatment effects as risk ratios (RR) with 95% confidence intervals, with an RR < 1.0 corresponding to a decreased risk for not being free of symptoms at the specified time (benefit of treatment). Time to event data were not available.

Unit of analysis issues

Neither cluster-randomized trials nor cross-over trials were identified.

For trials with multiple arms, we treated all treatment arms as a separate study, using the proportionate number of controls for assessment of efficacy. For example, in a trial with three different treatment arms (Kamin 2010b), the trial was reported as three substudies (Kamin 2010b - 10 mg; Kamin 2010b - 20 mg; Kamin 2010b - 30 mg), each with a third of the number of controls.

Dealing with missing data

Wherever possible, information was sought on missing data from the investigators.

In the case of missing outcome data due to drop-out, we applied a worst-case scenario for dichotomous variables. This means that all dropped out cases were considered treatment failure. High differential drop-out which might have resulted in the worst scenario leading to a clinically relevant difference in effect estimate as compared to a best-case scenario, was considered a source of high risk of bias, and led to the exclusion of the respective study from the analysis. Continuous outcome data were not used.

Assessment of heterogeneity

We examined heterogeneity by calculating the I2 statistic and performing the Chi2 test. If heterogeneity was considered relevant, e.g. I2 statistic greater than 0.50 and P < 0.10, we performed subanalyses as deemed clinically relevant, and subtotals only, or single trial results were reported.

Assessment of reporting biases

We assessed publication bias (positive outcome bias) or small study bias by drawing a funnel plot based on the primary outcome (failure to resolve all symptoms at prespecified day) from all trials, irrespective of disease type. As only eight trials were included in the analysis, statistical tests for funnel plot asymmetry were not applied.

Data synthesis

We included only grade A and B quality trials in the analysis. Separate meta-analyses were to be performed for children and adults, and by disease type. For adverse events, we pooled all studies irrespective of the indicated disease type and the dosage used.

Since time-to-event data were not available for any of the studies, complete recovery at day seven was used as the primary outcome. We pooled data using the Mantel-Haenszel method. In the absence of evidence for heterogeneity, e.g. I2 statistic less than 0.05 and P > 0.10, we used a fixed-effect model. Otherwise, we performed random-effects modeling.

We considered an absolute risk reduction of 10%, or a reduction in time to recovery of more than one day, to be a clinically relevant effect.

Subgroup analysis and investigation of heterogeneity

Planned subgroup analyses were to be performed by type of control, dosing and type of preparation (liquid, tablet, syrup). All included trials used placebo controls, and most studies used comparable dosing. Thus subgroup analyses were restricted to type of preparation (liquid versus tablet).

Sensitivity analysis

We planned sensitivity analyses to examine the effects of study quality, in particular adequacy of allocation concealment, but these could not be performed as most quality characteristics were identical in all studies.

Results

Description of studies

Results of the search

In total 1565 citations were identified; after elimination of duplicates with the Endnote® software 844 citations remained. The investigator notified us of eight published studies (all duplicates) and supplied further details on five more yet unpublished studies (no duplicates). Searching in clinical trial registries identified 56 hits, of which 34 were duplicates (Figure 1).

Figure 1.

Study flow diagram.

Overall, we screened 182 papers from the database search in more detail and selected 38 for full-text assessment. There were seven full reports on five RCTs, including two pairs of duplicate publications (Bereznoy 2003; Blochin 1999; Blochin 2000; Chuchalin 2005; Matthys 2003). Two additional studies were reported in a single abstract (Bachert 2005). One RCT was identified later during an updated search (Lizogub 2007). For the first version of this review the manufacturer had supplied nine unpublished manuscripts, of which six were RCTs, including the paper mentioned before by Lizogub. All others were also published as full papers by the time the current update was prepared and were identified by the search update (Bachert 2009; Kamin 2010a; Kamin 2010b; Kamin 2012; Matthys 2010). There was evidence for two trials on sore throat from a non-systematic review (Schulz 2003) based on data submitted for the drug approval procedure, but the available information was insufficient for evaluation and inclusion, and details on these trials were not available so these could not be listed as separate studies. The drug approval agency (BfArM) did not supply any information on trials (2008 version).

Five recently supplied, currently unpublished studies are still under consideration (1320 patients) (Bachert 2004; Beck 2001; Heger 2002; Heger 2003; Wolf 2011) as information was insufficient at the time the analyses were completed (April 2013).

Of the 22 citations identified in the clinical registry search, eight will be considered for inclusion once data are available. Seven of these are still ongoing (recruiting, or being analyzed) (EUCTR2007-004923-39-DE; EUCTR2007-005579-33-BG; EUCTR2007-005797-31-BG; EUCTR2011-002652-14-DE; ISRCTN77419032; JPRN-UMIN000003815; NCT01420445). One was completed several years ago, but more information could not yet been secured (ISRCTN86579667).

Included studies

Overall, 10 double-blind RCTs (all published at the time of the current review update) were selected for inclusion. Of these, four dealt with acute bronchitis in adults (Chuchalin 2005; Matthys 2003; Matthys 2007a; Matthys 2010) and three with acute bronchitis in children (Kamin 2010a; Kamin 2010b; Kamin 2012). There was one trial on sinusitis in adults (Bachert 2009), one on the common cold in adults (Lizogub 2007) and one on sore throat in children (Bereznoy 2003).

Two of the trials were multi-arm trials, comparing three different doses of P. sidoides versus placebo in a tablet preparation (10 mg, 20 mg, 30 mg three times a day) (Kamin 2010b; Matthys 2010). All other trials used a liquid preparation (alcoholic extract). All were placebo-controlled. There were no completed trials using the newly available syrup. All trials were initiated and funded by the manufacturing company, and performed in Eastern Europe (Russia, Ukraine). All identified studies used a threshold of less than 48 hours from the onset of symptoms for defining acute disease.

There were no trials for any of the other conditions, such as rhinitis, laryngitis or otitis media.

Excluded studies

Characteristics of excluded studies are presented in the Characteristics of excluded studies table. Most often, studies were excluded because there was no control group. All studies using active comparators were open-label and were thus excluded (Blochin 1999; Blochin 2000). Five studies were excluded as they did not deal with upper respiratory tract infection in otherwise healthy persons. There were two RCTs in children with asthma (Tahan 2013) or immunosuppression (hypogammaglobulinemia) (Patiroglu 2012), and one study in adults with COPD (Matthys 2013). Two studies were performed in healthy volunteers: one evaluating effects on running performance (Luna 2011), the other one examining interaction effects when Umckaloabo was used with penicillin V (Roots 2004).

Of the studies still under consideration one dealt with acute bronchitis in children (Heger 2002) and adults (Heger 2003), sinusitis in adults (Bachert 2004), children with non-streptococcal angina (Bachert 2004) and healthy volunteers (Wolf 2011).

Risk of bias in included studies

The risk of bias is illustrated in Figure 2 and Figure 3.

Figure 2.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Allocation

All included studies used central randomization procedures, blocking with concealed block sizes and other concealment procedures, such as using labeled containers. Confirmation on this was sought and received from the investigator (manufacturer) for all included studies.

Blinding

Double-blinding was reported for all studies and confirmed by the investigators. However, none of the studies attempted to examine the success and integrity of blinding. This was considered the more relevant due to the highly subjective nature of the outcome criterion and the obvious problems with differential drop-out (see below).

Incomplete outcome data

Two studies were excluded for high differential drop-out (Bereznoy 2003; Matthys 2007b). High differential drop-out was considered particularly problematic as the last observation carried forward approach was applied in these diseases with rapid spontaneous recovery. In both affected trials, the higher drop-out occurred within the placebo-treated group and was likely to have resulted in severe overestimation of the effect of Umckaloabo. In all other studies, drop-out rates per arm were below 10% with little difference between groups (Chuchalin 2005; Matthys 2007a) or close to 0 (remainder). All studies used ITT analysis, and most presented exact numbers on drop-outs and reasons for drop-out using flow charts. Numbers of drop-outs and reasons for loss were all confirmed (if reported), or supplied (if missing) by the investigator on request.

Selective reporting

Generally, the primary outcomes as defined by the investigators were presented quantitatively, as well as a selection of secondary outcomes. In one study, reporting of results was restricted to one of two studied dosings (Lizogub 2007). The reason for this unclear; we sought clarification but has so far not been received.

Other potential sources of bias

All studies suffered from poor outcome criteria definition. A change in symptom score was used as a primary outcome based on non-validated instruments in all assessed studies. However, upon request, data on the number of patients with complete resolution of symptoms (all symptoms, key symptoms) and other essential information were supplied by the investigator (manufacturer) for all included studies. Complete resolution was, in this case, assumed for a symptom score = 0.

Effects of interventions

See: Summary of findings for the main comparison P. sidoides for the treatment of acute bronchitis in adults; Summary of findings 2 P. sidoides for treating acute bronchitis in children; Summary of findings 3 P. sidoides versus placebo for treating acute sinusitis in adults; Summary of findings 4 P. sidoides for common cold in adults

Three studies including a total of 746 patients were included in the analysis of the treatment of acute bronchitis in adults (Chuchalin 2005; Matthys 2007a; Matthys 2010). There were no data on the time to complete resolution. The individual trials mostly showed positive effects for P. sidoides (Figure 4). However, heterogeneity was high for all primary outcomes assessed (complete resolution of all symptoms, I2 statistic = 98%, cough I2 statistic = 98%, sputum I2 statistic = 44%). This was not completely explained by type of preparation. In particular, heterogeneity was still present for the studies using liquid preparations, with the exception of sputum production (complete resolution of all symptoms, I2 statistic = 74%, cough I2 statistic = 78%, sputum I2 statistic = 0%) (Chuchalin 2005; Matthys 2007a). Therefore we only calculated pooled effects for failure to resolve sputum, the key symptom, which showed the superiority of P. sidoides (risk ratio (RR) 0.70, 95% confidence interval (CI) 0.60 to 0.82) (Analysis 1.3).

Figure 4.

Forest plot of comparison: 1 P. sidoides versus placebo, acute bronchitis in adults, outcome: 1.2 Failure to recover by day seven (complete resolution of all symptoms).

For acute bronchitis in children, three reports were eligible for inclusion (Kamin 2010a; Kamin 2010b; Kamin 2012), comprising 819 children (Figure 5). As for the adults, there was considerable heterogeneity (complete resolution of all symptoms, I2 statistic = 59%, cough I2 = 65%, sputum I2 statistic = 66%) (Analysis 2.1). Subgroup analyses showed some efficacy for the liquid preparation (complete resolution of all symptoms, RR 0.82, 95% CI 0.77 to 0.88; cough RR 0.82, 95% CI 0.76 to 0.88) (Kamin 2010a; Kamin 2012), but not for the tablet preparation (complete resolution of all symptoms, RR 0.96, 95% CI 0.89 to 1.03; cough RR 0.96, 95% CI 0.86 to 1.07; sputum RR 0.87, 95% CI 0.71 to 1.06) (Kamin 2010b) (Analysis 2.1; Analysis 2.2; Analysis 2.3).

Figure 5.

Forest plot of comparison: 2 P. sidoides versus placebo, acute bronchitis in children, outcome: 2.2 Failure to recover by day seven (complete resolution of all symptoms).

One study (n = 104 adults, 103 analyzed) (Bachert 2009) was available for the assessment of effectiveness in acute sinusitis and showed significant treatment effects for resolution of all symptoms (RR 0.43, 95% CI 0.30 to 0.62) (Figure 6) (Analysis 3.1), as well as key symptoms: nasal discharge (RR 0.21, 95% CI 0.11 to 0.40) (Analysis 3.2) and resolution of headaches (RR 0.23, 95% CI 0.12 to 0.44) (Analysis 3.3).

Figure 6.

Forest plot of comparison: 3 P. sidoides versus placebo, acute sinusitis in adults, outcome: 3.1 Failure to recover by day 21 (complete resolution of all symptoms).

For the common cold, there were no or small effects at day five for all outcomes (for example, resolution of all symptoms (RR 0.96, 95% CI 0.90 to 1.03) (Analysis 4.1) based on a single trial including 103 patients as a subpopulation of the original study collective (Lizogub 2007)) (Figure 7). For this entity, results were also available for day 10. At this time point, stronger effects were demonstrated (for example, resolution of all symptoms (RR 0.41, 95% CI 0.29 to 0.60)) (Figure 8) (Analysis 4.5).

Figure 7.

Forest plot of comparison: 4 P. sidoides versus placebo, the common cold in adults, outcome: 4.1 Failure to recover by day 5 (complete resolution of all symptoms).

Figure 8.

Forest plot of comparison: 4 P. sidoides versus placebo, the common cold in adults, outcome: 4.5 Failure to recover by day 10 (complete resolution of all symptoms).

Data on days off work were only available from one study, and showed a significant and relevant reduction in mean days off of 1.3 days (95% CI -2.06 to -0.54) when P. sidoides was used for the common cold (Lizogub 2007). However, the number of days off work was still very high in the treatment group (6.9 days; control group: 8.2 days), possibly as an effect of outliers (means were reported rather than medians). Data on need for antibiotics and quality of life were inconsistently reported, if at all. Meta-analyses could therefore not be performed for these secondary outcomes.

There were no valid data for the treatment of sore throat, nor any other acute respiratory infections beyond acute bronchitis, sinusitis and the common cold.

Adverse events were rarely reported, but were slightly more common in the treatment group (RR 1.32, 95% CI 1.04 to 1.66) (Figure 9). Gastrointestinal symptoms seemed to be particularly common. There were no severe adverse events. The number of adverse events leading to withdrawal was similar between the comparison groups.

Figure 9.

Forest plot of comparison: 5 P. sidoides versus placebo, any indication, outcome: 5.1 Patients with adverse events.

A funnel plot showed severe asymmetry for the main outcome (complete resolution of all symptoms) (Figure 10). Both large dose-finding trials using tablet preparations were close to no difference, while all small trials using alcoholic extract were strongly positive.

Figure 10.

Funnel plot of comparison: 5 P. sidoides versus placebo, any indication, outcome: 5.3 Failure to resolve all symptoms at prespecified day - publication bias.

Discussion

Summary of main results

On the basis of the available study data P. sidoides extract can be considered as effective for symptom resolution of acute bronchitis in adults and in children. Statistical heterogeneity was partly explained by the use of different preparations. Only the drops of P. sidoides extract showed superiority, referred to the cure rate at day seven. The tablet preparation was not effective. There was consistency across different outcomes (all symptoms, key symptoms) for the alcoholic extract. However, there were only two studies each per age group on the alcoholic extract, and one dose-finding, multi-arm study each for tablets. Overall the quality of the evidence for these outcomes is considered low (Summary of findings for the main comparison; Summary of findings 2).

There were only single studies available for the assessment of efficacy in sinusitis and the common cold in adults, and the overall quality for these two entities was considered very low (Summary of findings 3; Summary of findings 4). Patients with sinusitis might benefit from P. sidoides extract (higher cure rate at day 21). For the treatment of the common cold there are only few data. Only half of the collected data for this condition are published. The reported results show efficacy after 10 days, but not after five days.

Based on a pooled analyses of all studies, there was a slightly raised risk for adverse events in the treatment group. None of the reported events were serious. Besides gastrointestinal complaints such as nausea, vomiting, diarrhea or heartburn, allergic skin reactions with pruritus and urticaria were reported in the included trials.

Overall completeness and applicability of evidence

Although we performed a broad search for all acute respiratory infections (ARIs) in both children and adults, only a limited number of conditions were covered by clinical trials of sufficient quality. These included acute bronchitis in adults and children, and acute sinusitis and the common cold in adults only. For other frequent diseases such as rhinosinusitis, non-streptococcal pharyngitis or otitis media there were no trials, or only with high risk of bias (e.g. not blinded).

Very few studies reported on time to complete resolution of symptoms (preferred primary outcome), and none of the studies originally reported the number of patients free of symptoms at a prespecified point in time (alternative primary outcome). Therefore, we had to abstain from meta-analysis of the preferred primary outcome. All studies used a non-validated symptom score to show efficacy. Results of the individual studies were recalculated for this review by the investigator under the assumption that a score of 0 corresponds to complete resolution. Thus, in conclusion, although not available from the published reports, evidence could be pooled as prespecified and may thus be considered complete. However, data on quality of life and days lost from work were insufficiently reported.

Some concerns arose as all studies were performed based on a similar protocol, by the same investigator (i.e. the manufacturer) and in similar settings (multi-center outpatient, Ukraine or Russia). This narrow spectrum compromises the representativeness of the evidence. More studies including those from other investigators and/or other parts of the world (Germany, Bulgaria, Japan, Korea) are underway (see Characteristics of ongoing studies table and Studies awaiting classification). So far, results are not available from these studies.

With respect to the assessment of safety, the relatively small studies of short treatment duration included in this review cannot be expected to pick up rare but severe events with sufficient precision. To solve this issue, other data sources may be necessary to complement our findings.

Shorter duration of symptoms or of illness due to acute respiratory infection by using herbal medicines would need to be translated into fewer lost days of work and less inappropriate antibiotic use. Studies based on (often self reported) symptom improvement remain difficult to assess because of the lack of valid, responsive outcome measures (Linder 2003).

Quality of the evidence

All included studies used similar methods and all were individually considered of moderate risk of bias (Figure 3). While randomization procedures and concealment of allocation were standard for all included studies, we had some concerns about the effectiveness of the blinding, the use of unvalidated scores for outcome assessment, minor attrition problems and, in one instance (Lizogub 2007), selective reporting. This was reflected by downgrading (-1) for trial quality in the GRADE system for all main outcomes (Summary of findings for the main comparison; Summary of findings 2; Summary of findings 3; Summary of findings 4).

There were also concerns with respect to positive outcome, or small study bias. While the number of studies was insufficient for formal statistical testing, the combined funnel plot based on the main outcomes for all conditions and age groups was severely asymmetrical, suggesting publication bias. This resulted in further downgrading of the overall quality of the evidence (-1 for publication bias).

Statistical heterogeneity was present in several instances, even when different preparations were accounted for by sub-analyses. However, the direction of the results was rather uniform.

Lastly, the overall quality of the results was compromised by the low number of studies. In particular, this led to further downgrading of the quality of the evidence when only small, single studies were available (common cold and acute sinusitis). The results for these two conditions should be regarded with particular caution (very low quality).

Potential biases in the review process

A very broad search strategy was used in this review, including tailored search strategies for a large spectrum of different sources. Also, authors and investigators were very co-operative in providing information on unpublished studies. Despite this, there is some evidence of publication bias. This resulted in downgrading the overall quality of the evidence (see above).

As all authors are German, there may be a bias in that studies published in German, or German journals, may have been more likely to be identified than articles in other non-English languages, even though language restrictions were not applied.

Some evidence is still missing from a number of studies for which results are not yet available. This will be included in the next update of this review. At this time, all unpublished data used in the first version of this review have been published.

Quality scoring of individual studies may have been overly restrictive. For example, there was downgrading for failure to assess the success of blinding, since we considered blinding particularly important in view of the nature of the outcome assessment (symptom scores). Differential drop-out rates led to exclusion from the analyses due to the high risk of bias of two individual studies. Both were strongly positive so inclusion would have resulted in stronger effects favoring treatment.

Agreements and disagreements with other studies or reviews

Reducing the duration of illness due to acute respiratory infections is, of course, desirable. These infections are very common and are a major cause of lost days of work and of inappropriate antibiotic use (Gonzales 2000; Wenzel 2006).

Among the different treatment options studied so far for acute bronchitis, none have been reliable or highly effective in reducing the duration of illness. The use of ß2-agonists in the treatment of acute bronchitis in people without pulmonary disease is not supported by clinical data (Becker 2011). Although data from clinical trials are lacking, in some countries mucolytic or antitussive agents are commonly used, often in combination with antibiotics (Chalumeau 2013; Poole 2012; Wenzel 2006). Different meta-analyses of antibiotic treatment in acute bronchitis suggested that symptoms of acute bronchitis were reduced by less than a day (Bent 1999; Fahey 1998; Smith 2011). A recent large study of antibiotics versus placebo for acute lower respiratory tract infection was unable to show differences in the duration of symptoms rated "moderately bad" or worse (Little 2013). The limited effect of antibiotic treatment in acute bronchitis is accompanied by a trend toward increased adverse events and must be weighed against potential adverse event effects such as medialization of a self limited condition, the treatment costs of antibiotics and the risk of an increasing microbial resistance (Smith 2011). Similarly, antibiotic treatment cannot be recommended in acute laryngitis, otitis media in children and the common cold (Kenealy 2013; Reveiz 2013; Venekamp 2013).

The role of herbal medicines for symptom relief of acute respiratory infections is unclear. Studies with over-the-counter (OTC) medications in general did not show convincing results based on a recent Cochrane review (Smith 2012). According to a systematic review, the use of Chinese herbs for acute bronchitis cannot be recommended due to limitations in trial design and an unknown safety profile of Chinese herbs (Jiang 2012). Some evidence for limited effects of Echinacea on the incidence and duration of the common cold was reported (Shah 2007), but the meta-analytic approach in this study can be criticized. The authors of an earlier review summarized that there is no clear evidence that Echinacea may prevent common cold and, if there is any effect on the duration of the illness, only preparations of Echinacea purpurea might have this after the onset of cold symptoms (Linde 2008). A recent review showed again that Echinacea purpurea extract cannot prevent a common cold. For treatment of the common cold the extract might be effective, but issues surrounding dose and formulation require clarification (Nahas 2011). There is one study reporting that a preparation of thyme dry extract and primrose root dry extract was associated with a mean reduction in coughing fits (Kemmerich 2006). The same was shown for a fixed combination of thyme fluid extract and ivy leaves fluid extract (Kemmerich 2007). A further study showed higher cure rates for the fixed combination of a thyme fluid extract and primrose root tincture than placebo in adult patients with acute bronchitis (Gruenwald 2005). None of these study results has been replicated. Treatment effects have also been reported with a preparation containing nasturtium herb and horseradish root (Goos 2006; Goos 2007). Some of these studies have methodological flaws, and interpretation of the results is difficult. Recently a study with a more sophisticated methodology evaluated the same phytotherapy combination for prevention of acute respiratory tract infections in patients with a medical history of at least two such episodes in the last cold season (Fintelmann 2012). Compared with placebo the preparation was reported to be associated with a lower infection rate after 84 days, but the study was sponsored by the manufacturer and therefore the results have to be replicated by independent researchers.

For acute rhinosinusitis a study reported a higher rate of complete remission with a complex homeopathic medication versus placebo (Zabolotnyi 2007), but no differences in paracetamol concomitant use in the two arms. Since the study showed a large difference in drop-outs in the two arms, the last observation carried forward analysis approach may have overestimated symptom resolution in the active treatment arm. In a systematic review, oral glucocorticoids, given as adjunctive therapy to oral antibiotics, potential effects on short-term relief of symptoms in acute sinusitis were found, but the data are limited and of minor quality (Venekamp 2011). A subsequent randomized study by the same author indicates that the anti-inflammatory effect of monotherapy with oral corticosteroids seems to be of no benefit in clinically diagnosed acute rhinosinusitis (Venekamp 2012). Antibiotics have no role in uncomplicated acute rhinosinusitis, due to lack of major benefits (Ah-See 2007; Lemiengre 2012; Masood 2007; Williamson 2007).

To date, two other systematic reviews of P. sidoides extract have been published (Agbabiaka 2008; Ulbricht 2010). Agbabiaka et al reviewed the available data for acute bronchitis and came to conclusions similar to those presented here. The systematic review included six randomized controlled trials in adult patients with acute bronchitis. Two of the studies were unpublished at that time. The studies included by Agbabiaka were also reviewed in the present report. All but two studies (Blochin 1999; Matthys 2003) were eligible for the present review under the terms of our methodological requirements. In Ulbricht et al unpublished data were not reported. The authors included the results from blinded and unblinded observational study reports. They summarized that on basis of these data the positive evidence for the effects of P. sidoides in acute bronchitis is highly suggestive, albeit not definitive.

In the present analysis, adverse events were slightly more frequent with P. sidoides. There have been case reports of allergic reactions, liver toxicity and hemorrhage after treatment with the commercially available preparation (de Boer 2007). Recently, the Drug Commission of the German Medical Association (Arzneimittelkommission der deutschen Ärzteschaft AKDÄ) announced a possible relation between the consumption of Umckaloabo®, the proprietary medicinal product of P. sidoides on the German market, and the occurrence of hepatitis (AKDÄ 2011). On the basis of 19 case reports the commission concluded that a causal relationship between Umckaloabo® and very rarely occurring hepatitis cannot be ruled out. In contrast, the European Medicines Agency (EMA 2012) refers to a re-evaluation (Teschke 2012a; Teschke 2012b) of all available data concerning the hepatotoxic effects of P. sidoides. This assessment showed a lack of convincing evidence for a hepatotoxic risk associated with the treatment of P. sidoides when used as recommended. In none of the 15 analyzed cases could Pelargonium hepatotoxicity be confirmed as the final diagnosis.

A more recent report summarized the adverse events data of herbal medicines, published in systematic reviews (Posadzki 2013). The authors defined three classes of phytotherapeutics: one class comprises plant extracts, such as Piper methysticum and Cassia senna, which can cause serious side effects. The second class consists of plant extracts such as Aloe vera,Viscum album and Cimicifuga racemosa, with moderately severe side effects. The third class comprises phytotherapeutics with minor side effects such as Crataegus ssp., thyme and Echinacea spp. P. sidoides was assigned to the second class with moderate side effects, such as severe nausea or pruritus. Hepatotoxic effects of P. sidoides were not reported in this review.

Authors' conclusions

Implications for practice

Based on the limited evidence from very few clinical trials with acceptable methodology,P. sidoides might offer symptom relief in acute bronchitis, rhinosinusitis and the common cold. The clinical relevance of these effects remains uncertain.

Implications for research

More well-designed, placebo-controlled trials in acute bronchitis, rhinosinusitis and the common cold, with endpoints such as time to complete recovery, days lost from work, use of other drugs for symptom relief and antibiotics, are recommended to provide better evidence for a clinically relevant efficacy of the preparation in acute respiratory infections. It would be desirable if the available manufacturer-initiated studies from Eastern Europe could be complemented by more evaluations from independent researchers covering a larger variety of settings and methodological approaches.

Acknowledgements

M. Doerks (Bremen) and C. Fischer (Freiburg) participated in the screening and the retrieval and management of published articles. M. Kieser (2008 version) and T. Reineke (2013 update) of Schwabe Pharmaceuticals, Karlsruhe, provided unpublished manuscripts and information on missing data upon request. W. Kamin and H. Matthys responded to author enquiries. The review authors wish to thank the following people for commenting on the draft of this review (2008 version): Janet Wale, Rakesh Lodha, George Lewith, Mark Jones and Taixiang Wu.

Data and analyses

Download statistical data

Comparison 1. P. sidoides versus placebo, acute bronchitis in adults
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Failure to recover by day seven (complete resolution of all symptoms)5 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Liquid preparation2341Risk Ratio (M-H, Random, 95% CI)0.66 [0.52, 0.83]
1.2 Tablet preparation3405Risk Ratio (M-H, Random, 95% CI)0.95 [0.91, 0.99]
2 Failure to resolve key symptom by day seven: cough5 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Liquid preparation2341Risk Ratio (M-H, Random, 95% CI)0.63 [0.47, 0.85]
2.2 Tablet preparation3405Risk Ratio (M-H, Random, 95% CI)0.94 [0.90, 0.98]
3 Failure to resolve key symptom by day seven: sputum5746Risk Ratio (M-H, Random, 95% CI)0.70 [0.60, 0.82]
3.1 Liquid preparation2341Risk Ratio (M-H, Random, 95% CI)0.65 [0.54, 0.78]
3.2 Tablet preparation3405Risk Ratio (M-H, Random, 95% CI)0.73 [0.57, 0.94]
Analysis 1.1.

Comparison 1 P. sidoides versus placebo, acute bronchitis in adults, Outcome 1 Failure to recover by day seven (complete resolution of all symptoms).

Analysis 1.2.

Comparison 1 P. sidoides versus placebo, acute bronchitis in adults, Outcome 2 Failure to resolve key symptom by day seven: cough.

Analysis 1.3.

Comparison 1 P. sidoides versus placebo, acute bronchitis in adults, Outcome 3 Failure to resolve key symptom by day seven: sputum.

Comparison 2. P. sidoides versus placebo, acute bronchitis in children
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Failure to recover by day seven (complete resolution of all symptoms)5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Liquid preparation2420Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.77, 0.88]
1.2 Tablet preparation3399Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.89, 1.03]
2 Failure to resolve key symptom by day seven: cough5 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Liquid preparation2420Risk Ratio (M-H, Random, 95% CI)0.82 [0.76, 0.88]
2.2 Tablet preparation3399Risk Ratio (M-H, Random, 95% CI)0.96 [0.86, 1.07]
3 Failure to resolve key symptom by day seven: sputum5 Risk Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Liquid preparation2272Risk Ratio (M-H, Random, 95% CI)0.55 [0.33, 0.91]
3.2 Tablet preparation3399Risk Ratio (M-H, Random, 95% CI)0.87 [0.71, 1.06]
Analysis 2.1.

Comparison 2 P. sidoides versus placebo, acute bronchitis in children, Outcome 1 Failure to recover by day seven (complete resolution of all symptoms).

Analysis 2.2.

Comparison 2 P. sidoides versus placebo, acute bronchitis in children, Outcome 2 Failure to resolve key symptom by day seven: cough.

Analysis 2.3.

Comparison 2 P. sidoides versus placebo, acute bronchitis in children, Outcome 3 Failure to resolve key symptom by day seven: sputum.

Comparison 3. P. sidoides versus placebo, acute sinusitis in adults
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Failure to recover by day 21 (complete resolution of all symptoms)1103Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.30, 0.62]
2 Failure to resolve key symptom by day 21: nasal discharge1103Risk Ratio (M-H, Fixed, 95% CI)0.21 [0.11, 0.40]
3 Failure to resolve key symptom by day 21: headache1103Risk Ratio (M-H, Fixed, 95% CI)0.23 [0.12, 0.44]
Analysis 3.1.

Comparison 3 P. sidoides versus placebo, acute sinusitis in adults, Outcome 1 Failure to recover by day 21 (complete resolution of all symptoms).

Analysis 3.2.

Comparison 3 P. sidoides versus placebo, acute sinusitis in adults, Outcome 2 Failure to resolve key symptom by day 21: nasal discharge.

Analysis 3.3.

Comparison 3 P. sidoides versus placebo, acute sinusitis in adults, Outcome 3 Failure to resolve key symptom by day 21: headache.

Comparison 4. P. sidoides versus placebo, the common cold in adults
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Failure to recover by day 5 (complete resolution of all symptoms)1103Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.90, 1.03]
2 Failure to resolve key symptom by day 5: sore throat1103Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.66, 1.11]
3 Failure to resolve key symptom by day 5: nasal drainage1103Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.72, 0.95]
4 Failure to resolve key symptom by day 5: nasal congestion1103Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.72, 0.95]
5 Failure to recover by day 10 (complete resolution of all symptoms)1103Risk Ratio (M-H, Fixed, 95% CI)0.41 [0.29, 0.60]
6 Failure to resolve key symptom by day 10: sore throat1103Risk Ratio (M-H, Fixed, 95% CI)0.11 [0.01, 1.97]
7 Failure to resolve key symptom by day 10: nasal drainage1103Risk Ratio (M-H, Fixed, 95% CI)0.18 [0.04, 0.76]
8 Failure to resolve key symptom by day 10: nasal congestion1103Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.09, 1.01]
9 Days off work1103Mean Difference (IV, Fixed, 95% CI)-1.30 [-2.06, -0.54]
Analysis 4.1.

Comparison 4 P. sidoides versus placebo, the common cold in adults, Outcome 1 Failure to recover by day 5 (complete resolution of all symptoms).

Analysis 4.2.

Comparison 4 P. sidoides versus placebo, the common cold in adults, Outcome 2 Failure to resolve key symptom by day 5: sore throat.

Analysis 4.3.

Comparison 4 P. sidoides versus placebo, the common cold in adults, Outcome 3 Failure to resolve key symptom by day 5: nasal drainage.

Analysis 4.4.

Comparison 4 P. sidoides versus placebo, the common cold in adults, Outcome 4 Failure to resolve key symptom by day 5: nasal congestion.

Analysis 4.5.

Comparison 4 P. sidoides versus placebo, the common cold in adults, Outcome 5 Failure to recover by day 10 (complete resolution of all symptoms).

Analysis 4.6.

Comparison 4 P. sidoides versus placebo, the common cold in adults, Outcome 6 Failure to resolve key symptom by day 10: sore throat.

Analysis 4.7.

Comparison 4 P. sidoides versus placebo, the common cold in adults, Outcome 7 Failure to resolve key symptom by day 10: nasal drainage.

Analysis 4.8.

Comparison 4 P. sidoides versus placebo, the common cold in adults, Outcome 8 Failure to resolve key symptom by day 10: nasal congestion.

Analysis 4.9.

Comparison 4 P. sidoides versus placebo, the common cold in adults, Outcome 9 Days off work.

Comparison 5. P. sidoides versus placebo, any indication
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Patients with adverse events81771Risk Ratio (M-H, Fixed, 95% CI)1.32 [1.04, 1.66]
2 Adverse events leading to withdrawal81771Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.35, 2.27]
3 Failure to resolve all symptoms at prespecified day - publication bias8 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 5.1.

Comparison 5 P. sidoides versus placebo, any indication, Outcome 1 Patients with adverse events.

Analysis 5.2.

Comparison 5 P. sidoides versus placebo, any indication, Outcome 2 Adverse events leading to withdrawal.

Analysis 5.3.

Comparison 5 P. sidoides versus placebo, any indication, Outcome 3 Failure to resolve all symptoms at prespecified day - publication bias.

Appendices

Appendix 1. Electronic databases searched

Database (host) Update status Hits 2013 Search date
MEDLINE (via OvidSP)1946 to April Week 2 201311724 April 2013
MEDLINE Daily Update (via OvidSP)23 April 2013
MEDLINE in Process & Other Non-Indexed Citations (via OvidSP)23 April 2013

Journals@Ovid

(via OvidSP)

23 April 201382

The Cochrane Library

(via Wiley Online Library):

  
    - Cochrane ReviewsIssue 3 of 12, March 201324
    - Other ReviewsIssue 1 of 4, January 2013
    - Clinical TrialsIssue 3 of 12, March 2013

Biosis Previews

(via Web of Knowledge, Thomson Reuters)

1926 to 23 April 2013188
Web of Science (Thomson Reuters)

Present = 21 April 2013

Databases:

- SCI-EXP: 1945 to present

- SSCI: 1975 to present

- A&HCI: 1975 to present

- CPCI-S: 1990 to present

- CPCI-SSH: 1990 to present

- BKCI-S: 2005 to present

- BKCI-SSH: 2005 to present

253
CINAHL (via EBSCOhost)1981 to present51

CCMed

(via DIMDI www.dimdi.de)

1 January 2000 to 19 February 201389

XToxline

(via DIMDI www.dimdi.de)

1 January 1965 to 19 April 201325

Global Health

(via DIMDI www.dimdi.de)

1 January 1972 to 24 April 201381

AMED

(via DIMDI www.dimdi.de)

1 January 1985 to 8 April 201339

Derwent Drug File

(via DIMDI www.dimdi.de)

1 January 1983 to 23 April 201335

Derwent Drug Backfile

(via DIMDI www.dimdi.de)

1 January 1960 to 31 December 19825

IPA

(via DIMDI www.dimdi.de)

1 January 1970 to 18 April 201372

ISTPB + ISTP/ISSHP

(via DIMDI www.dimdi.de)

1 January 1978 to 21 April 201338
EMBASE (via DIMDI www.dimdi.de)1 January 1974 to 24 April 2013170
EMBASE Alert (via DIMDI www.dimdi.de)22 February 2013 to 24 April 2013
Deutsches Ärzteblatt (via www.dimdi.de)1 January 1996 to 22 April 20133
Thieme-Verlag (via DIMDI)6 August 2002 to 27 April 20122827 April 2012

Thieme-Verlag (via www.thieme-connect)

Not available via DIMDI any more

Publication year

2012 to 2013

825 April 2013
Springer (via SpringerLink www.springerlink.com)Search date 25 April 201313

Cambase

(via www.cambase.de)

Update status/time span unknown

Search date 25 April 2013

35

LILACS

http://lilacs.bvsalud.org/en/

Last update 1 March 2013829 April 2013
TRIPdatabase (via www.tripdatabase.com)

 

?

50

PubMed

(component “Supplied by Publisher”)

via www.pubmed.gov

Search date 30 April 20131230 April 2013

ScienceDirect

www.sciencedirect.com

Search date 30 April 201368

Web of Science: Cited Reference Search

of included articles for update 2013

Updated 26 April 2013712 May 2013
Total including duplicates   1565  
Total without duplicates   844  

Appendix 2. Medline (Ovid) search strategy

# Searches Results
1exp Pelargonium/150
2(umcka* or pelargoni* or eps 7630 or eps7630).mp.663
3(Gerani* adj3 (afri* or south* or sud* or root?)).mp.10
4(Ikhubalo or Icwayiba or iYeza lezikali or Yeza lezikali or kaloba? or Kalwerbossi or (Khoaara adj2 Nyenyane) or Rabassam or Uvendle).mp.1
5or/1-4                           facet intervention  (I)669
6exp Respiratory Tract Infections/276791
7exp Cough/11377
8exp Otorhinolaryngologic Diseases/285325
9exp Paramyxoviridae/27160
10exp Respiratory Syncytial Viruses/6310
11exp Haemophilus/14912
12exp Haemophilus Infections/9251
13exp Respiratory Syncytial Virus Infections/4316
14exp Respirovirus/6208
15exp Respirovirus Infections/2267
16Orthomyxoviridae Infections/6719
17Adenoviridae Infections/4483
18Adenovirus Infections, Human/1875
19(respirat* or URTI* or cold* or cough* or naso* or nasal* or nose or sinus* or ear* or otalg* or otit* or oto* or laryn* or pharyn* or retro-pharyn* or retropharyn* or throat* or tonsil* or trach* or epiglot* or rhin* or bronch* or whoop* or pertuss* or pulmo* or lung* or pneumo* or pleur* or paramyxovir* or respiratory syncytial virus* or rsv or haemophilus* or hemophilus* or influenza* or parainfluenza* or para-influenza*).mp.3077662
20or/6-19                         facet population/disease (P)3161448
215 and 20                      facet P + I106
22randomized controlled trial.pt.346442
23controlled clinical trial.pt.85736
24random*.ab.580401
25clinical trials as topic.sh.163995
26trial.ti.106747
27or/22-26           modified Cochrane-filter for random. trials (RCT)909459
285 and 27          facet I + RCT43
2921 or 28           facet I + (P or RCT)128
30exp animals/ not humans/3802336
3129 not 30         exclusion of animals107
32remove duplicates from 31105

Appendix 3. Search strategies (all databases)

MEDLINE (via OvidSP) 1946 to April Week 2 2013

Search date: 24 April 2013

# Searches Results
1exp Pelargonium/150
2(umcka* or pelargoni* or eps 7630 or eps7630).mp.663
3(Gerani* adj3 (afri* or south* or sud* or root?)).mp.10
4(Ikhubalo or Icwayiba or iYeza lezikali or Yeza lezikali or kaloba? or Kalwerbossi or (Khoaara adj2 Nyenyane) or Rabassam or Uvendle).mp.1
5or/1-4                           facet intervention  (I)669
6exp Respiratory Tract Infections/276791
7exp Cough/11377
8exp Otorhinolaryngologic Diseases/285325
9exp Paramyxoviridae/27160
10exp Respiratory Syncytial Viruses/6310
11exp Haemophilus/14912
12exp Haemophilus Infections/9251
13exp Respiratory Syncytial Virus Infections/4316
14exp Respirovirus/6208
15exp Respirovirus Infections/2267
16Orthomyxoviridae Infections/6719
17Adenoviridae Infections/4483
18Adenovirus Infections, Human/1875
19(respirat* or URTI* or cold* or cough* or naso* or nasal* or nose or sinus* or ear* or otalg* or otit* or oto* or laryn* or pharyn* or retro-pharyn* or retropharyn* or throat* or tonsil* or trach* or epiglot* or rhin* or bronch* or whoop* or pertuss* or pulmo* or lung* or pneumo* or pleur* or paramyxovir* or respiratory syncytial virus* or rsv or haemophilus* or hemophilus* or influenza* or parainfluenza* or para-influenza*).mp.3077662
20or/6-19                         facet population/disease (P)3161448
215 and 20                      facet P + I106
22randomized controlled trial.pt.346442
23controlled clinical trial.pt.85736
24random*.ab.580401
25clinical trials as topic.sh.163995
26trial.ti.106747
27or/22-26           modified Cochrane-filter for random. trials (RCT)909459
285 and 27          facet I + RCT43
2921 or 28           facet I + (P or RCT)128
30exp animals/ not humans/3802336
3129 not 30         exclusion of animals107
32remove duplicates from 31105

Legend:

.ab. = abstract
Adj3 = within 3 words in any order
Exp = explode
.mp. = title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier
.pt. = publication type
.sh. or / = Medical Subject Heading (MeSH)
.ti. = title
? or * = wildcard, truncation

MEDLINE Daily Update (via OvidSP) 23 April 2013

Search date: 24 April 2013 

# Searches Results
1exp Pelargonium/0
2(umcka* or pelargoni* or eps 7630 or eps7630).mp.1
3(Gerani* adj3 (afri* or south* or sud* or root?)).mp.0
4(Ikhubalo or Icwayiba or iYeza lezikali or Yeza lezikali or kaloba? or Kalwerbossi or (Khoaara adj2 Nyenyane) or Rabassam or Uvendle).mp.0
5or/1-4               facet intervention(I)1

Legend:

Exp = explode
Adj3 = within 3 words in any order
.mp. = title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier

MEDLINE In-Process & Other Non-Indexed Citations (via OvidSP) 23 April 2013

Search date: 24 April 2013

# Searches Results
1(umcka* or pelargoni* or eps 7630 or eps7630).mp.69
2(Gerani* adj3 (afri* or south* or sud* or root?)).mp.3
3(Ikhubalo or Icwayiba or iYeza lezikali or Yeza lezikali or kaloba? or Kalwerbossi or (Khoaara adj2 Nyenyane) or Rabassam or Uvendle).mp.0
4or/1-3               facet intervention  (I)70
5(respirat* or URTI* or cold* or cough* or naso* or nasal* or nose or sinus* or ear* or otalg* or otit* or oto* or laryn* or pharyn* or retro-pharyn* or retropharyn* or throat* or tonsil* or trach* or epiglot* or rhin* or bronch* or whoop* or pertuss* or pulmo* or lung* or pneumo* or pleur* or paramyxovir* or respiratory syncytial virus* or rsv or haemophilus* or hemophilus* or influenza* or parainfluenza* or para-influenza*).mp.                facet population/disease (P)153005
64 and 5                        facet I + P7
7(rando* or trial* or placebo*).mp.                  facet RCT73454
84 and 7                        facet I + RCT7
96 or 8               facet I + (P or RCT)12

Legend:

Adj3 = within 3 words in any order
.mp. = title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier
? or * = wildcard, truncation

Journals@Ovid Full Text (via OvidSP) 

Update status: 23 April 2013
Search date: 24 April 2013 

# Searches Results
1(umckaloabo* or umcka or pelargonium* or pelargonie* or eps* 7630* or eps7630*).mp.248
2(Gerani* adj3 (afri* or south* or sud* or root?)).mp.23
3(Ikhubalo or Icwayiba or iYeza lezikali or Yeza lezikali or kaloba? or Kalwerbossi or (Khoaara adj2 Nyenyane) or Rabassam or Uvendle).mp.1
4(respirat* or URTI* or cold* or cough* or naso* or nasal* or nose or sinus* or ear* or otalg* or otit* or oto* or laryn* or pharyn* or retro-pharyn* or retropharyn* or throat* or tonsil* or trach* or epiglot* or rhin* or bronch* or whoop* or pertuss* or pulmo* or lung* or pneumo* or pleur* or paramyxovir* or respiratory syncytial virus* or rsv or haemophilus* or hemophilus* or influenza* or parainfluenza* or para-influenza).mp.2593193
5(1 or 2 or 3) and 4     facet Intervention (I) + Disease (P) (in fulltext)155
6

(rando* or placebo*).mp. or trial*.ti,ab.    

Facet rando contr. trials (RCT)

1187891
7((systematic* adj3 (review* or overview*)) or meta-analy* or metaanaly*).mp.   facet syst. Rev.  (SR)232243
8

5 and (6 or 7)             

facet I + P + (RCT or SR)  (in fulltext)

75
9(umckaloabo* or umcka or pelargonium* or pelargonie* or eps* 7630* or eps7630*).ti,ab.92
10(Gerani* adj3 (afri* or south* or sud* or root?)).ti,ab.4
11(Ikhubalo or Icwayiba or iYeza lezikali or Yeza lezikali or kaloba? or Kalwerbossi or (Khoaara adj2 Nyenyane) or Rabassam or Uvendle).ti,ab.0
12(respirat* or URTI* or cold* or cough* or naso* or nasal* or nose or sinus* or ear* or otalg* or otit* or oto* or laryn* or pharyn* or retro-pharyn* or retropharyn* or throat* or tonsil* or trach* or epiglot* or rhin* or bronch* or whoop* or pertuss* or pulmo* or lung* or pneumo* or pleur* or paramyxovir* or respiratory syncytial virus* or rsv or haemophilus* or hemophilus* or influenza* or parainfluenza* or para-influenza).ti,ab.713671
13(9 or 10 or 11) and 12  facet I + P (in title or abstract)19
14

8 or 13 

facet I + P + (RCT or SR)  (in fulltext) OR

facet I + P (in title or abstract)

82

Legend:

.ti,ab. = title, abstract
.mp. = title, abstract, full text, caption text
?, * = Wildcard, truncation

The Cochrane Library (via Wiley Online Library) (www.thecochranelibrary.org)

Update status:

  • Cochrane Database of Systematic Reviews (CDSR): Issue 3 of 12, March 2013

  • Other Reviews (DARE):  Issue 1 of 4, January 2013

  • Cochrane Central Register of Controlled Trials (CENTRAL): Issue 3 of 12, March 2013

Search date: 24 April 2013

ID Search Hits
#1umcka* or pelargonium* or eps7630 or eps next 763024
#2Gerani* near (afri* or south* or sud* or root*)1
#3Ikhubalo or Icwayiba or (iYeza next lezikali) or (Yeza next lezikali) or kaloba* or Kalwerbossi or (Khoaara near Nyenyane) or Rabassam or Uvendle0
#4(#1 OR #2 OR #3)

24

CDSR: 2

DARE: 2

CENTRAL: 20

Biosis Previews (via Web of Knowledge, Thomson Reuters)

Update status: 1926 to present, updated 23 April 2013
Time span = all years

DocType=All document types; Language=All languages

 

Search date: 24 April 2013

  

Set Results Query
# 15 188

#14 OR #11 OR #10           

facet (I + P) or (I+humans) or (I+(RCT or SR))

# 14 32#4 and (#12 or #13)                  facet I + (RCT or SR)
# 13 46,491ts=("meta-analy*" or metaanaly* or (systematic near/3 (review or overview)))                     facet syst. Rev (SR)
# 12 401,718

ts=(randomi$ed or randomly or placebo*)     

                                      facet random. contr. Trials (RCTs)

# 11 100(#4) AND Taxa Notes=(Humans)           facet I + humans
# 10 118#9 AND #4                                 facet P + I
# 9 1,352,337#8 OR #7 OR #6 OR #5          facet patient/disease (P)
# 8 1,045,738ti=(respirat* or URTI* or cold* or cough* or naso* or nasal* or nose or sinus* or ear* or otalg* or otit* or oto* or laryn* or pharyn* or "retro-pharyn*" or retropharyn* or throat* or tonsil* or trach* or epiglot* or rhin* or bronch* or whoop* or pertuss* or pulmo* or lung* or pneumo* or pleur* or paramyxovir* or "respiratory syncytial virus*" or rsv or haemophilus* or hemophilus* or influenza* or parainfluenza* or "para-influenza")
# 7 215,298psd=respiratory system
# 6 112,317CC=(Pharmacology - Respiratory system)
# 5 363,118ds=respiratory system disease
# 4 2,923#3 OR #2 OR #1                     facet intervention (I)
# 30ts=(Ikhubalo or Icwayiba or "iYeza lezikali" or "Yeza lezikali" or kaloba$ or Kalwerbossi or (Khoaara near/2 Nyenyane) or Rabassam or Uvendle)
# 2 163ts=(Gerani* near/3 (afri* or south* or sud* or root$))
# 1 2,838ts=(umckaloabo* or umcka or pelargonium* or pelargonie* or (eps* near/3 7630*) or eps7630*)

Legend:

$ or * = Wildcard, truncation
CC = Concept Codes
DS = Disease Data
PSD = Parts & Structures Data
TA = Taxonomic Data
TI =Title
TS =Topic:
Searches in the following fields:
    Title field
    Foreign Title field
    Abstract field
    Major Concepts field
    Concept Code(s) field
    Taxonomic Data table
    Disease Data table
    Chemical Data table
    Gene Name Data table
    Sequence Data table
    Geographic Data table
    Geologic Time Data table
    Methods and Equipment Data table
    Parts & Structure Data table
    Miscellaneous Descriptors field

Web of Science (Thomson Reuters)

Update status: last updated 21 April 2013

Databases:

  • Science Citation Index Expanded (SCI-EXPANDED): 1945 to present

  • Social Sciences Citation Index (SSCI): 1975 to present

  • Arts & Humanities Citation Index (A&HCI): 1975 to present

  • Conference Proceedings Citation Index - Science (CPCI-S): 1990 to present

  • Conference Proceedings Citation Index - Social Science & Humanities (CPCI-SSH): 1990 to present

  • Book Citation Index– Science (BKCI-S) 2005 to present

  • Book Citation Index– Social Sciences & Humanities (BKCI-SSH) 2005 to present 

Search date: 24 April 2013

Set Results    Query
# 10 253#9 OR #6                 facet (I + P) or (I+(RCT or SR))
# 9 86#4 and (#7 or #8)                     facet I + (RCT or SR)
# 8 150,192ts=(systematic* near/3 (review* or overview*) or metaanaly* or meta-analy*)
# 7 1,631,845ts=(rando* or trial* or placebo*)
# 6 211#5 AND #4                           facet P + I
# 5 3,671,971

ts=(respirat* or URTI* or cold* or cough* or naso* or nasal* or nose or sinus* or ear* or otalg* or otit* or oto* or laryn* or pharyn* or "retro-pharyn*" or retropharyn* or throat* or tonsil* or trach* or epiglot* or rhin* or bronch* or whoop* or pertuss* or pulmo* or lung* or pneumo* or pleur* or paramyxovir* or "respiratory syncytial virus*" or rsv or haemophilus* or hemophilus* or influenza* or parainfluenza* or "para-influenza")

facet patient/disease (P)

# 4 1,606#3 OR #2 OR #1                     facet Intervention (I)
# 30ts=(Ikhubalo or Icwayiba or "iYeza lezikali" or "Yeza lezikali" or kaloba$ or Kalwerbossi or (Khoaara near/2 Nyenyane) or Rabassam or Uvendle)
# 2 97ts=(Gerani* near/3 (afri* or south* or sud* or root$)) 
# 1 1,557ts=(umckaloabo* or umcka or pelargonium* or pelargonie* or (eps* near/3 7630*) or eps7630*)

Legend:

$ or * = wildcard, truncation
TS=Topic: searches in the following fields: Title, Abstract, Author Keywords, Keywords Plus®
near/3 = within 3 words in any order

CINAHL (EBSCOhost)

Update status: 1981 to present
Search date: 24 April 2013

# Query Results
S4S1 or S2 or S3                                 facet intervention (I)51
S3TX (Ikhubalo or Icwayiba or iYeza lezikali or Yeza lezikali or kaloba# or Kalwerbossi or (Khoaara N2 Nyenyane) or Rabassam or Uvendle)0
S2TX (Gerani* N3 (afri* or south* or sud* or root* or wurzel*))6
S1TX umcka* or pelargonium* or pelargonie* or (eps* W3 7630*) or eps7630*50

Legend:

TX = all text
W3 = within 3 words in this order
# , * = wildcard, truncation

Current Contents Medizin (CCMed), vie DIMDI (www.dimdi.de)

Update status: 1 January 2000 to 19 February 2013
Search date: 24 April 2013 

No Hits  Query
1770327 CC00
288 UMCKA* OR PELARGONI* OR (EPS* # # 7630*) OR EPS7630*
3GERANI*, # # # (*AFRI* OR SOUTH* OR SUD* OR SUED* OR SÜD* OR ROOT* OR *WURZEL*)
4IKHUBALO OR ICWAYIBA OR *YEZA LEZIKALI OR KALOBA* OR KALWERBOSSI OR (KHOAARA AND NYENYANE) OR RABASSAM OR UVENDLE
589 2 TO 4             facet intervention (I)

Legend:

CC00 = Database CCMed
Text word search in the fields: Document Type, Title
# # # = within 3 words in any order

XTOXLINE (via DIMDI) (www.dimdi.de)

Update status 1 January 1965 to 19 April 2013
Search date: 24 April 2013 

No Hits  Query
13754759 T165
265 UMCKA* OR PELARGONIUM* OR PELARGONIE* OR (EPS* # # 7630*) OR EPS7630*
3GERANI*, # # # (*AFRI* OR SOUTH* OR SUD* OR SUED* OR SÜD* OR ROOT* OR *WURZEL*)
4IKHUBALO OR ICWAYIBA OR *YEZA LEZIKALI OR KALOBA* OR KALWERBOSSI OR (KHOAARA AND NYENYANE) OR RABASSAM OR UVENDLE
571 2 OR 3 OR 4               facet intervention (I)
6443748 RESPIRAT* OR URTI* OR COLD* OR COUGH* OR NASO* OR NASAL* OR NOSE OR SINUS* OR EAR* OR OTALG* OR OTIT* OR OTO* OR LARYN* OR PHARYN* OR RETRO-PHARYN* OR RETROPHARYN* OR THROAT* OR TONSIL* OR TRACH* OR EPIGLOT* OR RHIN* OR BRONCH*
7262219 WHOOP* OR PERTUSS* OR PULMO* OR LUNG* OR PNEUMO* OR PLEUR* OR PARAMYXOVIR* OR RESPIRATORY SYNCYTIAL VIRUS* OR RSV OR HAEMOPHILUS* OR HEMOPHILUS* OR INFLUENZA* OR PARAINFLUENZA* OR PARA-INFLUENZA*
8621326 6 OR 7            facet patient/disease (P)
921 5 AND 8         facet I + P
10211202 RANDO* OR PLACEBO* OR BLIND* OR (CONTROLLED # # # TRIAL*)
1116521 (SYSTEMATI* # # # *REVIEW*) OR META-ANALY* OR METAANALY*
12219397 10 OR 11        facet RCT or syst rev. (SR)
135 AND 12       facet I + (RCT or SR)
1425 9 OR 13    facet I + (P or RCT or SR)

Legend:

T165 = Database XTOXLINE

# # # = within 3 words in any order
Text word search in the fields: Abstract, Controlled Terms, Document Type, Gene Symbol, Index Term, Personal Name as Subject, Section Headings, Terminology, Title, Uncontrolled Terms

Global Health (via DIMDI) (www.dimdi.de)

Update status: 1 January 1972 to 24 April 2013
Search date: 24 April 2013 

No Hits Search expression
12113089 AZ72   
2264 UMCKA* OR PELARGONIUM* OR PELARGONIE* OR (EPS* # # 7630*) OR EPS7630*
323 GERANI*, # # # (*AFRI* OR SOUTH* OR SUD* OR SUED* OR SÜD* OR ROOT* OR *WURZEL*)
4IKHUBALO OR ICWAYIBA OR *YEZA LEZIKALI OR KALOBA* OR KALWERBOSSI OR (KHOAARA AND NYENYANE) OR RABASSAM OR UVENDLE
5277 2 TO 4                       facet intervention (I)
6256716 RESPIRAT* OR URTI* OR COLD* OR COUGH* OR NASO* OR NASAL* OR NOSE OR SINUS* OR EAR* OR OTALG* OR OTIT* OR OTO* OR LARYN* OR PHARYN* OR RETRO-PHARYN* OR RETROPHARYN* OR THROAT* OR TONSIL* OR TRACH* OR EPIGLOT* OR RHIN* OR BRONCH*
7154210 WHOOP* OR PERTUSS* OR PULMO* OR LUNG* OR PNEUMO* OR PLEUR* OR PARAMYXOVIR* OR RESPIRATORY SYNCYTIAL VIRUS* OR RSV OR HAEMOPHILUS* OR HEMOPHILUS* OR INFLUENZA* OR PARAINFLUENZA* OR PARA-INFLUENZA*
8341718 6 OR 7                            facet disease (P)
973 5 AND 8                              facet I + P
10128083 RANDO* OR PLACEBO* OR BLIND* OR (CONTROLLED # # # TRIAL*)
1116730 (SYSTEMATI* # # # *REVIEW*) OR META-ANALY* OR METAANALY*
12138748 10 OR 11                   facet rando (RCT) or syst. Rev. (SR)
1321 5 AND 12                          facet I + (RCT or SR)
1481 9 OR 13                         facet I + (P or  RCT or SR)

Legend:

AZ72 = Database GLOBAL HEALTH
# # # = within 3 words in any order
Text word search in the fields: Abstract, Broader Term, Controlled Term, Document Type, Section Heading, Title, Uncontrolled Term

AMED Allied and Complementary Medicine Database (via DIMDI) (www.dimdi.de)

Update status: 1 January 1985 to 8 April 2013
Search date: 24 April 2013

No Hits  Search expression
1273314 CB85
235 UMCKA* OR PELARGONIUM* OR PELARGONIE* OR (EPS* # # 7630*) OR EPS7630*
3GERANI*, # # # (*AFRI* OR SOUTH* OR SUD* OR SUED* OR SÜD* OR ROOT* OR *WURZEL*)
4IKHUBALO OR ICWAYIBA OR *YEZA LEZIKALI OR KALOBA* OR KALWERBOSSI OR (KHOAARA AND NYENYANE) OR RABASSAM OR UVENDLE
539 2 TO 4             facet intervention (I)

Legend:

CB85 = Database AMED
# # # = within 3 words in any order
Text word search in the fields: Abstract, Controlled Term, Document Type, Title, Uncontrolled Term

Derwent Drug File (via DIMDI) (www.dimdi.de)

Update status: 1 January 1983 to 23 April 2013
Search date: 24 April 2013 

No Hits  Search expression
11466135 DD83
231 UMCKA* OR PELARGONIUM* OR PELARGONIE* OR (EPS* # # 7630*) OR EPS7630*
3GERANI*, # # # (*AFRI* OR SOUTH* OR SUD* OR SUED* OR SÜD* OR ROOT* OR *WURZEL*)
4IKHUBALO OR ICWAYIBA OR *YEZA LEZIKALI OR KALOBA* OR KALWERBOSSI OR (KHOAARA AND NYENYANE) OR RABASSAM OR UVENDLE
535 2 TO 4             facet intervention (I)

Legend:

DD83 = Derwent Drug File
# # # = within 3 words in any order
Text word search in the fields: Abstract, Extension Abstract (ABEX) in Vers. DW, Controlled Term, Index Term, Section Heading, Title

Derwent Drug Backfile (via DIMDI) (www.dimdi.de)

Update status: 1 January 1960 to 31 December 1982
Search date: 24 April 2013 

No Hits  Search expression
1805789 DH64
2UMCKA* OR PELARGONIUM* OR PELARGONIE* OR (EPS* # # 7630*) OR EPS7630*
3GERANI*, # # # (*AFRI* OR SOUTH* OR SUD* OR SUED* OR SÜD* OR ROOT* OR *WURZEL*)
4IKHUBALO OR ICWAYIBA OR *YEZA LEZIKALI OR KALOBA* OR KALWERBOSSI OR (KHOAARA AND NYENYANE) OR RABASSAM OR UVENDLE
52 TO 4             facet intervention (I)

Legend:

DH64 = Derwent Drug Backfile
# # # = within 3 words in any order
Text word search in the fields: Controlled Term, Index Term, Section Heading, Title

IPA International Pharmaceutical Abstracts (via DIMDI) (www.dimdi.de)

Update status: 1 January 1970 to 18 April 2013
Search date: 24 April 2013 

No Hits  Search expression
1567686 IA70
267 UMCKA* OR PELARGONIUM* OR PELARGONIE* OR (EPS* # # 7630*) OR EPS7630*
3GERANI*, # # # (*AFRI* OR SOUTH* OR SUD* OR SUED* OR SÜD* OR ROOT* OR *WURZEL*)
4IKHUBALO OR ICWAYIBA OR *YEZA LEZIKALI OR KALOBA* OR KALWERBOSSI OR (KHOAARA AND NYENYANE) OR RABASSAM OR UVENDLE
572 2 TO 4             facet intervention (I)

Legend:

IA70 = IPA International Pharmaceutical Abstracts
# # # = within 3 words in any order
Text word search in the fields: Abstract, Controlled Term, Drug Name, Document Type, Group of Compound, Section Heading, Terminology, Title, Uncontrolled Term

ISTP (Index to Scientific and Technical Proceedings) and ISSHP (Index to Social Sciences & Humanities Proceedings) (via DIMDI) (www.dimdi.de)

Update status: 1 January 1978 to 21 April 2013 
Search date: 24 April 2013

No Hits  Search expression
19484576 II78
2180 UMCKA* OR PELARGONIUM* OR PELARGONIE* OR (EPS* # # 7630*) OR EPS7630*
3GERANI*, # # # (*AFRI* OR SOUTH* OR SUD* OR SUED* OR SÜD* OR ROOT* OR *WURZEL*)
4IKHUBALO OR ICWAYIBA OR *YEZA LEZIKALI OR KALOBA* OR KALWERBOSSI OR (KHOAARA AND NYENYANE) OR RABASSAM OR UVENDLE
5184 2 TO 4             facet intervention (I)
6478460 RESPIRAT* OR URTI* OR COLD* OR COUGH* OR NASO* OR NASAL* OR NOSE OR SINUS* OR EAR* OR OTALG* OR OTIT* OR OTO* OR LARYN* OR PHARYN* OR RETRO-PHARYN* OR RETROPHARYN* OR THROAT* OR TONSIL* OR TRACH* OR EPIGLOT* OR RHIN* OR BRONCH*
7109110 WHOOP* OR PERTUSS* OR PULMO* OR LUNG* OR PNEUMO* OR PLEUR* OR PARAMYXOVIR* OR RESPIRATORY SYNCYTIAL VIRUS* OR RSV OR HAEMOPHILUS* OR HEMOPHILUS* OR INFLUENZA* OR PARAINFLUENZA* OR PARA-INFLUENZA*
8556424 6 OR 7                facet disease (P)
917 5 AND 8          facet I + P
10183144 RANDO* OR PLACEBO* OR BLIND* OR (CONTROLLED # # # TRIAL*)
1112383 (SYSTEMATI* # # # *REVIEW*) OR META-ANALY* OR METAANALY*
12192421 10 OR 11            facet rando (RCT) or syst. Rev. (SR)
135 AND 12          facet I + (RCT or SR)
1420 9 OR 13           facet I + (P or  RCT or SR)
1526 TI=(UMCKALOABO* OR UMCKA OR PELARGONIUM* SIDOID* OR PELARGONIE* OR (EPS* # # 7630*) OR EPS7630*)
1638 14 OR 15             facet I in title or  I + (P or  RCT or SR)

Legend:

II78 = Database ISTP + ISSHP
# # # = within 3 words in any order
TI = Title
Text word search in the fields: Abstract, Book Title -  only to 1998, Conference, Document Type, Index Terms, Series, Section Headings, Title, Uncontrolled Term from 2001 on

EMBASE (via DIMDI)

Update status: 1 January 1974 to 24 April 2013
Search date: 24 April 2013 

No Hits  Search expression
121808651 EM74
2288 CT = PELARGONIUM OR CT = PELARGONIUM SIDOIDES EXTRACT
3546 UMCKA* OR PELARGONIUM* OR EPS 7630 OR EPS7630
4546 2 OR 3            facet intervention (I)
5230268 CT D RESPIRATORY TRACT INFECTION
652289 CT D COUGHING
746002 CT D PARAMYXOVIRUS OR CT D PARAMYXOVIRUS INFECTION
826054 CT D HAEMOPHILUS
9677 CT=HAEMOPHILUS INFECTION
101161 CT=RESPIRATORY SYNCYTIAL VIRUS INFECTION
1110866 CT D RESPIROVIRUS INFECTION OR CT=RESPIRATORY SYNCYTIAL PNEUMOVIRUS
121700 CT=ORTHOMYXOVIRIDAE INFECTION
131069 CT=ADENOVIRUS INFECTION OR CT=HUMAN ADENOVIRUS INFECTION
142911192 RESPIRAT* OR URTI* OR COLD* OR COUGH* OR NASO* OR NASAL* OR NOSE OR SINUS* OR EAR* OR OTALG* OR OTIT* OR OTO* OR LARYN* OR PHARYN* OR RETRO-PHARYN* OR RETROPHARYN* OR THROAT* OR TONSIL* OR TRACH* OR EPIGLOT* OR RHIN* OR BRONCH*
151352547 WHOOP* OR PERTUSS* OR PULMO* OR LUNG* OR PNEUMO* OR PLEUR* OR PARAMYXOVIR* OR RESPIRATORY SYNCYTIAL VIRUS* OR RSV OR HAEMOPHILUS* OR HEMOPHILUS* OR INFLUENZA* OR PARAINFLUENZA*
163746054 5 TO 15           facet disease (P)
17191 4 AND 16       facet I + P
18169 17 NOT SU=MEDLINE        (without unique medline citations)

Legend:

EM74 = EMBASE 1974 to present
CT = controlled term (EMTREE)
CT D = explode controlled term
* = Truncation
Text word search in the fields: Abstract, Book Title, Common Device Name, Controlled Term, Device Manufacturer’s Name, Document Type, Drug Trade Name, Drug Manufacturer's Name, EMCLAS Term, Terminology, Title, Uncontrolled Term

EMBASE Alert (via DIMDI)

Update status: 22 February 2013 to 24 April 2013
Search date: 24 April 2013 

No Hits  Search expression
1121963 EA08
2UMCKA* OR PELARGONIUM* OR PELARGONIE* OR EPS 7630 OR EPS7630

Legend:

EA08 = EMBASE Alert
* = Truncation
Text word search in the fields: Abstract, Book Title, Document Type, Title, Uncontrolled Term

Deutsches Ärzteblatt (via DIMDI)

Update status 1 January 1996 to 22 April 2013

 

Search date: 24 April 2013

 

No Hits  Search expression
164973 AR96
2UMCKA* OR PELARGONIUM* OR PELARGONIE* OR (EPS* # # 7630*) OR EPS7630*
3GERANI*, # # # (*AFRI* OR SOUTH* OR SUD* OR SUED* OR SÜD* OR ROOT* OR *WURZEL*)
4IKHUBALO OR ICWAYIBA OR *YEZA LEZIKALI OR KALOBA* OR KALWERBOSSI OR (KHOAARA AND NYENYANE) OR RABASSAM OR UVENDLE
52 TO 4

Legend:

AR96 = Database Deutsches Ärzteblatt
Text word search in the fields: Document Type, Section Heading, Text, Title

Thieme-Publisher (via DIMDI)

Update status: 6 August 2002 to 27 April 2012
Search date: 27 April 2012; database not available via DIMDI after 2012. See below: update search via publisher’s website Thieme-connect 

52 OR 3 OR 428
4Ikhubalo or Icwayiba or *Yeza lezikali or kaloba* or Kalwerbossi or (Khoaara and Nyenyane) or Rabassam or Uvendle
3Gerani*, # # # (*afri* or south* or sud* or sued* or süd* or root* or *wurzel*)
2umcka* or pelargonium* or pelargonie* or (eps* # # 7630*) or eps7630*
1TV01 TVPP  

TV01 = Database Thieme
TVPP = Database Thieme Preprint
Text word search in the fields: Abstract, Dokumenttyp, Title, Uncontrolled Terms
# # # = within 3 words in any order

Thieme-Publisher (via www.thieme-connect.de):

Publication years 2012 to 2013
Search date 25 April 2013 

Full-text searchModeAll years

Publication

years

2012 to 2013

Publication years

2012 to 2013

without dupl.

Eps 7630Phrase search494

 

 

8

Eps7630 
Umckaloabo* 565
pelargonium* rando*All words (AND)263

Springer publisher

www.springerlink.com

Search date 25 April 2013 

Query simple searchResults

umckaloabo OR "pelargonium sidoides" OR eps7630  OR "eps 7630"

Refine your search: By discipline  “Medicine” and by “articles”:

13

 Cambase (via www.cambase.de)

Search date 25 April 2013 

Query (all words) Results Results without duplicates
Pelargonium4135
Umckaloabo20
Eps76300
Eps 763025

LILACS

via http://lilacs.bvsalud.org/en/

Update status: 1 March 2013
Search date 29 April 2013

Search by iAH form:Results
B01.650.940.800.575.100.462.750 [DeCS Category] or pelargonium or eps 7630 or eps7630 or umckaloabo or kaloba [Words]8

Legend:

DeCS Category  number = Descriptores en Ciencias de la Salud (Descriptors on Health Sciences), identical to MeSH - Medical Subject Headings

TRIP Database www.tripdatabase.com

Search date: 29 April 2013

Search strategy: pelargonium or umckaloabo or eps7630 or "eps 7630"

Results: 105 (incl. Dupl)
1.      Evidence: 48 hits incl. dupl.
2.      MEDLINE Articles:

2.1. Therapy:  17 hits
Details: (("pelargonium"[MeSH Terms] OR "pelargonium"[All Fields]) OR umckaloabo[All Fields] OR ("EPs 7630"[Supplementary Concept] OR "EPs 7630"[All Fields]) OR ("EPs 7630"[Supplementary Concept] OR "EPs 7630"[All Fields] OR "eps 7630"[All Fields])) AND (randomized controlled trial[Publication Type] OR (randomized[Title/Abstract] AND controlled[Title/Abstract] AND trial[Title/Abstract]))

2.2. Etiology:  5 hits

Details: ((pelargonium or umckaloabo or eps7630 or "eps or 7630")) AND ((relative[Title/Abstract] AND risk*[Title/Abstract]) OR (relative risk[Text Word]) OR risks[Text Word] OR cohort studies[MeSH:noexp] OR (cohort[Title/Abstract] AND stud*[Title/Abstract]))
Wildcard search for 'stud*' used only the first 600 variations

2.3. Diagnosis:  4 hits

Details: (("pelargonium"[MeSH Terms] OR "pelargonium"[All Fields]) OR umckaloabo[All Fields] OR ("EPs 7630"[Supplementary Concept] OR "EPs 7630"[All Fields]) OR ("EPs 7630"[Supplementary Concept] OR "EPs 7630"[All Fields] OR "eps 7630"[All Fields])) AND specificity[Title/Abstract]

2.4. Systematic Reviews: 3 hits

Details: (("pelargonium"[MeSH Terms] OR "pelargonium"[All Fields]) OR umckaloabo[All Fields] OR ("EPs 7630"[Supplementary Concept] OR "EPs 7630"[All Fields]) OR ("EPs 7630"[Supplementary Concept] OR "EPs 7630"[All Fields] OR "eps 7630"[All Fields])) AND (meta analysis[ptyp] OR meta-analysis[tiab] OR "meta-analysis as topic"[MeSH Terms] OR (systematic[tiab] AND review[tiab]) NOT ((case[ti] AND report[ti]) OR editorial[ptyp] OR comment[ptyp] OR letter[ptyp] OR newspaper article[ptyp]))

Total in TRIP database without duplicates: 50 hits

PubMed: component 'Supplied by Publisher' (www.pubmed.gov)

Search date 30 April 2013

Search Query Items found
#5Search #4 AND publisher[sb] 12
#4Search (#2 OR #3) 345
#3Search pelargonium*[tw] OR "eps 7630"[tw] OR eps7630[tw] OR umckaloabo*[tw] 345
#2Search "Pelargonium"[MeSH] 147

Legend:

* = Truncation

[tw] = text word search in the fields: title, abstract, other abstract, MeSH terms, MeSH Subheadings, Publication Types, Substance Names, Personal Name as Subject, Corporate Author, Secondary Source, Comment/Correction Notes
[MeSH] = Medical Subject Heading with explode-function
[sb] = subset

ScienceDirect

www.sciencedirect.com

Search date 30 April 2013
Advanced search: 

14 articles found for: TITLE-ABSTR-KEY(umckaloabo*)
29 articles found for: TITLE-ABSTR-KEY("eps* 7630*")
60 articles found for: TITLE-ABSTR-KEY(pelargonium*)[All Sources(Medicine and Dentistry)]
Total: 103
Without duplicates: 68

Web of Science: Cited Reference Search (forward search) of:

Timmer Cochrane Review 2008 and of 12 selected articles for inclusion in Cochrane Review 2013

Databases=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, BKCI-S, BKCI-SH Timespan=All years

Search date 2 May 2013

Set Results  
 0

No hits from forward citations of:

Kamin W, Ilyenko LI, Malek FA, Kieser M. Treatment of acute bronchitis with EPs 7630: randomized, controlled trial in children and adolescents. Pediatrics international : official journal of the Japan Pediatric Society. 2012;54(2):219-26.

Kamin W, Maydannik V, Malek FA, Kieser M. Efficacy and tolerability of EPs 7630 in children and adolescents with acute bronchitis - a randomized, double-blind, placebo-controlled multicenter trial with a herbal drug preparation from Pelargonium sidoides roots. Int J Clin Pharmacol Ther. 2010;48(0946-1965 (Print), 0946-1965 (Linking), 3):184-91.

Matthys H, Lizogub VG, Funk P, Malek FA. [Pelargonium sidoides in acute bronchitis - Health-related quality of life and patient-reported outcome in adults receiving EPs 7630 treatment]. Wiener medizinische Wochenschrift (1946). 2010;160(21-22):564-70.

# 11 71#10 OR #9 OR #8 OR #7 OR #6 OR #5 OR #4 OR #3 OR #2 OR #1
# 10 3

Cited Author=(matthys) AND Cited Work=(curr*) AND Cited Year=(2010)

Matthys, H., et al., Efficacy and tolerability of EPs 7630 tablets in patients with acute bronchitis: a randomised, double-blind, placebo-controlled dose-finding study with a herbal drug preparation from Pelargonium sidoides. Curr Med Res Opin, 2010. 26(6): p. 1413-1422.

# 9 5

Cited Author=(matthys) AND Cited Work=(planta*) AND Cited Year=(2008)

Matthys, H. and P. Funk, EPs 7630 improves acute bronchitic symptoms and shortens time to remission. Results of a randomised, double-blind, placebo-controlled, multicentre trial. Planta Med, 2008. 74(6): p. 686-692.

# 8 2

Cited Author=(kamin) AND Cited Work=(acta*) AND Cited Year=(2010)

Kamin, W., et al., Efficacy and tolerability of EPs 7630 in patients (aged 6-18 years old) with acute bronchitis. Acta Paediatr, 2010. 99(4): p. 537-543.

# 7 10

Cited Author=(bachert) AND Cited Work=(rhinol*) AND Cited Year=(2009)

Bachert, C., et al., Treatment of acute rhinosinusitis with the preparation from Pelargonium sidoides EPs 7630: a randomized, double-blind, placebo-controlled trial. Rhinology, 2009. 1: p. 51-58.

# 6 21

Cited Author=(timmer) AND Cited Work=(cochr*) AND Cited Title=(pelargonium*)

Timmer A, Günther J, Rücker G, Motschall E, Antes G, Kern WV. Pelargonium sidoides extract for acute respiratory tract infections. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD006323. DOI: 10.1002/14651858.CD006323.pub2.

# 5 21

Cited Author=(matthys) AND Cited Work=(curr*) AND Cited Year=(2007)

Matthys, H. and M. Heger, Treatment of acute bronchitis with a liquid herbal drug preparation from Pelargonium sidoides (EPs 7630): a randomised, multicentre, double-blind, placebo-controlled study. Current Medical Research and Opinion, 2007. 23(2): p. 323-331.

# 4 17

Cited Author=(lizogub) AND Cited Work=(explore*) AND Cited Year=(2007)

Lizogub, V.G., D.S. Riley, and M. Heger, Efficacy of Pelargonium Sidoides Preparation in patients with the common cold: a randomized, double blind, placebo-controlled clinical trial. Explore, 2007. 3(6): p. 573-584.

# 3 8

Cited Author=(golovatiouk) AND Cited Work=(Phytopharmaka*) AND Cited Year=(2002)

Golovatiouk, A. and A.G. Chuchalin, Efficacy of pelargonium sidoides preparation (Eps (R) 7630) in adults with acute bronchitis. Phytopharmaka. Vol. 7. 2002, Darmstadt: Steinkopff. 3-12.

# 2 37

Cited Author=(chuchalin) AND Cited Work=(explore*) AND Cited Year=(2005)

Chuchalin, A.G., B. Berman, and W. Lehmacher, Treatment of acute bronchitis in adults with a pelargonium sidoides preparation (EPs 7630): a randomized, double blind, placebo-controlled trial. Explore, 2005. 1(6): p. 437-445.

# 1 4

Cited Author=(bachert) AND Cited Work=(focus*) AND Cited Year=(2006)

Bachert, C., et al. Treatment of acute bacterial maxillary sinusitis with EPs 7630-solution: a randomised, double-blind, placebo-controlled trial. Focus Alternative Complementary Therapy, 2006. 11: p.4.

Study registries: 

ClinicalTrials.gov -  via  www.clinicaltrials.gov
Deutsches Register klinischer Studien DRKS (German Clinical Trials Register)www.drks.de
International Clinical Trials Registry Platform (ICTRP) – WHO ICTRP – http://apps.who.int/trialsearch/default.aspx
Current Controlled Trialshttp://www.controlled-trials.com
EU Clinical Trials Register –  www.clinicaltrialsregister.eu 

Search date: 3 May 2013
Search terms: 

umckaloabo*, pelargoni*, gerani*, eps7630, eps 7630, kaloba*, Kalwerbossi, Rabassam, Uvendle
31 hits without duplicates

Appendix 4. Clinical study registries search strategy

Study register
ClinicalTrials.gov -  via  www.clinicaltrials.gov
Deutsches Register klinischer Studien DRKS (German Clinical Trials Register) - via www.drks.de
International Clinical Trials Registry Platform (ICTRP) – WHO ICTRP – via http://apps.who.int/trialsearch/default.aspx
Current Controlled Trials – via http://www.controlled-trials.com
EU Clinical Trials Register – via www.clinicaltrialsregister.eu
Total without duplicates: 22

What's new

DateEventDescription
23 April 2013New citation required but conclusions have not changedWe changed the types of outcome measures, i.e. we dropped the option of analyzing symptom scores rather than individual symptoms as a secondary outcome.
We changed the inclusion criteria and added double-blinding.
We clarified the exclusion criteria, i.e. "Also, studies restricted to patients with underlying chronic disease were not included." This was not entirely unequivocal from the previous wording, but current planned subanalyses did not accommodate this option. This criterion should be reconsidered and will probably be changed in subsequent updates of this review.
23 April 2013New search has been performedWe updated our searches. No new trials were identified. All previously included unpublished studies are now published and are, therefore, renamed.

History

Protocol first published: Issue 1, 2007
Review first published: Issue 3, 2008

DateEventDescription
8 May 2009AmendedContact details updated.
17 December 2007AmendedConverted to new review format.
9 December 2007New search has been performedSearches conducted.

Contributions of authors

Antje Timmer (AT) wrote the protocol, screened the search results, extracted the data, scored the quality, wrote the introduction, the methods and results section, the abstract and plain language summary, and compiled all entries on study description and references.
Edith Motschall (EM) devised the search strategy, carried out the searches and wrote the search strategy section of the review.
Judith Günther (JG) screened the search results, extracted the data, scored the quality and wrote the introduction section, the plain language summary and the discussion.
Winfried Kern (WK) extracted the data, scored the quality and wrote the introduction and discussion section.
Gerta Rücker (GR) advised on the review methods, was the final arbiter on study quality and cross checked all results.
Gerd Antes (GA) served as final arbiter and consulted on study selection and data extraction.
All authors contributed to the planning of the review, participated in the writing of the protocol and review, and approved the final versions.

Declarations of interest

Antje Timmer has received honoraria for scientific presentations from Ferring, Abbott and the Falk Foundation. She is involved in various pharmacoepidemiological research projects funded by Novartis, Sanofi Aventis, Takeda, Bayer and Celgene. All projects and presentations are unrelated to the content of this review, i.e. they neither dealt with ARI nor with cold medications.
Judith Günther's declaration of interest: "Participation in a public debate on the significance of phytotherapy in medical care as speaker for an evidence based approach. The debate was sponsored by Dr. Willmar Schwabe GmbH, Karlsruhe."
The remaining authors do not have any declarations of interest.

Sources of support

Internal sources

  • Faculty of Medicine, Freiburg, Germany.

External sources

  • German Ministry of Health (BMG), Germany.

Differences between protocol and review

Title changed from 'Pelargonium sidoides extract (Umckaloabo) for acute respiratory tract infections' to include all P. sidoides preparations.
The heterogeneity rule was changed by request of the Contact Editor (2008 version). Double-blinding was included as an additional inclusion criterion for studies (2013 version).

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Bachert 2009

MethodsRCT, double-blind, multi-center
Participants103 adults, acute bacterial sinusitis, diagnosis confirmed by radiography
Setting: ENT clinics and outpatient departments, Ukraine
Interventions P. sidoides (alcoholic root extract) 3 x 60 drops versus placebo for 21 days
OutcomesPrimary: difference in symptom score change at day 7
Secondary: change in individual symptom severity at day 7 and 21. Quality of life measures, physician assessment (IMOS). Adverse effects
NotesDetails on blocking/treatment assignment clarified by investigator; missing data supplied by investigator
Quality assessment: Grade B (moderate risk of bias)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomization list with balanced block randomization, p.53
Allocation concealment (selection bias)Low riskThe block length was not known to the investigator. Each investigator received a set of blocks with correspondingly numbered study medication. Eligible patients were sequentially allocated to a patient number in ascending order on entry in the trial, p.53
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blinding, integrity of blinding not assessed, p.53
Incomplete outcome data (attrition bias)
All outcomes
Low riskFlow chart provided, minimal withdrawal (0/51, 1/52), ITT, p.53
Selective reporting (reporting bias)Unclear riskPrimary outcome reported but not relevant to review, additional outcome information provided as requested
Validated outcome assessment
All outcomes
Unclear riskUnvalidated score used for reporting, additional information supplied (assumes score = 0 for absence of symptoms)

Chuchalin 2005

MethodsRCT, double-blind, multi-center
Participants124 adults, acute bronchitis, < 48 hours past onset
Setting: GP practices, Russia
Interventions P. sidoides (alcoholic root extract) 3 x 30 drops versus placebo for 7 days
OutcomesPrimary: difference in symptom score change at day 7
Secondary: change in individual symptom severity. Patient satisfaction (IMPSS), physician assessment (IMOS). Adverse effects
NotesDetails on treatment assignment clarified by investigator; missing data supplied by investigator
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskList generated on a computer, p.438
Allocation concealment (selection bias)Low riskResearch staff blinded to treatment allocation, p.438
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blinding, integrity of blinding not assessed, p.438 and investigator information
Incomplete outcome data (attrition bias)
All outcomes
Low riskFlow chart provided, low non-differential withdrawal (3/64, 4/60), ITT analysis, p.439
Selective reporting (reporting bias)Unclear riskPrimary outcome reported but not relevant to review, additional outcome information provided as requested
Validated outcome assessment
All outcomes
Unclear riskUnvalidated score used for reporting, additional information supplied (assumes score = 0 for absence of symptoms)

Kamin 2010a

MethodsRCT, double-blind, multi-center
Participants200 children (1 to 18 years), acute bronchitis, < 48 hours past onset
Setting: in- and outpatient departments, Russia
Interventions P. sidoides (alcoholic root extract) 3 x 10 to 30 drops (depending on age of child) versus placebo for 7 days
OutcomesPrimary: difference in symptom score change at day 7
Secondary: change in individual symptom severity. Patient satisfaction (IMPSS), physician assessment (IMOS). Adverse effects
NotesUnvalidated score used for reporting, additional information supplied (assumes score = 0 for absence of symptoms). Interim report was provided for 2008 version of review by the investigator (Schwabe Pharmaceuticals). Full paper published preceding current update
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random list, p.185
Allocation concealment (selection bias)Low riskConcealed block size, concealed allocation, p.185
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blinding, integrity of blinding not assessed, p.185 and investigator information
Incomplete outcome data (attrition bias)
All outcomes
Low riskFlow chart provided, low withdrawal (0/103, 3/97), ITT analysis, p.186
Selective reporting (reporting bias)Unclear riskPrimary outcome reported but not relevant to review, additional outcome information provided as requested
Validated outcome assessment
All outcomes
Unclear riskUnvalidated score used for reporting, additional information supplied (assumes score = 0 for absence of symptoms) score used for reporting, additional information supplied but assumes BSS = 0 for absence of symptoms

Kamin 2010b

MethodsDose-finding RCT (3 treatment arms), double-blind, multi-center
Participants405 children (6 to 18 years), acute bronchitis, < 48 hours past onset
Setting: in- and outpatient departments, Ukraine
Interventions P. sidoides 3 x 10/20/30 mg tablets versus placebo for 7 days
OutcomesPrimary: difference in symptom score change at day 7
Secondary: change in individual symptom severity. Patient satisfaction (IMPSS), physician assessment (IMOS). Adverse effects
NotesInterim report was provided for 2008 version of review by the investigator (Schwabe Pharmaceuticals). Full paper published preceding current update. For analysis, this study is divided into 3 parts (1 treatment arm, 1/3 of control numbers and control events)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random list, p.538
Allocation concealment (selection bias)Low riskInvestigator supplied information, p.538
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blinding, integrity of blinding not assessed, p.537, and investigator supplied
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskOverall 1 drop-out (?), no flow chart
Selective reporting (reporting bias)Unclear riskPrimary outcome reported but not relevant to review, additional outcome information provided as requested, p.435 and 560
Validated outcome assessment
All outcomes
Unclear riskUnvalidated score used for reporting, additional information supplied (assumes score = 0 for absence of symptoms)

Kamin 2010b - 10 mg

MethodsDose-finding RCT (first of 3 treatment arms), double-blind, multi-center
ParticipantsChildren (6 to 18 years), acute bronchitis, < 48 hours past onset
Setting: in- and outpatient departments, Ukraine
Interventions P. sidoides 3 x 10 mg tablets versus placebo for 7 days
OutcomesPrimary: difference in symptom score change at day 7
Secondary: change in individual symptom severity. Patient satisfaction (IMPSS), physician assessment (IMOS). Adverse effects
NotesInterim report was provided for 2008 version of review by the investigator (Schwabe Pharmaceuticals). Full paper published preceding current update. For analysis, this study is divided into 3 parts (1 treatment arm, 1/3 of control numbers and control events). This trial is part of Kamin 2010, representing 1 treatment arm and 1/3 each of the number of control events and the number of controls (see methods)

Kamin 2010b - 20 mg

MethodsDose-finding RCT (second of 3 treatment arms), double-blind, multi-center
ParticipantsChildren (6 to 18 years), acute bronchitis, < 48 hours past onset
Setting: in- and outpatient departments, Ukraine
Interventions P. sidoides 3 x 20 mg tablets versus placebo for 7 days
OutcomesPrimary: difference in symptom score change at day 7
Secondary: change in individual symptom severity. Patient satisfaction (IMPSS), physician assessment (IMOS). Adverse effects
NotesInterim report was provided for 2008 version of review by the investigator (Schwabe Pharmaceuticals). Full paper published preceding current update. For analysis, this study is divided into 3 parts (1 treatment arm, 1/3 of control numbers and control events). This trial is part of Kamin 2010, representing 1 treatment arm and 1/3 each of the number of control events and the number of controls (see Methods)

Kamin 2010b - 30 mg

MethodsDose-finding RCT (third of 3 treatment arms), double-blind, multi-center
ParticipantsChildren (6 to 18 years), acute bronchitis, < 48 hours past onset
Setting: in- and outpatient departments, Ukraine
Interventions P. sidoides 3 x 30 mg tablets versus placebo for 7 days
OutcomesPrimary: difference in symptom score change at day 7
Secondary: change in individual symptom severity. Patient satisfaction (IMPSS), physician assessment (IMOS). Adverse effects
NotesInterim report was provided for 2008 version of review by the investigator (Schwabe Pharmaceuticals). Full paper published preceding current update. For analysis, this study is divided into 3 parts (1 treatment arm, 1/3 of control numbers and control events). This trial is part of Kamin 2010, representing 1 treatment arm and 1/3 each of the number of control events and the number of controls (see Methods)

Kamin 2012

MethodsRCT, double-blind, multi-center
Participants220 children (1 to 18 years), acute bronchitis, < 48 hours past onset
Setting: in- and outpatient departments, Ukraine
Interventions P. sidoides (alcoholic root extract) 3 x 10 to 30 drops (depending on age of child) versus placebo for 7 days
OutcomesPrimary: difference in symptom score change at day 7
Secondary: change in individual symptom severity. Patient satisfaction (IMPSS), physician assessment (IMOS). Adverse effects
NotesInterim report was provided for 2008 version of review by the investigator (Schwabe Pharmaceuticals). Full paper published preceding current update
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random list, balanced block randomization, stratified by age group (p.220)
Allocation concealment (selection bias)Low riskLength of blocks withheld from study centers (p.220)
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blinding, integrity of blinding not assessed (p.220)
Incomplete outcome data (attrition bias)
All outcomes
Low riskFlow chart provided (p.221), low attrition (2/111; 2/107), non-differential, ITT analysis
Selective reporting (reporting bias)Unclear riskPrimary outcome reported, additional outcome information provided as requested
Validated outcome assessment
All outcomes
Unclear riskUnvalidated score used for reporting, additional information supplied but assumes BSS = 0 for absence of symptoms

Lizogub 2007

MethodsRCT, double-blind, multi-center
Participants103 adults (18 to 55 years), common cold, 24 to 48 hours past onset
Setting: in- and outpatient departments, practices, Ukraine
Interventions P. sidoides (alcoholic root extract) 3 x 30 drops versus placebo for 10 days
OutcomesPrimary: sum of symptom severity differences of cold intensity score day 1 to 5
Secondary: complete resolution; change in individual symptom severity. Patient satisfaction (IMPSS), physician assessment (IMOS). Days off work. Adverse effects
NotesMissing data supplied by investigator (2009 version, low dose only). High dose results not published (requested for 2013 version)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomization list (p.575)
Allocation concealment (selection bias)Low riskBlocks of study medication, block size not revealed (p.575)
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blinding, integrity of blinding not assessed (p.575, investigator information)
Incomplete outcome data (attrition bias)
All outcomes
Low riskFlow chart provided (p.576), low attrition (1/52; 1/51), non-differential, ITT analysis
Selective reporting (reporting bias)High riskResults for low dose only reported, some additional outcome information provided as requested
Validated outcome assessment
All outcomes
Unclear riskUnvalidated score used for reporting, additional information supplied but assumes BSS = 0 for absence of symptoms

Matthys 2007a

MethodsRCT, double-blind, multi-center
Participants217 adults, acute bronchitis, < 48 hours past onset
Setting: outpatient departments, Russia
Interventions P. sidoides (alcoholic root extract) 3 x 30 drops versus placebo for 7 days
OutcomesPrimary: difference in symptom score change at day 7
Secondary: change in individual symptom severity. Patient satisfaction (IMPSS), physician assessment (IMOS). Adverse effects
NotesDetails on treatment assignment clarified by investigator; missing data supplied by investigator
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomization schedules were prepared centrally, p.325
Allocation concealment (selection bias)Low riskCentral randomization, p.325 and investigator information
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blinding, integrity of blinding not assessed, p.325
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFlowchart provided, some differential loss to follow-up (withdrawals 6/108 and 13/109), ITT analysis, p.326
Selective reporting (reporting bias)Unclear riskAll main results reported, not all relevant to study question
Validated outcome assessment
All outcomes
Unclear riskUnvalidated score used for reporting, additional information supplied but assumes BSS = 0 for absence of symptoms

Matthys 2010

MethodsDose-finding RCT (3 treatment arms), double-blind, multi-center
Participants399 adults, acute bronchitis, < 48 hours past onset
Setting: in- and outpatient departments, Ukraine
Interventions P. sidoides 3 x 10/20/30 mg tablets versus placebo for 7 days
OutcomesPrimary: difference in symptom score change at day 7
Secondary: change in individual symptom severity. Patient satisfaction (IMPSS), physician assessment (IMOS). Adverse effects
NotesInterim report was provided for 2008 version of review by the investigator (Schwabe Pharmaceuticals). Full paper published preceding current update. For analysis, this study is divided into 3 parts (1 treatment arm, 1/3 of control numbers and control events)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random list, p.1414
Allocation concealment (selection bias)Low riskCentral randomization, block length withheld, p.1414 and investigator information
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blinding, integrity of blinding not assessed, p.1414 and investigator information
Incomplete outcome data (attrition bias)
All outcomes
Low riskFlowchart provided, minimal loss to follow-up (withdrawals 1/102, 2/102, 0/101, 1/101), ITT analysis, p.1416
Selective reporting (reporting bias)Unclear riskAll main results reported, not all relevant to study question
Validated outcome assessment
All outcomes
Unclear riskUnvalidated score used for reporting, additional information supplied but assumes BSS = 0 for absence of symptoms

Matthys 2010 - 10 mg

MethodsDose-finding RCT (first of 3 treatment arms), double-blind, multi-center
ParticipantsAdults, acute bronchitis, < 48 hours past onset
Setting: in- and outpatient departments, Ukraine
Interventions P. sidoides 3 x 10 mg tablets versus placebo for 7 days
OutcomesPrimary: difference in symptom score change at day 7
Secondary: change in individual symptom severity. Patient satisfaction (IMPSS), physician assessment (IMOS). Adverse effects
NotesInterim report was provided for 2008 version of review by the investigator (Schwabe Pharmaceuticals). Full paper published preceding current update. For analysis, this study is divided into 3 parts (1 treatment arm, 1/3 of control numbers and control events). This trial is part of Matthys 2010, representing 1 treatment arm and 1/3 each of the number of control events and the number of controls (see Methods)

Matthys 2010 - 20 mg

MethodsDose-finding RCT (second of 3 treatment arms), double-blind, multi-center
ParticipantsAdults, acute bronchitis, < 48 hours past onset
Setting: in- and outpatient departments, Ukraine
Interventions P. sidoides 3 x 20 mg tablets versus placebo for 7 days
OutcomesPrimary: difference in symptom score change at day 7
Secondary: change in individual symptom severity. Patient satisfaction (IMPSS), physician assessment (IMOS). Adverse effects
NotesInterim report was provided for 2008 version of review by the investigator (Schwabe Pharmaceuticals). Full paper published preceding current update. For analysis, this study is divided into 3 parts (1 treatment arm, 1/3 of control numbers and control events). This trial is part of Matthys 2010, representing 1 treatment arm and 1/3 each of the number of control events and the number of controls (see Methods)

Matthys 2010 - 30 mg

  1. a

    BSS: Bronchitis Severity Score
    ITT: intention-to-treat analysis
    RCT: randomized controlled trial

MethodsDose-finding RCT (third of 3 treatment arms), double-blind, multi-center
ParticipantsAdults, acute bronchitis, < 48 hours past onset
Setting: in- and outpatient departments, Ukraine
Interventions P. sidoides 3 x 30 mg tablets versus placebo for 7 days
OutcomesPrimary: difference in symptom score change at day 7
Secondary: change in individual symptom severity. Patient satisfaction (IMPSS), physician assessment (IMOS). Adverse effects
NotesInterim report was provided for 2008 version of review by the investigator (Schwabe Pharmaceuticals). Full paper published preceding current update. For analysis, this study is divided into 3 parts (1 treatment arm, 1/3 of control numbers and control events). This trial is part of Matthys 2010, representing 1 treatment arm and 1/3 each of the number of control events and the number of controls (see Methods)

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    COPD: chronic obstructive pulmonary disease
    n: number of persons in study
    RCT: randomized controlled trial

Bachert 2005

RCT, double -blind, n = 272

Adults with acute maxillary sinusitis

Intervention: P. sidoides (alcoholic root extract), comparator: placebo

Primary outcome: difference in symptoms

Reason for exclusion: insufficient data - data only available in abstract form. According to manufacturer full publication not planned due to flawed design (high drop-out rates). Abstract also includes data from another study for which unpublished data were available

Bereznoj 2009

Prospective cohort, open-label, n = 1000

Children and young adults with tonsillitis

Intervention: P. sidoides (alcoholic root extract)

Primary outcome: difference in symptoms

Reason for exclusion: uncontrolled design

Bereznoy 2003

RCT, double-blind, n = 144
Children with pharyngotonsillitis (non-streptococcal)

Primary outcome: difference in symptom score
Intervention: P. sidoides (alcoholic root extract), comparator: placebo

Reason for exclusion: high differential drop-out, problematic withdrawal criteria resulting in high risk of bias (attrition bias)

Blochin 1999

RCT, open-label, n = 60
Children with acute bronchitis

Intervention: P. sidoides (alcoholic root extract), comparator: acetylcysteine

Primary outcome: difference in symptom score

Reason for exclusion: open-label

Blochin 2000

RCT, open-label, n = 60
Children with tonsillopharyngitis

Intervention: P. sidoides (alcoholic root extract), comparator: therapeutic compresses ("Priessnitz Wickel") and gargling with vinegar
Primary outcome: difference in symptom score

Reason for exclusion: open-label

Dome 1996

Prospective cohort, open-label, n = 742
Children with acute bronchitis or acute exacerbation of chronic bronchitis
Primary outcome: difference in symptom score
Intervention: P. sidoides (alcoholic root extract)

Reason for exclusion: uncontrolled design

Haidvogl 1996

Prospective cohort, open-label, n = 259
Adults with acute bronchitis or acute exacerbation of chronic bronchitis. Duplicate publication - subset of Dome 1996
Primary outcome: difference in symptom score
Intervention: P. sidoides (alcoholic root extract)

Reason for exclusion: uncontrolled design

Koenig 1995

Narrative review including imprecise report on original study, obviously observational, n = 641

Children and adults with various respiratory tract infections

Intervention: P. sidoides (alcoholic root extract)

Primary outcome: improvement of symptoms, global assessment (self and physician)

Reason for exclusion: insufficient information, seems uncontrolled design

Luna 2011

RCT, double-blind, n = 28

Marathon runners

Primary outcome: difference in symptom score
Intervention: P. sidoides (alcoholic root extract), comparator: placebo

Primary outcome: IgA and cytokine expression

Reason for exclusion: not in respiratory tract infection

Martins Kirk 2007

Prospective cohort, open-label, n = 1667

Children and adults with pharyngotonsillitis

Intervention: P. sidoides (alcoholic root extract)

Primary outcome: improvement of symptoms

Reason for exclusion: uncontrolled design

Matthys 2003

RCT, double-blind, n = 468
Adults with acute bronchitis

Intervention: P. sidoides (alcoholic root extract), comparator: placebo
Primary outcome: difference in symptom score

Reason for exclusion: high differential drop-out, problematic withdrawal criteria resulting in high risk of bias (attrition bias)

Matthys 2007b

Prospective cohort, open-label, n = 205
Adults with acute bronchitis or acute exacerbation of chronic bronchitis
Intervention: P. sidoides (alcoholic root extract)

Primary outcome: improvement of symptoms

Reason for exclusion: uncontrolled design

Matthys 2007c

Prospective cohort, open-label, n = 2099

Children and adults with acute bronchitis

Intervention: P. sidoides (alcoholic root extract)

Primary outcome: improvement of symptoms

Reason for exclusion: uncontrolled design

Matthys 2013

RCT, double-blind, n = 200

Adults with COPD or chronic bronchitis

Intervention: P. sidoides (alcoholic root extract), comparator: placebo

Primary outcome: time to acute exacerbation of COPD

Reason for exclusion: underlying chronic disease (COPD)

Patiroglu 2012

RCT, double-blind, n = 28

Children with immunodeficiency of infancy

Intervention: P. sidoides (alcoholic root extract), comparator: placebo

Primary outcome: improvement of various cold symptoms

Reason for exclusion: underlying immunodeficiency

Perez 2011

Prospective cohort, open-label, n = 305

Mixed group (children and adult, bronchitis, sinusitis or tonsillitis)

Intervention: P. sidoides (alcoholic root extract)

Primary outcome: improvement of symptoms

Reason for exclusion: uncontrolled design

Roots 2004

RCT (phase II), open-label, n = 28

Healthy volunteers

Intervention: P. sidoides (alcoholic root extract), comparator: placebo

Primary outcome: pharmacodynamics

Reason for exclusion: not respiratory tract infection

Schapowal 2007

Prospective cohort, open-label, not controlled, n = 361

Children and adults with sinusitis (acute and chronic)

Intervention: P. sidoides (alcoholic root extract)

Primary outcome: improvement of score/symptoms

Reason for exclusion: uncontrolled design

Tahan 2013

RCT, open-label, n = 61

Children with upper respiratory tract infection and asthma
Intervention: P. sidoides (alcoholic root extract), comparator: placebo

Primary outcome: prevention of asthma attacks during viral infection

Reasons for exclusion: underlying chronic disease, open-label

Characteristics of studies awaiting assessment [ordered by study ID]

Bachert 2004

MethodsRCT, double-blind
Participants272 adults with acute maxillary sinusitis
Interventions P. sidoides alcoholic extract versus placebo
OutcomesNot known yet
NotesPerformed in Ukraine, unpublished material only (investigator supplied)

Beck 2001

MethodsRCT, double-blind
Participants124 children (age 6 to 10) with angina catarrhalis
Interventions P. sidoides alcoholic extract versus placebo
OutcomesNot known yet
NotesPerformed in Ukraine, unpublished material only (investigator supplied)

Heger 2002

MethodsRCT, double-blind
Participants215 children (age 6 to 12) with acute bronchitis
Interventions P. sidoides alcoholic extract versus acetylcysteine
OutcomesNot known yet
NotesPerformed in Russia, unpublished material only (investigator supplied)

Heger 2003

MethodsRCT, double-blind, 3 arms (2 treatment, 1 placebo)
Participants637 adults with acute bronchitis
Interventions P. sidoides alcoholic extract versus placebo
OutcomesNot known yet
NotesPerformed in Germany and Ukraine, unpublished material only (investigator supplied)

ISRCTN86579667

MethodsRCT
Participants78 children with acute non-streptococcal tonsillopharyngitis (6 to 10 years)
InterventionsEPs 7630, 20 drops per hour during the first 1 to 2 days, followed by 20 drops 3 times daily versus placebo
OutcomesNot known
NotesRegistry information only, need to be checked for publication, ISO Arzneimittel GmbH & Co KG (Germany); reported completed, started enrolment in 2003

Wolf 2011

  1. a

    RCT: randomized controlled trial

MethodsRCT, double-blind, 3 arms (2 treatment, 1 placebo)
Participants72 adult healthy volunteers
Interventions P. sidoides alcoholic extract versus placebo
OutcomesNot known yet
NotesPerformed in Germany, unpublished material only (investigator supplied)

Characteristics of ongoing studies [ordered by study ID]

EUCTR2007-004923-39-DE

Trial name or titleEfficacy and tolerability of EPs® 7630 film-coated tablets in patients (>=18 years old) with Acute Rhinopharyngitis (ARP)
MethodsRCT, double-blind
ParticipantsAdults with acute rhinopharyngitis, sample/target size not reported
InterventionsEPs® 7630 solution versus placebo
OutcomesArea under the curve (AUC) of the total score of rhinopharyngitis-relevant symptoms (RPS) from baseline (day 1, visit 1) to day 5 (visit 3). Change in total score of rhinopharyngitis-relevant symptoms (RPS), number of patients who experience a reduction in total score of RPS, number of patients with complete remission of RPS, change in individual rhinopharyngitis-relevant symptoms (RPS), patient's ability to work or to attend school/college, sleep quality, health-related quality of life, patient's satisfaction with treatment (IMPSS), consumption of paracetamol tablets, treatment outcome (IMOS)
Starting dateNovember 2007 (first enrolment)
Contact informationNot reported (Schwabe Pharmaceuticals)
NotesPerformed in Bulgaria, status not reported, potential duplicate of EUCTR2007-005579-33-BG

EUCTR2007-005579-33-BG

Trial name or titleEfficacy and tolerability of EPs® 7630 film-coated tablets in patients (>=18 years old) with Acute Rhinopharyngitis (ARP)
MethodsRCT, double-blind
ParticipantsAdults with acute rhinopharyngitis, sample/target size not reported
InterventionsEPs® 7630 solution versus placebo
OutcomesArea under the curve (AUC) of the total score of rhinopharyngitis-relevant symptoms (RPS) from baseline (day 1, visit 1) to day 5 (visit 3). Change in total score of rhinopharyngitis-relevant symptoms (RPS), number of patients who experience a reduction in total score of RPS, number of patients with complete remission of RPS, change in individual rhinopharyngitis-relevant symptoms (RPS), patient's ability to work or to attend school/college, sleep quality, health-related quality of life, patient's satisfaction with treatment (IMPSS), consumption of paracetamol tablets, treatment outcome (IMOS)
Starting dateAugust 2008 (first enrolment)
Contact informationNot reported (Schwabe Pharmaceuticals)
NotesPerformed in Bulgaria, status not reported, potential duplicate of EUCTR2007-004923-39-DE

EUCTR2007-005797-31-BG

Trial name or titleEfficacy and tolerability of EPs® 7630 film-coated tablets in patients (>=18 years old) with Acute Rhinopharyngitis (ARP)
MethodsRCT, double-blind
ParticipantsAdults with acute rhinopharyngitis, sample/target size not reported
InterventionsEPs® 7630 film-coated tablets versus placebo
OutcomesArea under the curve (AUC) of the total score of rhinopharyngitis-relevant symptoms (RPS) from baseline (day 1, visit 1) to day 5 (visit 3). Change in total score of rhinopharyngitis-relevant symptoms (RPS), number of patients who experience a reduction in total score of RPS, number of patients with complete remission of RPS, change in individual rhinopharyngitis-relevant symptoms (RPS), patient's ability to work or to attend school/college, sleep quality, health-related quality of life, patient's satisfaction with treatment (IMPSS), consumption of paracetamol tablets, treatment outcome (IMOS)
Starting dateAugust 2008 (first enrolment)
Contact informationNot reported (Schwabe Pharmaceuticals)
NotesPerformed in Bulgaria, status not reported

EUCTR2011-002652-14-DE

Trial name or titleSafety and tolerability of Pelargonium sidoides extract EPs® 7630 in children (1 to 5 years old) suffering from acute bronchitis: a randomized controlled trial
MethodsRCT, open-label, multi-center
Participants600 (target) children with acute bronchitis (1 to 5 years)
Interventions2.5 ml EPs® 7630 syrup 3 times/day or 10 drops EPs® 7630 solution 3 times/day for 7 consecutive days
OutcomesAdverse events, changes in individual respiratory tract infection symptoms as well as the total symptoms score
Starting date1 October 2011 (first enrolment)
Contact informationFA Malek; Dr. Willmar Schwabe GmbH & Co KG (Germany)
NotesPotential duplicate of ISRCTN77419032

ISRCTN77419032

Trial name or titleSafety and tolerability of Pelargonium sidoides extract EPs® 7630 in children (1 to 5 years old) suffering from acute bronchitis: a randomized controlled trial
MethodsRCT, open-label, multi-center
Participants600 (target) children with acute bronchitis (1 to 5 years)
Interventions2.5 ml EPs® 7630 syrup 3 times/day or 10 drops EPs® 7630 solution 3 times/day for 7 consecutive days
OutcomesAdverse events, changes in individual respiratory tract infection symptoms as well as the total symptoms score
Starting date1 October 2011 (first enrolment)
Contact informationFA Malek; Dr. Willmar Schwabe GmbH & Co KG (Germany)
NotesRegistry information only, reported recruiting, last entry February 2012

JPRN-UMIN000003815

Trial name or titleEfficacy of a Pelargonium sidoides preparation in patients with the upper respiratory infection
MethodsRCT, 2 arms
Participants200 children and adults (target), acute upper respiratory tract infection (cold)
Interventions P. sidoides alcoholic extract versus placebo (10 days)
OutcomesCold intensity score (CIS), General Well-Being Index
Starting dateJuly 2010 (first enrolment)
Contact informationK Nakayama, University of Tokyo Department of Infectious disease, Japan 
NotesPublic recruitment in Japan, public sponsor; registry information only, reported recruiting, last entry April 2013. Contact person contacted by email 22 May 2013.

NCT01420445

  1. a

    RCT: randomized controlled trial

Trial name or titleRandomized, Double-blind, Placebo/Active-controlled, Multi-center, Phase 3 Clinical Trial to Investigate the Safety/Tolerability and Efficacy of YHD001 After Oral Administration in Patients With Acute or Chronic Bronchitis
MethodsRCT, double-blind, 4 arms (2 YHD001, 1 Pelargonium sidoides, 1 placebo)
Participants116 adults with acute bronchitis
InterventionsYHD001 (dose-finding) versus P elargonium sidoides versus placebo
OutcomesChange of total symptom score from baseline to the end of treatment (time frame: 7 days); safety assessment (time frame: 7 days); time to response (time frame: 7 days)
Starting dateSeptember 2011 (first enrolment)
Contact informationYuhan Corporation, Korea
NotesPerformed in Korea, registry information only, reported ongoing (recruitment closed), last entry February 2012. No contact person provided. 2 physicians in the recruitment center approached by email for more information 22 May 2013

Ancillary