Are b2-agonists Effective Treatment for Acute Bronchitis or Acute Cough in Patients Without Underlying Pulmonary Disease? A Systematic Review

Acute bronchitis is characterized by cough associated with other symptoms of upper respiratory infection. Although this condition is self-limited, most patients feel ill, and many do not perform their usual activities. The optimal treatment for this common condition in patients who do not have underlying pulmonary disease is not clear. Clinicians often prescribe antibiotics,^1,2 in spite of the fact that they are of little overall benefit.^3,4 It is important to examine the effectiveness of alternative approaches.

b2-agonists have been proposed, because healthy patients have impaired airflow when infected with pathogens known to cause acute bronchitis.^5-7 Also, cough is the primary symptom for some patients who have asthma,⁸ and many of these patients benefit from b2-agonists.⁹ b2-agonists are effective in reducing cough due to other causes, such as bronchoscopy¹⁰ and intravenous fentany^1,11

We conducted this systematic review to determine whether b2-agonists are effective for patients who have acute bronchitis without underlying pulmonary disease. If b2-agonists are effective, then they should be more widely used; only a minority of US family physicians currently prescribe them for acute bronchitis.^2,12

Methods

We attempted to locate all controlled trials that compared b2-agonists with placebo or an alternative treatment in patients older than 2 years who presented with acute bronchitis or acute cough without a clear etiology (eg, pneumonia, pertussis, or sinusitis). We included patients with acute cough, because the clinical definition of acute bronchitis is not standardized. Textbooks^13-15 and clinician studies^16,17 instruct that cough in association with an acute respiratory infection is required for a diagnosis; otherwise, there are differing criteria regarding the need for other symptoms and signs, such as dyspnea, abnormal chest findings, and sputum.

We searched MEDLINE (1966-2000), EMBASE (1974-2000), and The Cochrane Library (through August 2000) using the key words “bronchitis” or “cough”, together with the terms “adrenergic beta-agonist (exp),” “bronchodilator agents (exp),” “sympathomimetic (exp),” “albuterol,” “salbutamol,” “bitolterol,” “isoetharine,” “metaproterenol,” “pirbuterol,” “salmeterol,” “terbutaline,” “fenoterol,” “formoterol,” or “procaterol” (note that albuterol and salbutamol are the same compound). We also searched conference proceedings databases (Inside Conferences, 1993-99; Conference Papers Index, 1973-99); the System for Information on Grey Literature in Europe database (1980-2000); the reference lists of retrieved articles, review articles, and textbooks; and the Science Citation Index (1990-2000). Finally, we wrote to all US manufacturers of brand name b2-agonists. There were no language restrictions in our search.

Two investigators (C.F., J.S.) independently reviewed all the retrieved titles and abstracts. Studies selected by either investigator as possibly meeting the inclusion criteria were retrieved in their entirety. One investigator (J.S.) then deleted the journal of publication, title, authors, affiliations, and results sections of each study that met the inclusion criteria, and compiled a list of all the reported outcomes. The list of outcomes was forwarded to the other 3 investigators who independently, and then through discussion, determined which outcomes would be included in our review. The main criterion for selection was that the outcome should be directly important to patients. The same 3 investigators then graded the quality of each study using the 5-point Jadad scale, with points given for method of randomization (0-2), adequacy of blinding (0-2), and description of withdrawals (0-1).¹⁸ The Jadad scale is a validated, well-accepted, and frequently used quality assessment scale. Agreement on quality was assessed with a k score, and disagreements were resolved by discussion. Trials were excluded if all investigators agreed that the trial did not meet our inclusion criteria. The remaining articles in their entirety were then distributed to all investigators, each of whom independently extracted data for the selected outcomes. Disagreements were resolved by discussion. We attempted to contact authors to obtain missing data.

Summary statistics were calculated using Review Manager 4.1 software (Update Software, Oxford, England). We used fixed effects models for outcomes without statistically significant heterogeneity (at P <.10) and random effects models for outcomes with significant heterogeneity. For dichotomous outcomes, we reported relative risks (RRs), absolute risk reductions, and numbers needed to treat (NNTs), and for continuous outcomes, standardized mean differences (SMD). We considered a level of P less than .05 to be statistically significant.

Results

Included Studies

The major characteristics of the trials are shown in Table 1. We included 6 controlled trials comparing b2-agonists and placebo,^19-24 and one trial comparing a b2-agonist with erythromycin.²⁵ A trial comparing a b2-agonist with placebo in children²⁶ was excluded because all participants had recurrent cough and the mean duration of cough (8 weeks) was much longer than the maximum of 30 days used in the other trials.

All trials enrolled patients that presented to primary care settings. The stated diagnoses were “acute bronchitis,”^21,22,25 “acute cough,”^19,20 and “acute transient cough.”^23,24 Both trials in children excluded participants with abnormal lung examinations¹⁹ or “with bronchial obstruction needing bronchodilating medication.”²³ None of the adult trials excluded patients with wheezing; the percentage with wheezing ranged from 20% to 44% in the 4 trials that mentioned it. All adult trials included both smokers an nonsmokers.

The only trial that mentioned how well patients adhered to study medications²⁵ reported more than 95% compliance for both groups. Regarding co-interventions, 3 trials prohibited other antitussives^19,23,24 ; 3 trials allowed them and recorded their use as an outcome^20,21,25 ; and one trial did not mention co-interventions. ²² One trial prohibited the use of antibiotics²⁴ ; other trials comparing b2-agonists to placebo allowed the use of antibiotics at the discretion of the clinician (except as noted for the 1994 study by Hueston²¹). No trials were clearly sponsored by pharmaceutical manufacturers, but the medications were supplied free of charge by manufacturers in 3 studies.^19,22,24

The quality of the trials varied from 2 to 4 on the Jadad scale Table 1. The k score for reviewers’ quality scores was 0.27, indicating only fair agreement. The majority of the disagreements related to different initial interpretations of the adequacy of blinding and description of withdrawals. These differences were resolved with further discussion.

Data Analysis

The clinical heterogeneity of the trials was so great that examining them as a single group did not seem reasonable. Therefore, we initially examined the trials as follows: (1) those in children, (2) those in adults comparing b2-agonists with placebo, and (3) those in adults comparing b2-agonists with erythromycin. We then combined the data from the trial that compared a b2-agonist with erythromycin with that from the other trials in adults in a secondary analysis.

Trials in Children

Neither trial involving children demonstrated any benefits from albuterol Table 2. Combining the daily cough scores for days 1 to 3 for these trials revealed a trend toward worse scores in the group receiving albuterol Table 3. The results from the 2 trials were homogeneous.

Trials in Adults Comparing b2-agonists with Placebo

The results of the placebo-controlled trials in adults were mixed; one trial found no benefit from b2-agonists, and 3 found at least one benefit. Combining the daily cough severity scores for the 3 trials that included this outcome^20,22,24showed a small nonsignificant trend toward improvement on all days. The results from the individual trials were heterogeneous for day 1 and homogeneous for the other days.

Combining data from the trials that examined persistence of symptoms after a full 7 days of treatment^20-22 yielded no significant difference in presence of cough or night cough Table 4. Combined data also do not show a difference regarding the presence of a productive cough after 7 days or a difference regarding whether patients were working after 4 days. There was significant heterogeneity for 3 of the 4 dichotomous outcomes: cough, productive cough, and return to work.

Trials in Adults Comparing b2-agonists with Erythromycin

In the 1994 Hueston study,²¹ patients given albuterol were less likely to have a cough or a productive cough after 7 days than those given erythromycin, but there were no differences in the presence of night cough after 7 days or in mean days until improvement in cough, well-being, or return to work or normal activities. When the data from this study are combined with that from the other adult trials, there are no significant differences regarding presence after 7 days of cough (RR=0.77; 95% confidence interval [CI], 0.54-1.09), productive cough (RR=0.66; 95% CI, 0.35-1.25), or night cough (RR=0.85; 95% CI, 0.57-1.26).

Adverse Effects

In the trials in children, 11% of the patients given albuterol had shaking or tremor versus 0% given placebo or only dextromethorphan (RR=6.76; 95% CI, 0.86-53.18; NNT=9; 95% CI, 5-100); the results were homogeneous. There were no differences regarding other adverse effects in the trials in children. In the adult trials, patients given b2-agonists were more likely to report tremor, shaking, or nervousness; the percentage of patients having these side effects in the 3 trials that reported specific side effects ranged from 35% to 67% versus control rates of 0% to 23% (RR=7.94; 95% CI, 1.17-53.94; NNT=2.3; 95% CI, 2-3). These data are from the trials that used inhaled fenoterol and oral albuterol.^20,22,25 However, in the 1991 Hueston study,²⁵ only 9% of the patients given inhaled albuterol reported any side effects; therefore, there is considerable heterogeneity among the results of the individual trials. There were no significant differences regarding other adverse effects between the b2-agonist group and control groups as a whole, but the trial comparing albuterol with erythromycin noted more gastrointestinal side effects in the erythromycin group (NNT=3; 95% CI, 2-8).

Subgroup Analyses

In the study by Melbye and colleagues,²² the subgroup of patients with evidence of airway obstruction (defined as wheezing on initial examination, a forced expiratory volume in 1 second of <80% predicted, or a positive response to a methacholine challenge test) who were given fenoterol had lower symptom scores beginning at day 2 than those in this subgroup who were given placebo. This was also true for the smaller subgroup that just had wheezing, but no difference was noted for patients with a normal lung examination. No other trial did a subgroup analysis limited to patients with evidence of airflow obstruction. The 1994 Hueston study²¹ reported that among patients given albuterol, those with wheezing were slightly less likely to be coughing after 7 days than those without wheezing, but the difference was not statistically significant.

Melbye and coworkers²² found that patients who smoked or had also received antibiotics had greater reductions in total symptom scores on day 7 if given fenoterol. Smokers had similar responses to nonsmokers in the studies by Hueston.^21,25 Littenberg and colleagues²⁰ found that patients given erythromycin trended toward lower cough severity scores if given albuterol instead of placebo, and patients not given erythromycin showed a trend toward higher scores if given albuterol. The 1994 Hueston study²¹ reported that the differences between the groups given and not given albuterol persisted after stratification by erythromycin use.

Discussion

The findings from our review do not support the routine use of b2-agonists for patients who do not have underlying pulmonary disease and present with an acute cough or acute bronchitis. These results must be interpreted in light of the patients that were enrolled in the trials. In particular, because the 2 trials in children excluded patients who were wheezing, the utility of b2-agonists in children with acute cough and evidence of airway obstruction is unknown. b2-agonists do lead to modest short-term improvements in clinical scores in children younger than 2 years who have bronchiolitis.²⁷

The discordant results seen in the trials of adults may reflect different patient populations. Although the inclusion criteria were similar in these trials, more patients were wheezing on initial examination in the Hueston studies^21,25 than in the studies by Littenberg and coworkers²⁰ or Melbye and colleagues.²² Wheezing in unforced expiration is a specific finding for airflow obstruction²⁸; and therefore, more patients in the Hueston trials^21,25 were likely to have had obstruction than in Littenberg and coworkers’ study²⁰ (and since the lungs were auscultated in forced expiration in the latter trial, the actual number with airflow obstruction may have been even less than indicated). The fact that only the subgroup with airway obstruction improved with b2-agonists in the trial by Melbye and colleagues²² reflects the possible importance of this baseline characteristic.

Limitations

Our review has some limitations. Although it includes all of the available data regarding the effectiveness of b2-agonists for patients with acute bronchitis or acute cough, the number of studies and total number of patients included are small. Therefore, our review has limited power to detect differences between patients who were and were not given b2-agonists. In the combined data of trials in adults, there was a trend toward improvements regarding cough, productive cough, night cough, and return to work, but these differences did not reach statistical significance. The midpoint estimates for the relative risk reductions range from 14% to 24% for these outcomes, but all overlap 0. There was also a clinically minor and statistically nonsignificant trend toward lower daily cough severity scores in patients randomized to the b2-agonists.

The studies were also all of a short duration. There is no information as to whether treatment with b2-agonists would alter outcomes beyond 3 to 7 days. This is an important omission, because many patients in these studies were still bothered by symptoms at the end of the trials.

Only 2 studies evaluated inhaled b2-agonists, which would currently be the most likely formulation used in adults and older children. Neither of these studies used spacing devices. The delivery of the medicine may have been suboptimal and resulted in less benefit than might have been seen had spacers been used.

Overall, the quality of the trials was fair to good . There may have been additional biases, however, because most of the trials had unequal distribution of co-interventions and did not record compliance with study medications. Also, even though the studies were all double-blinded, the fact that the majority of the patients in one trial knew which study medication they had been given indicates that the blinding may not have been adequate in these studies because of the taste or side effects of the study medications.

Conclusions

Our review highlights the gaps in evidence regarding the utility of b2-agonists in the treatment of acute cough and acute bronchitis in patients without underlying pulmonary disease. Although there is a possibility that these agents may be useful, additional data demonstrating benefit is required before they can be routinely recommended. There is a particular need for identifying clinical characteristics that can predict which patients might benefit. For example, there is a complete lack of data in children older than 2 years who have signs of airway obstruction. More evidence on the risk-benefit ratio of b2-agonists in adults with clinical signs of airflow limitation is also necessary. Additional areas of useful research would be in evaluating long-acting b2-agonists (because of ease of adherence), in evaluating the benefits of inhaled b2-agonists with spacing devices, and in comparing b2-agonists with other symptomatic treatments.

Acknowledgments

We thank Bill Hueston, Ben Littenberg, Hasse Melbye, and Peter Rowe for providing unpublished information; Bill Grant for assistance with statistics; and Ron D’Souza and Steve MacDonald of the Cochrane Collaboration and Bette Jean Ingui for assistance with database searches.

Acute bronchitis is characterized by cough associated with other symptoms of upper respiratory infection. Although this condition is self-limited, most patients feel ill, and many do not perform their usual activities. The optimal treatment for this common condition in patients who do not have underlying pulmonary disease is not clear. Clinicians often prescribe antibiotics,^1,2 in spite of the fact that they are of little overall benefit.^3,4 It is important to examine the effectiveness of alternative approaches.

b2-agonists have been proposed, because healthy patients have impaired airflow when infected with pathogens known to cause acute bronchitis.^5-7 Also, cough is the primary symptom for some patients who have asthma,⁸ and many of these patients benefit from b2-agonists.⁹ b2-agonists are effective in reducing cough due to other causes, such as bronchoscopy¹⁰ and intravenous fentany^1,11

We conducted this systematic review to determine whether b2-agonists are effective for patients who have acute bronchitis without underlying pulmonary disease. If b2-agonists are effective, then they should be more widely used; only a minority of US family physicians currently prescribe them for acute bronchitis.^2,12

Methods

We attempted to locate all controlled trials that compared b2-agonists with placebo or an alternative treatment in patients older than 2 years who presented with acute bronchitis or acute cough without a clear etiology (eg, pneumonia, pertussis, or sinusitis). We included patients with acute cough, because the clinical definition of acute bronchitis is not standardized. Textbooks^13-15 and clinician studies^16,17 instruct that cough in association with an acute respiratory infection is required for a diagnosis; otherwise, there are differing criteria regarding the need for other symptoms and signs, such as dyspnea, abnormal chest findings, and sputum.

We searched MEDLINE (1966-2000), EMBASE (1974-2000), and The Cochrane Library (through August 2000) using the key words “bronchitis” or “cough”, together with the terms “adrenergic beta-agonist (exp),” “bronchodilator agents (exp),” “sympathomimetic (exp),” “albuterol,” “salbutamol,” “bitolterol,” “isoetharine,” “metaproterenol,” “pirbuterol,” “salmeterol,” “terbutaline,” “fenoterol,” “formoterol,” or “procaterol” (note that albuterol and salbutamol are the same compound). We also searched conference proceedings databases (Inside Conferences, 1993-99; Conference Papers Index, 1973-99); the System for Information on Grey Literature in Europe database (1980-2000); the reference lists of retrieved articles, review articles, and textbooks; and the Science Citation Index (1990-2000). Finally, we wrote to all US manufacturers of brand name b2-agonists. There were no language restrictions in our search.

Two investigators (C.F., J.S.) independently reviewed all the retrieved titles and abstracts. Studies selected by either investigator as possibly meeting the inclusion criteria were retrieved in their entirety. One investigator (J.S.) then deleted the journal of publication, title, authors, affiliations, and results sections of each study that met the inclusion criteria, and compiled a list of all the reported outcomes. The list of outcomes was forwarded to the other 3 investigators who independently, and then through discussion, determined which outcomes would be included in our review. The main criterion for selection was that the outcome should be directly important to patients. The same 3 investigators then graded the quality of each study using the 5-point Jadad scale, with points given for method of randomization (0-2), adequacy of blinding (0-2), and description of withdrawals (0-1).¹⁸ The Jadad scale is a validated, well-accepted, and frequently used quality assessment scale. Agreement on quality was assessed with a k score, and disagreements were resolved by discussion. Trials were excluded if all investigators agreed that the trial did not meet our inclusion criteria. The remaining articles in their entirety were then distributed to all investigators, each of whom independently extracted data for the selected outcomes. Disagreements were resolved by discussion. We attempted to contact authors to obtain missing data.

Summary statistics were calculated using Review Manager 4.1 software (Update Software, Oxford, England). We used fixed effects models for outcomes without statistically significant heterogeneity (at P <.10) and random effects models for outcomes with significant heterogeneity. For dichotomous outcomes, we reported relative risks (RRs), absolute risk reductions, and numbers needed to treat (NNTs), and for continuous outcomes, standardized mean differences (SMD). We considered a level of P less than .05 to be statistically significant.

Results

Included Studies

The major characteristics of the trials are shown in Table 1. We included 6 controlled trials comparing b2-agonists and placebo,^19-24 and one trial comparing a b2-agonist with erythromycin.²⁵ A trial comparing a b2-agonist with placebo in children²⁶ was excluded because all participants had recurrent cough and the mean duration of cough (8 weeks) was much longer than the maximum of 30 days used in the other trials.

All trials enrolled patients that presented to primary care settings. The stated diagnoses were “acute bronchitis,”^21,22,25 “acute cough,”^19,20 and “acute transient cough.”^23,24 Both trials in children excluded participants with abnormal lung examinations¹⁹ or “with bronchial obstruction needing bronchodilating medication.”²³ None of the adult trials excluded patients with wheezing; the percentage with wheezing ranged from 20% to 44% in the 4 trials that mentioned it. All adult trials included both smokers an nonsmokers.

The only trial that mentioned how well patients adhered to study medications²⁵ reported more than 95% compliance for both groups. Regarding co-interventions, 3 trials prohibited other antitussives^19,23,24 ; 3 trials allowed them and recorded their use as an outcome^20,21,25 ; and one trial did not mention co-interventions. ²² One trial prohibited the use of antibiotics²⁴ ; other trials comparing b2-agonists to placebo allowed the use of antibiotics at the discretion of the clinician (except as noted for the 1994 study by Hueston²¹). No trials were clearly sponsored by pharmaceutical manufacturers, but the medications were supplied free of charge by manufacturers in 3 studies.^19,22,24

The quality of the trials varied from 2 to 4 on the Jadad scale Table 1. The k score for reviewers’ quality scores was 0.27, indicating only fair agreement. The majority of the disagreements related to different initial interpretations of the adequacy of blinding and description of withdrawals. These differences were resolved with further discussion.

Data Analysis

The clinical heterogeneity of the trials was so great that examining them as a single group did not seem reasonable. Therefore, we initially examined the trials as follows: (1) those in children, (2) those in adults comparing b2-agonists with placebo, and (3) those in adults comparing b2-agonists with erythromycin. We then combined the data from the trial that compared a b2-agonist with erythromycin with that from the other trials in adults in a secondary analysis.

Trials in Children

Neither trial involving children demonstrated any benefits from albuterol Table 2. Combining the daily cough scores for days 1 to 3 for these trials revealed a trend toward worse scores in the group receiving albuterol Table 3. The results from the 2 trials were homogeneous.

Trials in Adults Comparing b2-agonists with Placebo

The results of the placebo-controlled trials in adults were mixed; one trial found no benefit from b2-agonists, and 3 found at least one benefit. Combining the daily cough severity scores for the 3 trials that included this outcome^20,22,24showed a small nonsignificant trend toward improvement on all days. The results from the individual trials were heterogeneous for day 1 and homogeneous for the other days.

Combining data from the trials that examined persistence of symptoms after a full 7 days of treatment^20-22 yielded no significant difference in presence of cough or night cough Table 4. Combined data also do not show a difference regarding the presence of a productive cough after 7 days or a difference regarding whether patients were working after 4 days. There was significant heterogeneity for 3 of the 4 dichotomous outcomes: cough, productive cough, and return to work.

Trials in Adults Comparing b2-agonists with Erythromycin

In the 1994 Hueston study,²¹ patients given albuterol were less likely to have a cough or a productive cough after 7 days than those given erythromycin, but there were no differences in the presence of night cough after 7 days or in mean days until improvement in cough, well-being, or return to work or normal activities. When the data from this study are combined with that from the other adult trials, there are no significant differences regarding presence after 7 days of cough (RR=0.77; 95% confidence interval [CI], 0.54-1.09), productive cough (RR=0.66; 95% CI, 0.35-1.25), or night cough (RR=0.85; 95% CI, 0.57-1.26).

Adverse Effects

In the trials in children, 11% of the patients given albuterol had shaking or tremor versus 0% given placebo or only dextromethorphan (RR=6.76; 95% CI, 0.86-53.18; NNT=9; 95% CI, 5-100); the results were homogeneous. There were no differences regarding other adverse effects in the trials in children. In the adult trials, patients given b2-agonists were more likely to report tremor, shaking, or nervousness; the percentage of patients having these side effects in the 3 trials that reported specific side effects ranged from 35% to 67% versus control rates of 0% to 23% (RR=7.94; 95% CI, 1.17-53.94; NNT=2.3; 95% CI, 2-3). These data are from the trials that used inhaled fenoterol and oral albuterol.^20,22,25 However, in the 1991 Hueston study,²⁵ only 9% of the patients given inhaled albuterol reported any side effects; therefore, there is considerable heterogeneity among the results of the individual trials. There were no significant differences regarding other adverse effects between the b2-agonist group and control groups as a whole, but the trial comparing albuterol with erythromycin noted more gastrointestinal side effects in the erythromycin group (NNT=3; 95% CI, 2-8).

Subgroup Analyses

In the study by Melbye and colleagues,²² the subgroup of patients with evidence of airway obstruction (defined as wheezing on initial examination, a forced expiratory volume in 1 second of <80% predicted, or a positive response to a methacholine challenge test) who were given fenoterol had lower symptom scores beginning at day 2 than those in this subgroup who were given placebo. This was also true for the smaller subgroup that just had wheezing, but no difference was noted for patients with a normal lung examination. No other trial did a subgroup analysis limited to patients with evidence of airflow obstruction. The 1994 Hueston study²¹ reported that among patients given albuterol, those with wheezing were slightly less likely to be coughing after 7 days than those without wheezing, but the difference was not statistically significant.

Melbye and coworkers²² found that patients who smoked or had also received antibiotics had greater reductions in total symptom scores on day 7 if given fenoterol. Smokers had similar responses to nonsmokers in the studies by Hueston.^21,25 Littenberg and colleagues²⁰ found that patients given erythromycin trended toward lower cough severity scores if given albuterol instead of placebo, and patients not given erythromycin showed a trend toward higher scores if given albuterol. The 1994 Hueston study²¹ reported that the differences between the groups given and not given albuterol persisted after stratification by erythromycin use.

Discussion

The findings from our review do not support the routine use of b2-agonists for patients who do not have underlying pulmonary disease and present with an acute cough or acute bronchitis. These results must be interpreted in light of the patients that were enrolled in the trials. In particular, because the 2 trials in children excluded patients who were wheezing, the utility of b2-agonists in children with acute cough and evidence of airway obstruction is unknown. b2-agonists do lead to modest short-term improvements in clinical scores in children younger than 2 years who have bronchiolitis.²⁷

The discordant results seen in the trials of adults may reflect different patient populations. Although the inclusion criteria were similar in these trials, more patients were wheezing on initial examination in the Hueston studies^21,25 than in the studies by Littenberg and coworkers²⁰ or Melbye and colleagues.²² Wheezing in unforced expiration is a specific finding for airflow obstruction²⁸; and therefore, more patients in the Hueston trials^21,25 were likely to have had obstruction than in Littenberg and coworkers’ study²⁰ (and since the lungs were auscultated in forced expiration in the latter trial, the actual number with airflow obstruction may have been even less than indicated). The fact that only the subgroup with airway obstruction improved with b2-agonists in the trial by Melbye and colleagues²² reflects the possible importance of this baseline characteristic.

Limitations

Our review has some limitations. Although it includes all of the available data regarding the effectiveness of b2-agonists for patients with acute bronchitis or acute cough, the number of studies and total number of patients included are small. Therefore, our review has limited power to detect differences between patients who were and were not given b2-agonists. In the combined data of trials in adults, there was a trend toward improvements regarding cough, productive cough, night cough, and return to work, but these differences did not reach statistical significance. The midpoint estimates for the relative risk reductions range from 14% to 24% for these outcomes, but all overlap 0. There was also a clinically minor and statistically nonsignificant trend toward lower daily cough severity scores in patients randomized to the b2-agonists.

The studies were also all of a short duration. There is no information as to whether treatment with b2-agonists would alter outcomes beyond 3 to 7 days. This is an important omission, because many patients in these studies were still bothered by symptoms at the end of the trials.

Only 2 studies evaluated inhaled b2-agonists, which would currently be the most likely formulation used in adults and older children. Neither of these studies used spacing devices. The delivery of the medicine may have been suboptimal and resulted in less benefit than might have been seen had spacers been used.

Overall, the quality of the trials was fair to good . There may have been additional biases, however, because most of the trials had unequal distribution of co-interventions and did not record compliance with study medications. Also, even though the studies were all double-blinded, the fact that the majority of the patients in one trial knew which study medication they had been given indicates that the blinding may not have been adequate in these studies because of the taste or side effects of the study medications.

Conclusions

Our review highlights the gaps in evidence regarding the utility of b2-agonists in the treatment of acute cough and acute bronchitis in patients without underlying pulmonary disease. Although there is a possibility that these agents may be useful, additional data demonstrating benefit is required before they can be routinely recommended. There is a particular need for identifying clinical characteristics that can predict which patients might benefit. For example, there is a complete lack of data in children older than 2 years who have signs of airway obstruction. More evidence on the risk-benefit ratio of b2-agonists in adults with clinical signs of airflow limitation is also necessary. Additional areas of useful research would be in evaluating long-acting b2-agonists (because of ease of adherence), in evaluating the benefits of inhaled b2-agonists with spacing devices, and in comparing b2-agonists with other symptomatic treatments.

Acknowledgments

We thank Bill Hueston, Ben Littenberg, Hasse Melbye, and Peter Rowe for providing unpublished information; Bill Grant for assistance with statistics; and Ron D’Souza and Steve MacDonald of the Cochrane Collaboration and Bette Jean Ingui for assistance with database searches.

Acute bronchitis is characterized by cough associated with other symptoms of upper respiratory infection. Although this condition is self-limited, most patients feel ill, and many do not perform their usual activities. The optimal treatment for this common condition in patients who do not have underlying pulmonary disease is not clear. Clinicians often prescribe antibiotics,^1,2 in spite of the fact that they are of little overall benefit.^3,4 It is important to examine the effectiveness of alternative approaches.

b2-agonists have been proposed, because healthy patients have impaired airflow when infected with pathogens known to cause acute bronchitis.^5-7 Also, cough is the primary symptom for some patients who have asthma,⁸ and many of these patients benefit from b2-agonists.⁹ b2-agonists are effective in reducing cough due to other causes, such as bronchoscopy¹⁰ and intravenous fentany^1,11

We conducted this systematic review to determine whether b2-agonists are effective for patients who have acute bronchitis without underlying pulmonary disease. If b2-agonists are effective, then they should be more widely used; only a minority of US family physicians currently prescribe them for acute bronchitis.^2,12

Methods

We attempted to locate all controlled trials that compared b2-agonists with placebo or an alternative treatment in patients older than 2 years who presented with acute bronchitis or acute cough without a clear etiology (eg, pneumonia, pertussis, or sinusitis). We included patients with acute cough, because the clinical definition of acute bronchitis is not standardized. Textbooks^13-15 and clinician studies^16,17 instruct that cough in association with an acute respiratory infection is required for a diagnosis; otherwise, there are differing criteria regarding the need for other symptoms and signs, such as dyspnea, abnormal chest findings, and sputum.

We searched MEDLINE (1966-2000), EMBASE (1974-2000), and The Cochrane Library (through August 2000) using the key words “bronchitis” or “cough”, together with the terms “adrenergic beta-agonist (exp),” “bronchodilator agents (exp),” “sympathomimetic (exp),” “albuterol,” “salbutamol,” “bitolterol,” “isoetharine,” “metaproterenol,” “pirbuterol,” “salmeterol,” “terbutaline,” “fenoterol,” “formoterol,” or “procaterol” (note that albuterol and salbutamol are the same compound). We also searched conference proceedings databases (Inside Conferences, 1993-99; Conference Papers Index, 1973-99); the System for Information on Grey Literature in Europe database (1980-2000); the reference lists of retrieved articles, review articles, and textbooks; and the Science Citation Index (1990-2000). Finally, we wrote to all US manufacturers of brand name b2-agonists. There were no language restrictions in our search.

Two investigators (C.F., J.S.) independently reviewed all the retrieved titles and abstracts. Studies selected by either investigator as possibly meeting the inclusion criteria were retrieved in their entirety. One investigator (J.S.) then deleted the journal of publication, title, authors, affiliations, and results sections of each study that met the inclusion criteria, and compiled a list of all the reported outcomes. The list of outcomes was forwarded to the other 3 investigators who independently, and then through discussion, determined which outcomes would be included in our review. The main criterion for selection was that the outcome should be directly important to patients. The same 3 investigators then graded the quality of each study using the 5-point Jadad scale, with points given for method of randomization (0-2), adequacy of blinding (0-2), and description of withdrawals (0-1).¹⁸ The Jadad scale is a validated, well-accepted, and frequently used quality assessment scale. Agreement on quality was assessed with a k score, and disagreements were resolved by discussion. Trials were excluded if all investigators agreed that the trial did not meet our inclusion criteria. The remaining articles in their entirety were then distributed to all investigators, each of whom independently extracted data for the selected outcomes. Disagreements were resolved by discussion. We attempted to contact authors to obtain missing data.

Summary statistics were calculated using Review Manager 4.1 software (Update Software, Oxford, England). We used fixed effects models for outcomes without statistically significant heterogeneity (at P <.10) and random effects models for outcomes with significant heterogeneity. For dichotomous outcomes, we reported relative risks (RRs), absolute risk reductions, and numbers needed to treat (NNTs), and for continuous outcomes, standardized mean differences (SMD). We considered a level of P less than .05 to be statistically significant.

Results

Included Studies

The major characteristics of the trials are shown in Table 1. We included 6 controlled trials comparing b2-agonists and placebo,^19-24 and one trial comparing a b2-agonist with erythromycin.²⁵ A trial comparing a b2-agonist with placebo in children²⁶ was excluded because all participants had recurrent cough and the mean duration of cough (8 weeks) was much longer than the maximum of 30 days used in the other trials.

All trials enrolled patients that presented to primary care settings. The stated diagnoses were “acute bronchitis,”^21,22,25 “acute cough,”^19,20 and “acute transient cough.”^23,24 Both trials in children excluded participants with abnormal lung examinations¹⁹ or “with bronchial obstruction needing bronchodilating medication.”²³ None of the adult trials excluded patients with wheezing; the percentage with wheezing ranged from 20% to 44% in the 4 trials that mentioned it. All adult trials included both smokers an nonsmokers.

The only trial that mentioned how well patients adhered to study medications²⁵ reported more than 95% compliance for both groups. Regarding co-interventions, 3 trials prohibited other antitussives^19,23,24 ; 3 trials allowed them and recorded their use as an outcome^20,21,25 ; and one trial did not mention co-interventions. ²² One trial prohibited the use of antibiotics²⁴ ; other trials comparing b2-agonists to placebo allowed the use of antibiotics at the discretion of the clinician (except as noted for the 1994 study by Hueston²¹). No trials were clearly sponsored by pharmaceutical manufacturers, but the medications were supplied free of charge by manufacturers in 3 studies.^19,22,24

The quality of the trials varied from 2 to 4 on the Jadad scale Table 1. The k score for reviewers’ quality scores was 0.27, indicating only fair agreement. The majority of the disagreements related to different initial interpretations of the adequacy of blinding and description of withdrawals. These differences were resolved with further discussion.

Data Analysis

The clinical heterogeneity of the trials was so great that examining them as a single group did not seem reasonable. Therefore, we initially examined the trials as follows: (1) those in children, (2) those in adults comparing b2-agonists with placebo, and (3) those in adults comparing b2-agonists with erythromycin. We then combined the data from the trial that compared a b2-agonist with erythromycin with that from the other trials in adults in a secondary analysis.

Trials in Children

Neither trial involving children demonstrated any benefits from albuterol Table 2. Combining the daily cough scores for days 1 to 3 for these trials revealed a trend toward worse scores in the group receiving albuterol Table 3. The results from the 2 trials were homogeneous.

Trials in Adults Comparing b2-agonists with Placebo

The results of the placebo-controlled trials in adults were mixed; one trial found no benefit from b2-agonists, and 3 found at least one benefit. Combining the daily cough severity scores for the 3 trials that included this outcome^20,22,24showed a small nonsignificant trend toward improvement on all days. The results from the individual trials were heterogeneous for day 1 and homogeneous for the other days.

Combining data from the trials that examined persistence of symptoms after a full 7 days of treatment^20-22 yielded no significant difference in presence of cough or night cough Table 4. Combined data also do not show a difference regarding the presence of a productive cough after 7 days or a difference regarding whether patients were working after 4 days. There was significant heterogeneity for 3 of the 4 dichotomous outcomes: cough, productive cough, and return to work.

Trials in Adults Comparing b2-agonists with Erythromycin

In the 1994 Hueston study,²¹ patients given albuterol were less likely to have a cough or a productive cough after 7 days than those given erythromycin, but there were no differences in the presence of night cough after 7 days or in mean days until improvement in cough, well-being, or return to work or normal activities. When the data from this study are combined with that from the other adult trials, there are no significant differences regarding presence after 7 days of cough (RR=0.77; 95% confidence interval [CI], 0.54-1.09), productive cough (RR=0.66; 95% CI, 0.35-1.25), or night cough (RR=0.85; 95% CI, 0.57-1.26).

Adverse Effects

In the trials in children, 11% of the patients given albuterol had shaking or tremor versus 0% given placebo or only dextromethorphan (RR=6.76; 95% CI, 0.86-53.18; NNT=9; 95% CI, 5-100); the results were homogeneous. There were no differences regarding other adverse effects in the trials in children. In the adult trials, patients given b2-agonists were more likely to report tremor, shaking, or nervousness; the percentage of patients having these side effects in the 3 trials that reported specific side effects ranged from 35% to 67% versus control rates of 0% to 23% (RR=7.94; 95% CI, 1.17-53.94; NNT=2.3; 95% CI, 2-3). These data are from the trials that used inhaled fenoterol and oral albuterol.^20,22,25 However, in the 1991 Hueston study,²⁵ only 9% of the patients given inhaled albuterol reported any side effects; therefore, there is considerable heterogeneity among the results of the individual trials. There were no significant differences regarding other adverse effects between the b2-agonist group and control groups as a whole, but the trial comparing albuterol with erythromycin noted more gastrointestinal side effects in the erythromycin group (NNT=3; 95% CI, 2-8).

Subgroup Analyses

In the study by Melbye and colleagues,²² the subgroup of patients with evidence of airway obstruction (defined as wheezing on initial examination, a forced expiratory volume in 1 second of <80% predicted, or a positive response to a methacholine challenge test) who were given fenoterol had lower symptom scores beginning at day 2 than those in this subgroup who were given placebo. This was also true for the smaller subgroup that just had wheezing, but no difference was noted for patients with a normal lung examination. No other trial did a subgroup analysis limited to patients with evidence of airflow obstruction. The 1994 Hueston study²¹ reported that among patients given albuterol, those with wheezing were slightly less likely to be coughing after 7 days than those without wheezing, but the difference was not statistically significant.

Melbye and coworkers²² found that patients who smoked or had also received antibiotics had greater reductions in total symptom scores on day 7 if given fenoterol. Smokers had similar responses to nonsmokers in the studies by Hueston.^21,25 Littenberg and colleagues²⁰ found that patients given erythromycin trended toward lower cough severity scores if given albuterol instead of placebo, and patients not given erythromycin showed a trend toward higher scores if given albuterol. The 1994 Hueston study²¹ reported that the differences between the groups given and not given albuterol persisted after stratification by erythromycin use.

Discussion

The findings from our review do not support the routine use of b2-agonists for patients who do not have underlying pulmonary disease and present with an acute cough or acute bronchitis. These results must be interpreted in light of the patients that were enrolled in the trials. In particular, because the 2 trials in children excluded patients who were wheezing, the utility of b2-agonists in children with acute cough and evidence of airway obstruction is unknown. b2-agonists do lead to modest short-term improvements in clinical scores in children younger than 2 years who have bronchiolitis.²⁷

The discordant results seen in the trials of adults may reflect different patient populations. Although the inclusion criteria were similar in these trials, more patients were wheezing on initial examination in the Hueston studies^21,25 than in the studies by Littenberg and coworkers²⁰ or Melbye and colleagues.²² Wheezing in unforced expiration is a specific finding for airflow obstruction²⁸; and therefore, more patients in the Hueston trials^21,25 were likely to have had obstruction than in Littenberg and coworkers’ study²⁰ (and since the lungs were auscultated in forced expiration in the latter trial, the actual number with airflow obstruction may have been even less than indicated). The fact that only the subgroup with airway obstruction improved with b2-agonists in the trial by Melbye and colleagues²² reflects the possible importance of this baseline characteristic.

Limitations

Our review has some limitations. Although it includes all of the available data regarding the effectiveness of b2-agonists for patients with acute bronchitis or acute cough, the number of studies and total number of patients included are small. Therefore, our review has limited power to detect differences between patients who were and were not given b2-agonists. In the combined data of trials in adults, there was a trend toward improvements regarding cough, productive cough, night cough, and return to work, but these differences did not reach statistical significance. The midpoint estimates for the relative risk reductions range from 14% to 24% for these outcomes, but all overlap 0. There was also a clinically minor and statistically nonsignificant trend toward lower daily cough severity scores in patients randomized to the b2-agonists.

The studies were also all of a short duration. There is no information as to whether treatment with b2-agonists would alter outcomes beyond 3 to 7 days. This is an important omission, because many patients in these studies were still bothered by symptoms at the end of the trials.

Only 2 studies evaluated inhaled b2-agonists, which would currently be the most likely formulation used in adults and older children. Neither of these studies used spacing devices. The delivery of the medicine may have been suboptimal and resulted in less benefit than might have been seen had spacers been used.

Overall, the quality of the trials was fair to good . There may have been additional biases, however, because most of the trials had unequal distribution of co-interventions and did not record compliance with study medications. Also, even though the studies were all double-blinded, the fact that the majority of the patients in one trial knew which study medication they had been given indicates that the blinding may not have been adequate in these studies because of the taste or side effects of the study medications.

Conclusions

Our review highlights the gaps in evidence regarding the utility of b2-agonists in the treatment of acute cough and acute bronchitis in patients without underlying pulmonary disease. Although there is a possibility that these agents may be useful, additional data demonstrating benefit is required before they can be routinely recommended. There is a particular need for identifying clinical characteristics that can predict which patients might benefit. For example, there is a complete lack of data in children older than 2 years who have signs of airway obstruction. More evidence on the risk-benefit ratio of b2-agonists in adults with clinical signs of airflow limitation is also necessary. Additional areas of useful research would be in evaluating long-acting b2-agonists (because of ease of adherence), in evaluating the benefits of inhaled b2-agonists with spacing devices, and in comparing b2-agonists with other symptomatic treatments.

Acknowledgments

We thank Bill Hueston, Ben Littenberg, Hasse Melbye, and Peter Rowe for providing unpublished information; Bill Grant for assistance with statistics; and Ron D’Souza and Steve MacDonald of the Cochrane Collaboration and Bette Jean Ingui for assistance with database searches.