A Systemic Review of Clinical Trials Using Medication for Acute Bronchitis: A Pre-study on the Development of Traditional Korean Medicine Clinical Practice Guideline

Article information

J Korean Med. 2017;38(1):93-111
Publication date (electronic) : 2017 March 31
doi : https://doi.org/10.13048/jkm.17009
1Department of Internal Medicine, College of Korean Medicine, Daejeon University
2Department of Rehabilitation Medicine of Korean Medicine, College of Korean Medicine, Daejeon University
3Department of acupuncture & Moxibustion Medicine, College of Korean Medicine, Daejeon University
4Department of Neuropsychology, College of Korean Medicine, Daejeon University
Correspondence to:박양춘(Yang-Chun Park) 대전대학교 한의과대학 폐계내과학교실 대전광역시 서구 대덕대로 176번길 75 대전대학교 둔산한방병원 한방내과 Tel:+82-42-470-9126, Fax:+8242-470-9005, E-mail: omdpyc@dju.kr. 정인철(In-Chul Jung) 대전대학교한의과대학 신경정신과학교실 대전광역시 서구 대덕대로 176번길 75 대전대학교 둔산한방병원 한방신경정신과 Tel:+82-42-470-9129, Fax:+82-42-470-9005, E-mail: npjeong@dju.kr
Received 2017 March 9; Revised 2017 March 24; Accepted 2017 March 24.

Abstract

Objectives

The aim of this study is to make evidence-based data for developing a traditional Korean medicine clinical practice guideline for acute bronchitis.

Methods

We searched 3 international databases(PubMed, EMBASE, CENTRAL) and 7 domestic databases (KoreaMed, Kmbase, NDSL, KISS, KISTI, OASIS, KoreaTK) to identify randomized controlled trials (RCTs) of acute bronchitis using medicine in recent 10 years. The chosen trials were analyzed by their study design, age range, intervention group, control group, primary and second outcome measure, inclusion and exclusion of participants and adverse events.

Results

15 RCTs are finally included in this study and most of their medications are herbal medicine. For diagnosis and outcome measure of acute bronchitis, Bronchitis Severity Score(BSS) was mostly used. Other measurements eligible are coughing fits, quality of life scale, sputum viscosity, change of individual symptoms and patient’s satisfaction. Test duration was for average 7days and safety assessment was held by recording adverse events. Except for anti-inflammatory and antibiotic trials, all medications are found to be effective and well-tolerated. General risk of bias of chosen trials is evaluated low.

Conclusions

A well designed clinical trials for traditional Korean medicine of acute bronchitis is needed and this study is expected to make it available.

Fig. 1

Flowchart of trial selection process

Fig. 2

Risk of bias graph of the included studies

Fig. 3

Risk of bias summary of the included studies(+ indicates low risk of bias; − high risk of bias; ? unclear risk of bias)

Characteristics of the Studies Included in the Review

Inclusion and Exclusion Criteria of the Studies Included in the Review

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Article information Continued

Fig. 1

Flowchart of trial selection process

Fig. 2

Risk of bias graph of the included studies

Fig. 3

Risk of bias summary of the included studies(+ indicates low risk of bias; − high risk of bias; ? unclear risk of bias)

Table 1

Characteristics of the Studies Included in the Review

First author (Year) Test drug Age range (years) Sample size Intervention group Control group Test duration (days) Primary outcome measure Second outcome measure Adverse event Treatment outcome
Cwientzek U (2011)21) Ivy leaves extracts ≥2 590 Hedelix® (24,16,12drops 3x/d)(N=295) Prospan® (24,16,12drops.3x/d)(N =295) 7d(±1) Bronchitis Severity Score (BSS)
  1. Other clinical symptoms

  2. Body temperature

  3. Ability to go to work or school

16 AEs Non inferior
Ding H (2010)22) Oriental medicine 18–65 288 Gankeshuangqing capsule(3Tab.3x/d) (AB=68, URTI=70) Qingganchu anxinlian(3 Tab.3x/d) (AB=69, URTI=70) 7d the rates of cure
  1. Other clinical symptoms

  2. Time to decrease body temperature

  3. Number of days with frequent cough

  4. Time to treatment

  5. Adverse event

1 AE tolerated & effective
Fischer J (2013)23) Essential oil 18–70 242 Cineole 200mg. 3x/d (N=121) placebo (N=121) 10d Bronchitis Sum Score
  1. Frequency of coughing fits

  2. Cough documentation

5 AEs effective
Gillissen A (2013)24) Essential oil ≥18 398 Myrtol ® 300 mg. 4x/d (N=196) placebo (N=202) 14d±2 Frequency of day-time coughing fits
  1. Response to treatment

  2. Bronchitis Severity Score (BSS)

  3. Difficulty to cough-up mucus during the day

  4. Sleep disturbance due to coughing at night

  5. Work incapacitation

  6. Diary data

  7. Visit data

39 AEs effective
Hu S.-Y. (2016)25) Oriental medicine 1–13 96 QingfeiXiaoyan Pill(10,20,30,40,60 mg.3x/d)(N=59) Xiaoerfeire kechuan syrup (N=31) 5d the rates of cure
  1. The rates of resolving individual symptoms

none tolerate & effective
Kamin W (2010)26) Pelargonium sidoides 6–18 400 EPs 7630 (30, 60,90mg) (N=100/99/99) placebo (N=101) 7d Bronchitis Specific Score (BSS)
  1. Treatment response according to three criteria

  2. Onset of effect

  3. Change of individual symptoms of the total score

  4. FGK questionnaire

  5. IMOS, IMPSS

80 AEs tolerate & effective
Kamin W’(2010)27) Pelargonium sidoides 1–17 200 EPs 7630 (10,20,30drops.3x/d) (N=103) placebo (N=97) 7d Bronchitis Specific Score (BSS)
  1. Change of individual symptoms of the BSS

  2. FGK questionnaire

  3. Duration of bed rest and ability to attend kindergarten, school or work

  4. IMOS, IMPSS

59 AEs tolerate & effective
Kamin W(2012)28) Pelargonium sidoides 1–18 220 EPs 7630 (10,20,30drops.3x/d)(N=111) placebo (N=109) 7d Bronchitis Specific Score (BSS)
  1. Change of the individual symptoms of the BSS

  2. Change of further general symptoms

  3. Onset of treatment effect

  4. FGK questionnaire

  5. IMOS, IMPSS

  6. Duration of bed rest and ability to attend kindergarten, school or work

3 AEs tolerate & effective
Kemmerich B(2007)29) thyme herb and primrose root ≥18 361 thyme-primrose combination [Bronchipret TP Filmtabletten] (1Tab.3x/d) (N=183) Placebo (N=178) 11d coughing fits[N/daytime] (manual counter)
  1. Response to treatment

  2. Change in mean BSS

  3. Change in the ability to cough up mucus during the daytime

  4. Change in sleep disturbance induced by coughing

  5. Change in the patient’s general well-being

3 AEs tolerate & effective
Lior C (2013)30) anti-inflammatory or antibiotic 18–70 416
  1. ibuprofen 600mg(3x/d) (N=136)

  2. amoxicillin -clavulanic acid 500mg/125mg (3x/d)(N=137)

Placebo (N=140) 10d Number of days with frequent cough
  1. Efficacy of the treatment at the end of the second follow-up visit

  2. Time of resolution of the total symptom scores

27 AEs Ineffective
Matthys H (2007)31) Pelargonium sidoides 18–66 217 EPs 7630 (30drop.3x/) (N=108) placebo (N=109) 7d Bronchitis Severity Score (BSS)
  1. Individual symptoms,

  2. Patinet satisfaction

  3. Adverse events

47 AEs tolerated & effective
Matthys H (2010)32) Pelargonium sidoides ≥18 406 EPs 7630 (30,60,90mg.3x/d)( N=102, 102, 101) placebo (N=100) 7d Bronchitis Severity Score (BSS)
  1. IMOS, IMPSS

  2. EQ-5

  3. Duration of activity limitation and inability to work assessed

  4. Change of general symptoms,

92 AEs tolerated & effective
Nduba VN (2008)33) antibiotic ≥18 660 amoxicillin500mg. 3x/d(N=330) placebo (N=330) 7d. Acute Bronchitis Severity Score (ABSS)
  1. Treatment compliance

  2. Side effects

  3. Current symptoms

369 AEs Ineffective
Schulz V (2007)34) Pelargonium sidoides ≥18 124 EPs 7630 30drops. 3x/d(N=64) Placebo(N= 60) 7d Bronchitis Severity Score (BSS)
  1. BSS<5 points at study end

  2. Decrease of BSS ≥5 points between baseline and study end

  3. Onset of treatment effect

  4. Consumption of paracetamol

  5. Change of individual symptoms of BSS

  6. Patient’s health status using the health-related quality of life questionnaires(SF-12 Health Survey, EQ-5D)

  7. IMOS, IMPSS

  8. Occurrence of adverse events

35 AEs Effective
Zansai A (2014)35) homeopathic syrup ≥18 80 homeopathic syrup15mL.4x/d (N=40) Placebo (N=40) 7d VCD-cough severity
  1. Sputum viscosity

  2. Subjective assessments of mucus

5 AEs Effective

Table 2

Inclusion and Exclusion Criteria of the Studies Included in the Review

First author (Year) Study design Inclusion criteria Exclusion criteria
Cwientzek U (2011) double-blind, randomized study
  1. at least 2 years of age with a confirmed clinical diagnosis of acute bronchitis

  2. a baseline BSS ≥ 5 points

  3. duration of not more than 48 h

  1. previous medications which may influence the course of the study indication or the evaluation of the target criteria, such as these stated under “Concomitant therapy”.

  2. patients with concomitant diseases like allergic asthma or bronchial hyper reactivity, chronic bronchitis, other chronic or inherited lung diseases, or severe cardiac, hepatic, or renal disorders

Ding H (2010) multicenter, double blind, double dummy, randomized and parallel positive drug controlled
  1. 18–65 years old

  2. diagnosed with wind-heat syndrome (Chinese medicine symptom score≥ 5)

  3. diagnosed with acute upper respiratory infection or acute bronchitis

  4. within 48hours for acute upper respiratory infection; within 5days from onset for acute bronchitis

  5. symptom severity with mild or moderate, body temperature below 38.5°C

  6. consent to participate

  1. take previous west medication within 2weeks for UTRI

  2. disease like tuberculosis, measles, pertussis, acute tonsillitis, fungus, lung cancer, asthma, bronchial hyper reactivity, pulmonary infection

  3. acute bronchitis with asthma

  4. a pregnant or breast feeding

  5. allergic disease

  6. inflammatory gastrointestinal or hepatic disease or inflammation of the gallbladder or bile duct

  7. symptom severity with serious

Fischer J (2013) double-blind, placebo-controlled, multi-center-study
  1. aged 18 – 70 years

  2. not longer than 7 days

  3. Bronchitis-Sum-Score of 7 or higher

  1. have severe medical conditions with relevant influence on the acute bronchitis

Gillissen A (2013) double-blind, parallel-group fashion
  1. at least 18 years of age

  2. Brocaindex between 0.75 and 1.30

  3. clinical diagnosis of acute bronchitis as characterized by: ≥ 10 coughing fits during the last day

  4. a baseline BSS ≥ 5 points

  5. on set of first symptoms (bronchial mucus production with impaired ability to cough up) within 2 days before the start of the investigational treatment.

  1. history or presence of confounding respiratory disease (e.g. upper respiratory tract infection within the last 4 weeks, chronic bronchitis or COPD or acute exacerbations of bronchiectasis, asthma, suspected pneumonia, cystic fibrosis, lung cancer);

  2. concomitant bacterial infection

  3. elevated body temperature(>39.5°C rectally or >39.0°C axillary or otic)

  4. active cigarette smoking > 1 pack per day

  5. hypersensitivity to the trial medication

  6. inflammatory gastrointestinal or hepatic disease or inflammation of the gallbladder or bile duct, history or presence of clinically relevant cardiovascular, renal, metabolic, hematological, dermatologic, neurological, psychiatric, systemic or infectious disease

  7. pregnancy or breast feeding, women of childbearing potential without highly effective contraception (failure rate<1%)

  8. participation in a clinical research study within the last 6 weeks

  9. evidence or suspicion of non-compliance, inability to provide informed consent.

Hu S.-Y. (2016) random, open, parallel-group controlled, and multi-center clinical studies
  1. diagnosed with acute bronchitis for child

  2. diagnosed with wind-heat syndrome

  3. aged 1–13 years old

  4. symptoms starting within 72h, not yet used antibiotics, antitussive, expectorants and any other drugs that could affect test medication

  5. body temperature within 24h from baseline ≤ 38.5°C

  1. UTRI, suppurative tonsillitis, bronchial asthma, bronchiolitis, pneumonia, lung abscess, measles, pertussis, influenza, an acute infectious disease

  2. malnutrition or immunosuppression

  3. granulocytosis(e.g. suspected bacterial infection), severe heart, renal or liver diseases, immunosuppression

  4. known or supposed hypersensitivity to trial medication

  5. evidence or suspicion of non-compliance

Kamin W (2010) randomized, double-blind, placebo controlled clinical dose-finding study with 4 parallel treatment groups
  1. aged 6–18 years old

  2. acute bronchitis with symptoms starting within 48h

  3. BSS≥5 points at screening

  1. treatment with antibiotics, bronchodilators or glucocorticoids during the last 4 weeks, or with analgetics, secretolytics, mucolytics or antitussive during the last 7 days prior to study inclusion

  2. indication for treatment with antibiotics

  3. allergic asthma, tendency to bleed, severe heart, renal or liver diseases and/or immunosuppression, known hypersensitivity against P. sidoides, chronic obstructive pulmonary disease and pregnancy.

Kamin W’ (2010) double-blind randomized clinical trial
  1. aged 1–18 years suffering from acute bronchitis

  2. symptoms starting 48 hours prior to inclusion into the study

  3. BSS≥5points at screening

  1. treatment with antibiotics

  2. allergic asthma, COPD, tendency to bleed, severe heart, renal or liver diseases and/or immunosuppression;

  3. known hypersensitivity against Pelargonium sidoides

  4. pregnancy

Kamin W (2012) randomized, double-blind, placebo controlled clinical trial
  1. aged 1–18 years old

  2. symptoms starting 48h prior to inclusion in the study

  3. BSS≥5points at screening

  1. concomitant medication that may impair the study results (e.g. antibiotics, bronchodilators, glucocorticoids, analgesics other than paracetamol, secretolytics, mycolytics, anti-tussiva, or other bronchitis medication)

  2. allergic asthma, chronic obstructive pulmonary disease, tendency to bleed, severe heart, renal or liver diseases and/or immunosuppression

  3. known hypersensitivity to Pelargonium sidoides

  4. pregnancy

Kemmerich B(2007) double-blind, placebo controlled, multicenter Phase IV study
  1. at least 18 years of age,

  2. ≥10 coughing fits during the day

  3. onset of bronchial mucus production with impaired ability to cough up at a maximum of 2 days prior to recruitment

  4. BSS ≥ 5points at screening

  1. pregnancy, no contraception for women of child bearing age and lactation for females

  2. the principal ones being concomitant fever(> 39 °C)

  3. pneumonia, history of chronic bronchial or pulmonary disease such as chronic bronchitis, chronic obstructive pulmonary disease (including acute episode), bronchiectasis, bronchial asthma, mucoviscidosis, history of clinically relevant chronic cardiovascular, kidney, gastrointestinal or liver disease, known hypersensitivity to one or more of the active or inactive ingredients of the investigational product, malignant growth, or any severe somatopathic, neurological and/or psychiatric disease.

  4. treatment with other drugs, such as immunosuppressives, systemic antibiotics and systemic or inhaled glucocorticosteroids (within 4 weeks prior to enrolment into the study or concomitantly), mucoactive substances other than the study medication(within 2 weeks prior to enrolment or concomitantly), antitussive drugs and other mucoactive measures except for steam inhalation were not allowed

  5. treatment with angiotensin converting enzyme (ACE) inhibitors was no reason for exclusion if started more than 4 weeks prior to Visit(Paracetamol could be taken in case of fever, other non-steroidal anti-inflammatory drugs were not allowed during the study)

Lior C (2013) Parallel group, single blinded, placebo controlled randomized clinical trial
  1. aged 18 to 70 without associated respiratory comorbidity or immunosuppression

  2. respiratory tract infection of less than one week’s duration

  3. with cough as the predominant symptom and discolored sputum and at least one other criterion of lower respiratory tract infection such as dyspnea, wheezing, chest discomfort, or chest pain

  1. antibiotic, anti-inflammatory, or corticosteroid use in the previous two weeks

  2. the presence of radiological signs of pneumonia; signs of severe infection such as confusion

  3. respiratory rate >25 breaths per minute or pulse >120 beats per minute

  4. history of gastrointestinal hemorrhage or intolerance to anti-inflammatory treatment

  5. hypersensitivity to β lactams or intolerance to clavulanic acid or lactose

  6. pregnancy, lactation, and absence of contraception in women of fertile age

  7. associated comorbidity (bronchial asthma, chronic obstructive pulmonary disease, moderate-severe heart failure, dementia, stroke, immunosuppression or the use of immunosuppressive drugs)

  8. emergency situation

  9. in residential care; unable to provide informed consent; difficulty in attending the programmed visits; previous participation in the study; and refusal to participate.

Matthys H (2007) randomized, double-blind, placebo controlled multicenter clinical trial
  1. acute bronchitis with symptoms starting within 48h

  2. BSS ≥ 5 points at screening

  1. indication of antibiotic treatment or treatment with antibiotics during the 4-weeks prior to enrolment in the trial

  2. allergic bronchial asthma, tendency to bleed, severe heart, renal or liver diseases, immunosuppression, known or supposed hypersensitivity to trial medication

  3. concomitant medication that might affect trial results or interact with the study medication(e.g. antibiotics)

  4. participation in another clinical trial during the preceding 3 months and patients irresponsible of unable to understand the nature of the study

Matthys H (2010) randomised, double-blind, placebo-controlled, multicentre dose-finding trial
  1. ≥18 years old

  2. symptoms starting 48h or less

  1. participation in any other trial at the same time or within 4 weeks prior to study inclusion

  2. indication for antibiotic treatment, suspected pneumonia

  3. treatment with antibiotics, ACE-inhibitors, β-blockers, bronchodilators, or glucocorticoids within 4 weeks prior to study inclusion

  4. treatment with analgesics, secretolytics, mucolytics, or antitussives during the 7 days prior to study inclusion

  5. allergic bronchial asthma, concomitant bacterial disease or diseases of the upper respiratory tract tendency to bleed, severe heart, renal, or liver diseases and/or immunosuppression

  6. if patients had a fever(39°C), they were allowed to take 500mg paracetamol tablets, but no more than three tablets daily

Nduba VN (2008) a triple blind, randomized, equivalence trial
  1. aged >18 years old

  2. presenting with a productive cough of 2 weeks duration

  1. another potential explanation for cough (history of chronic bronchitis, allergic rhinitis, sinusitis, asthma or gastric reflux),

  2. serious medical comorbidity (heart disease or diabetes), penicillin allergy, antibiotic use in the preceding 2 weeks or a concurrent infection (including tuberculosis) requiring antibiotic treatment.

Schulz V (2007) randomized, double-blind, placebo controlled clinical trial
  1. ≥18 years old

  2. acute bronchitis with a BSS ≥ 5 points

  3. duration of complaints ≤ 48 hours

  1. indication for antibiotic treatment, treatment with antibiotics during the past four weeks before inclusion in the trial

  2. allergic bronchial asthma, tendency to bleed, severe heart, renal, or liver diseases, immunosuppression, known or supposed hypersensitivity to the investigational medication

  3. concomitant medication that might impair the study results(eg, antibiotics) or supposed interactions of the concomitant medication with the investigational medication

  4. participation in another clinical trial during the past three months

  5. patients who are known or suspected by their mental capability to be noncompliant

Zansai A (2014) randomized, double blind, placebo controlled clinical trial.
  1. ≥18 years old

  2. cough induced by URTIs lasting from 3 to 5 days.

  1. pre-existing respiratory problems

  2. having undergone antibiotic treatment within 7 days prior to enrollment in the study

  3. use of antitussive agents or any other medication that might positively or negatively affect the cough symptom.