Pelargonium sidoides preparation (EPs[R] 7630) in the treatment of acute bronchitis in adults and children.
Acute bronchitis, although mostly caused by viral infections, is commonly treated with antibiotics. As antibiotics should only be prescribed upon strict indication, treatment options like a liquid herbal drug preparation from the roots of Pelargonium sidoides (EPs[R] 7630) gain more and more interest.
To evaluate the efficacy and safety of treatment with EPs[R] 7630 in patients with acute bronchitis, a multi-centre, prospective, open observational study was conducted in 440 study sites located in Germany. A total of 2099 patients aged 0-93 years with productive cough for less than six days without indication for treatment with antibiotics were given EPs[R] 7630-solution in an age-dependent dosage for 14 days. The primary outcome criterion was the mean change of the Bronchitis Severity Score (BSS: cough, sputum, rales/rhonchi, chest pain at cough, dyspnoea) from baseline to patient's individual last observation.
During treatment, the mean BSS of all patients decreased from 7.1[+ or -]2.9 points at baseline to 1.0[+ or -]1.9 points at patients' individual last visit. Subgroup analysis for children showed a decrease of mean BSS from 6.3[+ or -]2.8 points to 0.9[+ or -]1.8 points and analysis of children younger than three years showed a decrease of mean BSS from 5.2[+ or -]2.5 points to 1.2[+ or -]2.1 points. Adverse events occurred in 26/2099 (1.2%) patients. Serious adverse events were not reported.
In conclusion, EPs[R] 7630 is an effective and well tolerated treatment of acute bronchitis in adults, children and infants outside the strict indication for antibiotic treatment.
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Keywords: Acute bronchitis; Children; Herbal medicine; Bronchitis severity score; EPs[R] 7630; Umckaloabo[R]
Acute bronchitis is defined as a lower respiratory tract infection and is one of the most common diagnoses made by primary care physicians (Knutson and Braun, 2002). Although in up to 95% of cases the cause is viral, acute bronchitis has traditionally been treated with antibiotics (Hueston and Mainous, 1998). Because of increasing concern about antibiotic resistance and the scant evidence of benefit, this practice has been questioned (File and Hadley, 2002; Flaherty et al., 2001).
Outside the strict indication for antibiotic treatment, treatment with a liquid herbal drug preparation from the roots of Pelargonium sidoides, EPs[R] 7630 (1) has gained increasing interest. For EPs[R] 7630, antimicrobial and immunomodulatory principles have been shown (Kayser and Kolodziej, 1997; Kayser et al., 2001; Kolodziej et al., 2003) which account for the therapeutic effect in respiratory tract infections demonstrated in several clinical trials: In a randomized, double-blind, placebo-controlled trial with 124 adult patients published by Chuchalin et al. (2005), in which the efficacy and safety in the treatment of acute bronchitis in adults has been evaluated, treatment with EPs[R] 7630 for seven days clearly reduced bronchitis specific symptoms more effectively and faster than placebo. Tolerability was rated as good or very good in more than 95% of patients. Good results are also obtained by studies in the treatment of acute bronchitis in children (Dome and Schuster, 1996; Haidvogl et al., 2006). An open multicentre study published by Haidvogl et al. (2006) included 742 children in the age of 0-12 years with acute bronchitis or acute exacerbation of chronic bronchitis. After two weeks of treatment with EPs[R] 7630 in an age-dependent dosing, complete or partial remission of symptoms was seen in over 80% of the children. Improvement of health condition was noted in 83.5% in the first week of treatment. A subsequent antibiotic therapy was needed in only 2% of cases. The tolerability of EPs[R] 7630 was very good with adverse events of mild to moderate severity in only 1.8% of patients.
In the present study, the efficacy and tolerability of EPs[R] 7630 in the treatment of acute bronchitis was evaluated in a large population of patients.
This multi-centre, prospective, open observational study was designed to investigate the efficacy and safety of EPs[R]-solution in the treatment of acute bronchitis. A total of 2099 patients met the inclusion criteria, presenting productive cough for less than six days, but without a mandatory indication for treatment with antibiotics. Exclusion criteria were antibiotic treatment during the past four weeks before enrolment into the study, treatment with any other medication for acute bronchitis, known or supposed hypersensitivity against the investigational medication, known alcohol or drug abuse, and multimorbidity.
The patients were instructed to take EPs[R] 7630 three times daily 30 min prior to meal over a period of 14 days EPs[R]-solution contained 80g EPs[R] 7630 in 100ml solution. Dosage was adapted to age as following:
* adults and children > 12 years: 30 drops,
* children aged > 6-12 years: 20 drops,
* children aged 6 years or less: 10 drops.
At baseline visit, demographic data, clinical diagnosis, concomitant diseases and concomitant medication prior to the study were assessed, as well as bronchitis-specific symptoms according to the Bronchitis Severity Score (BSS), i.e. cough, sputum, rales/rhonchi, chest pain at cough, dyspnoea, rated on a 5-point rating scale (from 0 = absent to 4 = very severe). Additionally, further symptoms (hoarseness, headache, pain in the limbs, fatigue/exhaustion), rated on a four-point rating scale (from 0 = absent to 3 = severe), fever, and supporting measures for the treatment of bronchitis were assessed. Three follow-up visits included the assessment of treatment compliance and outcome, adverse events, assessment of tolerability of the investigational medication and changes in bronchitis-specific symptoms, further symptoms, supporting measures and concomitant medication.
The primary efficacy parameter was the mean change of the BSS from baseline to the patient's individual last observation. Standard descriptive sample statistics were used to analyse the data. The analysis of efficacy was performed using the last observation carried forward (LOCF) method, i.e. if a single item was missing at a contact, the value of the last available contact was taken. Subgroup analysis of efficacy and safety were performed for children and infants.
Demographics and baseline characteristics
A total of 2099 patients from 440 study sites in Germany were included. The age ranged from 0 to 93 years with a mean age of 34.5[+ or -]20.3 (35) years (here and in the following arithmetic mean[+ or -]standard deviation (median)). One hundred and twenty seven patients (6.1%) were > 6-12 years of age and 241 patients (11.5%) were [less than or equal to] 6 years of age. The majority of patients was female (59.0%).
Concomitant diseases were documented in 556/2099 patients (26.5%) and intake of concomitant medication in 465/2099 patients (22.2%). An episode of acute bronchitis during 12 months prior to the study was reported in 750/2099 patients (35.7%). The onset of productive cough before enrolment in the study was within 24 and 48 hours in 900/2099 patients (42.9%). In the majority of patients (95.5%) acute bronchitis was diagnosed by clinical symptoms.
Course of the study
The mean duration of treatment was 14.6[+ or -]7.0 (14) days. Premature termination of treatment was documented in 378/2099 patients (18.0%) at the first follow-up, thereof 83.6% (316/378) were free of symptoms. At the second follow-up 603/2099 patients (28.7%) had terminated treatment of which 90.9% (548/603) were free of symptoms. The compliance as assessed at the individual last follow-up was 'good' in 2023/2099 patients (96.4%).
The analysis of efficacy was performed for all patients as well as for the subgroups of children and infants. The subgroup of children (n = 498) included all patients with less than 18 years of age. The subgroup of infants (n = 78) included all patients aged less than 3 years.
Analysis of all patients
At baseline the mean value of BSS of all patients (n = 2099) was 7.1[+ or -]2.9 (7) points. Until the first follow-up it decreased by 3.4[+ or -]2.8 (3) points to a mean value of 3.6[+ or -]2.8 (3) points. At the second follow-up the mean value was 1.7[+ or -]2.1 (1) and at the third follow-up it was 1.0[+ or -]1.9 (0) points (Fig. 1). According to a response criterion defined as decrease of BSS of at least five points from baseline to the third follow-up, the responder rate was 68.0%.
The remission rate at the individual last observation for the five bronchitis-specific symptoms was above 80% each, except for cough, which showed a remission rate of 59.7% (Fig. 2).
Further symptoms showed remission rates of more than 80% each, ranging from 80.2% for fatigue/exhaustion to 94.6% for fever (Fig. 3).
The investigators documented complete recovery for 1458/2099 patients and major improvement for 519/2099 at the individual last visit.
In the subgroup of children (n = 498) the baseline mean value of BSS was 6.3[+ or -]2.8 (6) points. It decreased to 3.3[+ or -]2.6 (3) points at the first follow-up, to 1.6[+ or -]1.9 (1) points at the second follow-up and to 0.9[+ or -]1.8 (0) points at the third follow-up (Fig. 4).
[FIGURE 1 OMITTED]
In the subgroup of infants which included all children with less than 3 years of age (n = 78) the mean value at baseline was 5.2[+ or -]2.5 (5) points. At the first follow-up the BSS decreased to 3.1[+ or -]2.4 (3) points, at the second follow-up to 1.6[+ or -]1.7 (1) and at the third follow-up to 1.2[+ or -]2.1 (0) points.
Subgroup analysis for adverse events were conducted for children (aged 3-18 years, n = 420) and for infants (aged two years or less, n = 78). A total of 28 adverse events occurred in 26/2099 patients (1.2%), thereof 14 in children (13/420 patients, 3.1%) and 4 in infants (3/78 patients, 3.8%). There was an accumulation of adverse events in the organ class coded "gastrointestinal disorders" with 11/28 (39.3%) and in the organ class coded "infections and infestations" with 9/28 (32.1%). Intensity of adverse events was classified as "mild" in 13 cases, as "moderate" in 12 cases and as "severe" in 3 cases. All severe adverse events occurred in the subgroup of children and were coded in the organ class "infections and infestations", but none was assessed as related to the study medication. For 9/28 (32.1%) adverse events in all patients a causal relationship to the investigational medication could not be excluded, but was assessed as unlikely in 8/9 (88.9%) cases. In one child the relation to study medication of an hypersensitivity reaction was assessed as "possible", but further possibly allergic agents were not sought after. Serious or significant adverse events did not occur. Overall, the results suggest that the study medication is a safe and well-tolerated treatment for acute bronchitis in adults, children and infants.
[FIGURE 4 OMITTED]
The results of this study showed good efficacy and safety of EPs[R] 7630-solution in the treatment of children, infants and adults with acute bronchitis.
The BSS of all patients decreased from a median of 7 points at baseline to a median of 0 points at the third follow-up, corresponding to an average decrease of median 6 points. Subgroup analyses for children and infants show similar results. Complete recovery or major improvement was documented in 94.2% of all patients.
Bronchitis specific symptoms showed remission rates above 80% for all patients except for the symptom cough, which showed a remission rate of 59.7%. This is in line with previous findings that cough can last for two weeks or more in 26% of patients (Chesnutt et al., 2002). Further symptoms like hoarseness and headache showed remission rates above 80% in all patients. The efficacy of treatment with EPs[R] 7630 is supported by analysis of early study termination. Almost one-third of patients did not complete the third follow-up, because they were already free of symptoms.
Tolerability of EPs[R] 7630 was very good. Serious adverse events were not reported. The rate of adverse events was 1.2% of all patients and thus even lower than in previous studies (Haidvogl et al., 2006). This supports the use of EPs[R] 7630 in the treatment of acute bronchitis.
The benefit of EPs[R] 7630 has also been studied in comparison to non-antibiotic treatment of acute bronchitis. A prospective, randomized, controlled study in 60 children aged 5-14 years compared the efficacy of EPs[R] 7630 to N-acetylcysteine (NAC) (Blochin et al., 1999). After 7 days of treatment bronchitis specific symptoms were reduced more effectively and faster by EPs[R] 7630 than by NAC. Tolerability was rated as very good in 46.7% of patients treated with EPs[R] 7630 vs. 33.3% of patients treated with NAC. The authors conclude that EPs[R] 7630 can reduce bronchitis specific symptoms better than NAC and leads to a higher rate of satisfaction with the treatment.
In conclusion, treatment with EPs[R] 7630 is effective in acute bronchitis and, being well tolerated, a useful alternative to the treatment with antibiotics for use outside the strict indication for antibiotic treatment.
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H. Matthys (a,*), W. Kamin (b), P. Funk (c), M. Heger (d)
(a) Department of Pneumology, University Hospital, Freiburg, Germany
(b) Clinical Research Department, Children's Hospital, University of Mainz, Germany
(c) Clinical Research, Dr. Willmar Schwabe GmbH & Co. KG, Karlsruhe, Germany
(d) Clinical Research, ISO-Arzneimittel, Ettlingen, Germany
[star] Funding: The study was financially supported by the firm of Dr. Willmar Schwabe GmbH & Co KG, Germany.
*Corresponding author. Lungs at Home, Hochruttestr. 17, D-79117 Freiburg i. Br., Germany. Tel.: +49 761 62822; fax: +49 761 6008580.
E-mail address: email@example.com (H. Matthys).
(1) Marketed by Spitzner Arzneimittel. Ettlingen, Germany.
% patients with remission at last individual visit Cough 59.7 Sputum 80.7 Rales/Rhonchi 93.1 Chest pain at cough 94.1 Dyspnoea 93.2 Fig. 2. Remission rates from baseline to last observation for bronchitis specific symptoms in all patients (n = 2099). Note: Table made from bar graph. % patients with remission at individual last visit Hoarse ness 91.4 Head ache 90.7 Pain in the limbs 94.3 Fatigue/Exhaustion 80.2 Fever 94.6 Fig. 3. Remission rates from baseline to last observation for further symptoms in all patients (n = 2099). Note: Table made from bar graph.