Introduction

Acute cough and respiratory tract infection are terms used to describe a wide variety of clinical syndromes. Symptoms range from cough without sputum to an illness characterised by expectoration of mucopurulent sputum, fever, general malaise, and dyspnoea,¹ but coughing is nearly always present.^1-4 Therefore, although the terms acute bronchitis, upper respiratory tract infection, common cold, and chest infection are used in a clinical context to define separate disease entities, they represent a range of respiratory tract infection whose symptoms, causative agents, and resolution vary. ^{1 2}

Acute cough is a common reason for consulting a general practitioner. The fourth national morbidity survey in the United Kingdom found that the overall consultation rate for acute upper respiratory infections (code 465 of the international classification of diseases, ninth revision (ICD-9)) and acute bronchitis and bronchiolitis (ICD-9 code 466) was 772 and 719 per 10 000 person years at risk.⁵

View larger version (113K): [in this window] [in a new window]   Data from the nine included trials are available on our website at www.bmj.com, as well as citation details of excluded trials

The clinical syndrome of cough is nearly always preceded and associated with a viral nasopharyngitis. ^{1 2} The causes of such infection are usually influenza virus, para-influenza virus, respiratory syncytial virus, rhinovirus, coronavirus, and adenovirus. ^{2 6 7} Infection with non-viral organisms such as Bordetella pertussis, Mycoplasma pneumoniae, and Chlamydia pneumonia may also occur, some studies reporting a high prevalence of infection with Mycoplasma spp, particularly in young adults. ^{7 8} Secondary bacterial infection occurs in a certain proportion of cases, usually with Haemophilus influenzae and Streptococcus pneumoniae. ^{1 2 7} Because bacteria are carried as normal resident flora in the upper respiratory tract, the aetiological role of bacteria cultured from sputum samples is unclear.² In a study based in the United Kingdom 25% of sputum culture samples from people being treated for acute bronchitis grew recognised or potential respiratory bacterial pathogens.⁹ A community based longitudinal study in the United Kingdom showed that a potential pathogen was cultured in only 29% of cases, with viruses being identified more frequently than Mycoplasma spp and bacteria being identified least of all.⁴ In a community based study in the United Kingdom of 206 patients with more severe respiratory tract infection (inclusion criteria were productive cough, focal signs on chest examination, and prescription of antibiotic) an aetiological diagnosis was established in 91 (44%) patients.¹⁰ The most commonly identified pathogens were S pneumoniae (36%), H influenzae (10%), and influenza viruses (13%).¹⁰ An accompanying editorial highlighted the difficulty in clinically differentiating between the more severe forms of bronchitis and pneumonia in the community.¹¹

Microbiological investigation of acute bronchitis is rare in general practice. ^{1 9 12} Differentiation between viral and bacterial infection is difficult on the basis of symptoms alone,¹ and therefore general practitioners have substantially different diagnostic and treatment thresholds for respiratory tract infection in the community. ^{1 12 13}

Concern about the treatment of acute cough with antibiotics is not new. ^{14 15} Review articles have questioned the value of antibiotic treatment for acute bronchitis and related conditions. ^{1 16-19} To our knowledge, the absolute risk of illness without antibiotic treatment, the likely benefits and risks of treatment, and the balance of risk and benefit for individual patients have not been measured. We therefore carried out a systematic review of randomised controlled trials to establish whether antibiotics are effective in the treatment of acute cough in the community.

	Methods

Inclusion and exclusion criteria
We included studies of patients aged greater than 12 years who were attending a family practice clinic, community based outpatient department, or an outpatient department attached to a hospital. We included patients who complained of acute cough with or without purulent sputum that had not been treated in the preceding week with antibiotic. Patients with chronic obstructive airways disease were excluded. The included studies were prospective trials in which antibiotic was allocated by formal randomisation or by quasi-randomisation, such as alternate allocation to treatment and placebo groups. Only placebo controlled trials were included; comparative studies between different classes of antibiotics were excluded. Categorical and continuous outcomes were reported in the randomised controlled trials identified at the start of the review.^20-28 Many different outcomes were reported in individual randomised controlled trials; we concentrated on the three most commonly reported outcomes: the proportion of subjects reporting productive cough, the proportion of subjects who had not improved clinically at re-examination, and the proportion of subjects who reported side effects from taking antibiotic or placebo.

Systematic search
We searched Medline and EMBASE databases from 1966 and 1982 respectively using the recommended Cochrane Collaboration search strategy²⁹ and the medical subject heading (MeSH) terms "cough," "bronchitis," "sputum," and "respiratory tract infections." The search was not restricted to the English language. We also searched for references from published research by using the Science Citation Index and searching references in published studies and abstracts, particularly for those published before 1966. We conducted a search on the Controlled Trials Register from the Cochrane Library³⁰ with the search terms "bronchitis," "chest infection," and "common cold." We contacted authors of published trials requesting knowledge of any unpublished studies. We also wrote to drug companies in the United Kingdom that manufacture antibiotics (as given in the British National Formulary) requesting unpublished trials.

Assessment of quality and extraction of data
Each trial was read independently by TF and NS, who then assessed the quality of each study according to the four criteria outlined in the Cochrane Collaboration Handbook.³¹ Each criterionselection bias, performance bias, attrition bias, and detection biaswas scored from 1 to 3, so the highest score for an individual trial was 12. Measurement of agreement between reviewers was calculated by means of the kappa statistic and disagreement resolved by consensus. Data were extracted independently; when data were missing or incomplete we contacted the authors of the trial for clarification.

Analysis
Because the events in the treatment and control arms occurred frequently, significance and clinical importance were evaluated by estimating relative risk.³² We explored differences in baseline risk and heterogeneity between studies by using L'Abbe plots (see fig 1).³³ As the inclusion criteria and event rates reported in the control arms varied, the pooled relative risks were estimated with 95% confidence intervals by means of both random effects and fixed effects models.³⁴ Antibiotic is significantly better than placebo in improving a condition when the upper limit of the 95% confidence interval is <1. Conversely, side effects of antibiotic treatment are significant when the lower 95% confidence limit of the relative risk is >1.

View larger version (19K): [in this window] [in a new window]   Fig 1.    L'Abbe plots of proportion of subjects with productive cough at follow up at 7-11 days (six trials) and of proportion of subjects who had not improved clinically at 7-11 days (five trials)

	Results

Trials found
Our search uncovered nine trials that met the inclusion criteria for this review (M Stephenson, unpublished data).^21-28 The losses to follow up, antibiotic regimen, outcome measured, recommendation for antibiotic treatment, and characteristics of patients for these nine trials are available as two tables on the BMJ's website (www.bmj.com).

View larger version (25K): [in this window] [in a new window]   Fig 2.    Comparison of antibiotic and placebo treatment on resolution of productive cough at days 7-11

Assessment of quality
The kappa scores for agreement between reviewers for each of the four variables measuring the quality of trials were 0.5 (moderate agreement) for selection, 0.57 (moderate agreement) for performance, 0.85 (substantial agreement) for attrition, and 1 (almost perfect agreement) for blinding. The overall kappa for trial quality was 0.54 (moderate agreement).

Baseline risk and diagnosis
The six trials that reported resolution of productive cough as an outcome measure had varied considerably in this measure (fig 1) (M Stephenson, unpublished data). ^{21 23 25-27} Such differences highlight the range of illness and the differences between trials in diagnosis of acute cough. However, the five trials that had outcome data on the course of clinical improvement were similar in the reported resolution of illness (fig 1). ^{21 23-26}

Efficacy of antibiotic
Antibiotic treatment was no better than placebo when the resolution of cough at days 7-11 was assessed (relative risk 0.85 (95% confidence interval 0.73 to 1.00)) (fig 2). Similarly, when the proportion of subjects who had not improved clinically was assessed at days 7-11 in five trials antibiotic treatment did not significantly improve the resolution of illness (relative risk 0.62 (0.36 to 1.09)) (fig 3). ^{21 23-26} Inclusion of a subgroup of 75 patients with tracheobronchitis in a trial of the common cold who were randomly allocated to co-amoxiclav or placebo³⁷ did not alter the pooled results for resolution of illness (relative risk 0.71 (0.43 to 1.18), ² test for heterogeneity=16.87, df=5, P<0.5).

View larger version (23K): [in this window] [in a new window]   Fig 3.   Comparison of antibiotic and placebo treatment on clinical improvement at days 7-11

Side effects of treatment
The mean percentage of subjects reporting side effects from antibiotic treatment in seven trials was 19% (range 12% to 36%). In all but one trial²⁴ the percentage of subjects reporting side effects was higher in the antibiotic arm; subsequent pooling of data showed that a course of antibiotic was associated with a non-significant increase in the risk of side effects from antibiotic (relative risk 1.51 (0.86 to 2.64)) (fig 4). When the one trial which reported an increase in side effects from placebo was excluded,²⁴ the heterogeneity between trials was reduced and side effects were significantly associated with antibiotic use (relative risk 1.9 (1.19 to 3.02), ² test for heterogeneity=1.73, df=4, P>0.5).

View larger version (24K): [in this window] [in a new window]   Fig 4.   Comparison of antibiotic and placebo treatment on rate of reporting of side effects

	Discussion

This systematic review shows that antibiotic treatment has no effect on the resolution of acute cough. For both measures of efficacythe proportion of subjects coughing and the proportion whose symptoms had not improved at days 7-11antibiotic was no different from placebo. Furthermore, treatment with antibiotic may incur side effects in a few patients.

Shortcomings
This review has several shortcomings. Firstly, the outcomes chosen and assessed in each of the randomised trials were varied and different. Consequently, when the results were pooled several important outcomes were reported only in some of the trials and were measured in different ways. For example, time off work was measured as a continuous outcome in two trials, ^{23 28} as a categorical outcome in three others, ^{21 22 25} as a categorical and continuous outcome in one trial,²⁷ and not at all in the remaining trials (M Stephenson, unpublished data). ^{24 26}

Diagnosis and prognosis
The clinical course of resolution of acute cough was different between trials (fig 1). Such differences reflect the fact that acute cough is primarily diagnosed on history and examination alone. Additional diagnostic tests such as sputum culture and chest radiography are seldom used in general practice, ^{1 9 12} so diagnostic classification is imprecise. The diagnostic nomenclature has also changed over time. For example, an early non-randomised study of acute respiratory infection³⁸ found that the signs reported by the enrolled cohort were no different from those in subjects classed as having acute bronchitis in the 1980s. ^{22-25 27} In addition, the relation between diagnostic category and likelihood of bacterial infection is poorly defined and uncertain in clinical practice.

Implications
In the clinical context of everyday management of acute cough in general practice, treatment with antibiotics is common. The variation in rate of prescribing antibiotics varies substantially between countries. One fifth of consultations in the Netherlands end with an antibiotic being prescribed, up to 80% in the United Kingdom, and an even higher proportion in the United States.^40-42 Results from our systematic review suggest that most patients receive no benefit from antibiotic treatment.

Conclusions
This systematic review shows that antibiotic is unlikely to alter the course of illness in most adult patients presenting with acute cough. A minority may have side effects from treatment. When managing individual patients the potential risks from treatmentincluding side effects, costs of antibiotic, alteration in consulting behaviour, and increased bacterial resistanceshould all be considered before initiating treatment.