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T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e Richard P. Wenzel, M.D., and Alpha A. Fowler III, M.D.
This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors’ clinical recommendations. A 40-year-old man with no underlying lung disease has a 7-day history of mild shortness
of breath with exertion, as well as cough that is now productive of purulent sputum.
He reports no paroxysms of cough and no contact with ill persons in his community.
He does not appear to be in distress. His temperature is 37°C, his pulse 84 beats per
minute, and his respiratory rate 17 breaths per minute. On auscultation of the lungs,
no rales are heard; scattered wheezes are heard in the lung bases. How should he be
evaluated and treated?
Acute bronchitis is a clinical term implying a self-limited inflammation of the large From the Department of Internal Medi- airways of the lung that is characterized by cough without pneumonia. The disorder Richmond. Address reprint requests to affects approximately 5% of adults annually,1,2 with a higher incidence observed dur- Dr. Wenzel at the Department of Internal ing the winter and fall than in the summer and spring. In the United States, acute Medicine, Virginia Commonwealth Univer- sity, 1101 E. Broad St., P.O. Box 980663, bronchitis is the ninth most common illness among outpatients, as reported by phy- Richmond, VA 23298, or at rwenzel@ Viruses are usually considered the cause of acute bronchitis but have been isolated in a minority of patients.1,4 Those isolated in acute bronchitis (from the most to the Copyright 2006 Massachusetts Medical Society. least common in large series) include influenza A and B viruses, parainfluenza virus, respiratory syncytial virus, coronavirus, adenovirus, and rhinovirus. Human meta-pneumovirus has been identified as a causative agent.5-7 A recent French study in-volving adults who had been vaccinated against influenza showed a viral cause in 37% of 164 cases of acute bronchitis, of which 21% were rhinovirus.4 Thus, the yield of specific pathogens varies according to several factors, including the presence or ab-sence of an epidemic, the season of the year, and the influenza vaccination status of the population.
Bacterial species commonly implicated in community-acquired pneumonias are isolated from the sputum in a minority of patients with acute bronchitis.1 However, the role of these species in the disease or its attendant symptoms remains unclear, because bronchial biopsies have not shown bacterial invasion. In some cases, atypi-cal bacteria are important causes, including Bordetella pertussis, Chlamydophila (Chlamydia) pneumoniae, and Mycoplasma pneumoniae.1 Some data have suggested that B. pertussis may underlie 13 to 32% of cases of cough lasting 6 days or longer, although in a recent prospective study, B. pertussis comprised only 1% of cases of acute bronchitis.8 Pathobiology
Acute bronchitis is thought to reflect an inflammatory response to infections of the epithelium of the bronchi. Epithelial-cell desquamation and denuding of the airway to the level of the basement membrane in association with the presence of a lympho-cytic cellular infiltrate have been demonstrated after influenza A tracheobronchitis9; n engl j med 355;20 www.nejm.org november Downloaded from www.nejm.org at HENNEPIN COUNTY MEDICAL CENTER on October 23, 2009 . Copyright 2006 Massachusetts Medical Society. All rights reserved. T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e microscopical examination has shown thickening epithelium and inflammatory cells, and its posi-of the bronchial and tracheal mucosa correspond- tive predictive value for the presence of alveolar ing to the inflamed areas. Such pathological disease is low (approximately 10%).15findings are consistent with reports of proximal A study of the quality of life of patients with lower airway inflammation confined to the bron- upper respiratory tract infections, some of whom chi, as detected by positron-emission tomography had received a diagnosis of acute bronchitis, with 18F-fluorodeoxyglucose as a tracer, in the showed significant decrements in seven subscales setting of acute bronchitis.10 of the Medical Outcomes Study 36-item Short- However, there are wide variations in the ana- Form General Health Survey, including vitality and tomical distribution of many pathogens that cause social functioning,16 but such decrements are pre-acute bronchitis. In a study involving volunteers sumed to be transient. Data on short- or long-term exposed to rhinovirus infections, for example, outcomes are limited, but one study indicated that virus was detected in specimens of induced spu- within a month after the initial visit, up to 20% tum obtained from all the subjects, in approxi- of patients had reconsulted their physicians be-mately one third of bronchial biopsy specimens, cause of persistent or recurrent symptoms.1 The in almost a quarter of bronchoalveolar lavage effect of an episode of acute bronchitis on a pa-specimens, and in more than a third of bronchial tient’s subsequent lung health is uncertain. In one brushing specimens.11 Such data indicating viral study, 34% of patients with acute bronchitis re-infection of the lower airways may help to explain ceived a new diagnosis of chronic bronchitis or the relationship observed between rhinovirus in- asthma at 3 years of follow-up.17 In another study, fection (and other presumed upper respiratory mild bronchial asthma was diagnosed on the basis viral infections) and exacerbation of asthma.12 of spirometry or bronchial provocation in 65% of Thus, although its name suggests only large-air- patients with recurrent episodes of acute bronchi-way disease, acute bronchitis may be accompanied tis.18 However, these studies lacked control groups, by an array of symptoms, depending on the de- and it is unclear whether acute bronchitis led di-gree of viral involvement of the large and small rectly to the chronic condition or whether the airways.
chronic disorder or the propensity for its devel-opment was present at the time of the inflamma- Natural History
During the first few days of infection, the symp-toms of mild upper respiratory infections cannot S t r a t e g i e s a n d E v i d e n c e be distinguished from those of acute bronchitis.
However, with acute bronchitis, coughing persists Diagnosis
for more than 5 days, and during this protracted Acute bronchitis should be differentiated from
period the results of pulmonary function testing acute inflammation of the small airways — asth-
may become abnormal. Forty percent of patients ma or bronchiolitis — which typically presents as
have significant reductions in the forced expirato- progressive cough accompanied by wheezing,
ry volume in 1 second (i.e., a value below 80% of tachypnea, respiratory distress, and hypoxemia.
the predicted value)13 or bronchial hyperreactivity, It should also be distinguished from bronchiecta-
as measured by bronchial provocation,14 with im- sis,19 a distinct phenomenon associated with per-
provement during the following 5 to 6 weeks.
manent dilatation of bronchi and chronic cough. Cough after acute bronchitis typically persists The diagnosis of chronic bronchitis is reserved for 10 to 20 days but occasionally may last for 4 or for patients who have cough and sputum produc-more weeks. In a recent report on a clinical trial tion on most days of the month for at least 3 months of the efficacy of an acellular pertussis vaccine in- of the year during 2 consecutive years.20 The acute volving 2781 healthy adults, the median duration exacerbation of chronic bronchitis, identified by of cough from acute bronchitis due to all causes the worsening air flow and symptoms in such pa-was 18 days (mean, 24).8 In addition, approximate- tients, is not discussed here.
ly 50% of patients with acute bronchitis report A careful history taking, including reports of the production of purulent sputum. In otherwise contact with ill people, and physical examination healthy patients, purulent sputum usually indi- may suggest a specific cause (Table 1). A common cates the presence of sloughed tracheobronchial presentation of pertussis is cough of 2 to 3 weeks’ n engl j med 355;20 www.nejm.org november Downloaded from www.nejm.org at HENNEPIN COUNTY MEDICAL CENTER on October 23, 2009 . Copyright 2006 Massachusetts Medical Society. All rights reserved. Table 1. Recognized Causes of Acute Bronchitis and Options for Therapy.*
Pathogen
Comments†
Options for Therapy
Precipitous onset with fever, chills, headache, and Oseltamivir (Tamiflu, Roche) for 5 days at a dose of cough. Myalgias are common and may be ac- 75 mg twice daily21 or zanamivir (Relenza, companied by myositis, myoglobinuria, and GlaxoSmithKline) for 5 days at a dose of elevated serum levels of muscle enzymes.
two puffs (5 mg/puff) twice daily, for a total daily dose of 20 mg21 Epidemics may occur in autumn. Outbreaks may occur in nursing homes. Croup in a child at home suggests the presence of the organism.
Family history is important: approximately 45% of family members exposed to an infant (≤1 yr of age) with bronchiolitis become infected.22 Outbreaks occur in winter or spring. Twenty percent of adults have ear pain.23 Pathogen can cause severe respiratory symptoms in elderly patients. Epidemics of strain 0C43 with high attack rates have been reported among military recruits.24 Infection is clinically similar to influenza, with Fever is uncommon, and infection is generally mild.
Atypical bacteria
Bordetella pertussis
Incubation period is 1–3 wk. Primarily affects ado- lescents and young adults. In some series, 10 to Azithromycin (Zithromax, Pfizer) for 5 days at 20% of patients have cough with a duration of >2 wk.13 Whooping occurs in a minority of pa- tients.19 Fever is uncommon. A marked leukocy- Erythromycin (Ery-Tab, Abbott) for 14 days at tosis with lymphocytic predominance can occur.
Clarithromycin (Biaxin, Abbott) for 7 days at Trimethoprim–sulfamethoxazole (Bactrim, Roche) for 14 days at a dose of 1600 mg once daily or 800 mg twice daily Incubation period is 2–3 wk. Gradual onset (2–3 Azithromycin for 5 days at a dose of 500 mg on days) distinguishes this infection from influen- day 1 and 250 mg on days 2–5 or doxycy- za. Clusters occur among military recruits and cline (Vibramycin, Pfizer) for 5 days at a dose of 100 mg twice daily or no therapy‡ Incubation period is 3 wk. Onset of symptoms, Azithromycin for 5 days at a dose of 500 mg on which include hoarseness before cough, is grad- day 1 and 250 mg on days 2–5 or doxycy- ual. Clusters reported among military recruits, cline for 5 days at a dose of 100 mg twice college students, and patients in nursing homes.
* The cause of many cases remains uncertain. The presence or absence of a community epidemic, the time of year, the population affected, and influenza immunization status are important risk factors for specific pathogens. Viruses generally have an incubation period of 2 to 7 days, whereas the three atypical bacteria have longer incubation periods. Such information may be helpful if the interval after contact with ill persons is known. A gradual onset of symptoms (2 to 3 days) is more characteristic of bacterial causes than of most viral causes.
† Diagnostic testing is most useful for identifying treatable causes when an infectious agent is circulating in the community and for identify- ‡ There are no compelling data suggestive of improved outcomes of acute bronchitis as a result of treatment with antibiotic agents.
duration in an adolescent or young adult; fever is have a positive predictive value of 79% for this
less common in pertussis than in viral bronchi- condition.27
tis.18,26 However, in the absence of an epidemic,
the positive predictive value of young age, pro- Diagnostic Testing
longed cough, or the absence of fever is low for At the bedside, cough in the absence of fever, tachy-
pertussis. During an epidemic of influenza, the cardia, and tachypnea suggests bronchitis, rather
finding of both cough and fever was reported to than pneumonia. In fact, the presence of normal
n engl j med 355;20 www.nejm.org november Downloaded from www.nejm.org at HENNEPIN COUNTY MEDICAL CENTER on October 23, 2009 . Copyright 2006 Massachusetts Medical Society. All rights reserved. T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e vital signs and the absence of rales and egophony showed a significant but minor reduction in the on chest examination minimize the likelihood of duration of cough (0.6 day).33 There was a nonsig-pneumonia to the point at which further diagnos- nificant reduction in the number of days of feel-tic testing is usually unnecessary.28 An exception, ing ill and a nonsignificant increase in adverse however, is cough in elderly patients; pneumonia events attributed to antibiotics (relative risk of in elderly patients is often characterized by an ab- adverse events, 1.22; 95% confidence interval, 0.94 sence of distinctive signs and symptoms. Among to 1.58).
patients 75 years of age or older who had commu- Antimicrobial therapy may be more beneficial nity-acquired pneumonia, only 30% had a tempera- when a treatable pathogen is identified than when ture above 38°C, and only 37% had a heart rate of a treatable pathogen is not identified. For exam-more than 100 beats per minute.29 ple, anti-influenza agents (including oseltamivir Rapid diagnostic tests exist for several patho- and zanamivir) decrease the duration of symptoms gens currently linked to acute bronchitis. However, by approximately 1 day and result in an earlier not all the rapid tests are widely available, and return to normal activity (by 0.5 day) among pa-their routine use is not cost-effective in an outpa- tients with infections caused by susceptible virus-tient setting. Rapid tests should be used primarily es. Prompt antibiotic treatment of patients with when the suspected organism is treatable, the in- pertussis is indicated to limit transmission, but fection is known to be circulating in the commu- (with the possible exception of therapy initiated nity, and the patient has suggestive symptoms or during the first week of symptoms) there are no signs (e.g., testing for influenza during influenza compelling data to support the prospect that season in patients with cough and fever) (Table 1). cough will be less severe or less prolonged with Multiplex polymerase-chain-reaction (PCR) testing antibiotic therapy. Similarly, although several class-of nasopharyngeal swabs or aspirates is being es of antibiotics have in vitro activity against developed to diagnose infections resulting from M. pneumoniae and C. pneumoniae, it is unclear B. pertussis, M. pneumoniae, or C. pneumoniae with whether antibiotic treatment of bronchitis linked clinically useful sensitivity and specificity, as com- to these organisms influences outcomes. Table 1 pared with culture or monoplex PCR.30 includes suggested antimicrobial therapy for cases in which such therapy is considered.
Treatment
Antimicrobial agents are not recommended in most The few randomized, placebo-controlled trials that cases of acute bronchitis. Systematic analyses of have examined the effect of β -agonists adminis- clinical trials have suggested that antibiotics may tered orally or by aerosol for cough associated with reduce the duration of symptoms, but at best mod- acute bronchitis have involved small numbers of estly. Specifically, a meta-analysis of eight trials patients and have had mixed results.34-36 In these involving patients with acute bronchitis suggest- studies, among patients without preexisting lung ed that symptoms were reduced by a fraction a day disease, daily cough scores and the likelihood of with the use of erythromycin, doxycycline, or tri- persistent cough after 7 days did not differ signifi-methoprim–sulfamethoxazole. The results were cantly between the active treatment and placebo statistically significant but clinically trivial.31 Re- groups. However, in one trial, a subgroup of pa-sults of a randomized, double-blind trial com- tients with evidence of airflow limitation had sig-paring a 5-day course of azithromycin in 112 pa- nificantly lower scores for symptoms on day 2 after tients with vitamin C in 108 patients (total dose of treatment with β -agonists.34 A recent Cochrane each agent, 1.5 g), published after the meta-analy- Review of five trials involving 418 adults showed sis had been completed, showed no difference that even among patients with airflow obstruction, between groups in the health-related quality of the potential benefit of β -agonists is not well life at 7 days (the primary outcome) or in the pro- supported and should be balanced against the ad-portion of patients who returned to work, school, verse effects of treatment.37 In practice, a brief trial or usual activities at home on day 3 or 7.32 (7 days) of inhaled or oral corticosteroids may be A Cochrane Review of nine randomized, con- reasonable for troublesome cough (i.e., cough per- trolled trials of antibiotic agents (including three sisting for more than 20 days), but there are no trials not included in the previous review31) also clinical trial data to support this approach. Data n engl j med 355;20 www.nejm.org november Downloaded from www.nejm.org at HENNEPIN COUNTY MEDICAL CENTER on October 23, 2009 . Copyright 2006 Massachusetts Medical Society. All rights reserved. from clinical trials are also not available to support are only occasionally useful, and there is no rou-the use of mucolytic or antitussive agents.
tine role for inhaled bronchodilators or muco-lytic agents.43 However, these guidelines note that subgroups of patients with chronic airflow ob-struction at baseline or wheezing at the onset of Distinguishing the minority of cases of acute bron- illness do have a benefit from β -agonists. In- chitis due to a treatable cause from those due to haled anticholinergic agents are not recommended. currently nontreatable viruses is often challeng- These guidelines have been criticized on the ing. Recently, the measurement of serum levels of grounds that many of the recommendations were procalcitonin, which is typically elevated in bacte- based “more on opinion than on evidence.” 44rial infections, has been proposed as a means of Both the ACCP guidelines and guidelines of the identifying patients in whom treatment with an- Centers for Disease Control and Prevention (CDC) tibiotics is warranted. In one clinical trial, low lev- recommend macrolides as first-line therapy for els of procalcitonin (<0.1 μg per liter) were used pertussis.25,43 For infection with influenza A virus, to discriminate safely between patients with cough in January 2006 the CDC recommended therapy or dyspnea who did not require antibiotic therapy, with either oseltamivir or zanamivir,21 noting that such as those with acute bronchitis,38 and patients the circulating H3N2 strains of influenza A virus who did require such therapy. However, more data were almost uniformly resistant to both first-gen-are needed to validate the usefulness of the pro- eration drugs (amantadine and rimantadine).
calcitonin test for discriminating between patients with bronchitis and those with pneumonia.
S u m m a r y a n d R e c o m m e n d a t i o n s Although clinicians might argue that the pres- sure of time influences the prescribing of antibi- The patient described in the vignette most likely otics, the data do not support this contention. has a viral infection causing uncomplicated acute A recent study involving almost 4000 adults with bronchitis. On the basis of data from clinical upper respiratory tract infections showed that the trials, antibacterial agents are not recommended. mean duration of an office visit was 14.2 minutes Chest radiography is not indicated, given the ab-when antibiotics were prescribed, as compared sence of signs of pneumonia on physical examina-with 15.2 minutes when no prescription for anti- tion. In the absence of an influenza outbreak in biotics was given.39 the community, no rapid testing for viral causes Previous studies involving volunteers exposed to should be ordered, and no antiviral therapy rhinovirus showed that nonsteroidal drugs alone should be prescribed; influenza is especially un-or in combination with antihistamines reduced the likely in a patient who is afebrile. In the absence severity of symptoms, including cough.40 However, of a history of contact with a person with sus-the effects of either drug alone or their combina- pected pertussis (or a person with a history of tion in naturally occurring acute bronchitis have persistent cough), this diagnosis is unlikely. If not been evaluated. Results of a single randomized paroxysms of cough developed later or if whoop-trial involving 486 adults with acute bronchitis ing or post-tussive vomiting occurred, testing for suggested a clinical benefit of an extract of the pertussis would be reasonable. The patient should roots of Pelargonium sidoides, but the data require be advised that the cough may persist for an ad-confirmation.41 ditional 10 to 21 days and that infrequently, it persists longer. For his wheezing and shortness of breath with activity, clinical experience suggests that a β -agonist such as albuterol may provide According to the 2001 guidelines of the Ameri- relief, although data from clinical trials are incon-can College of Physicians for the treatment of un- sistent. On the basis of clinical experience, the pa-complicated acute bronchitis, antibiotic treatment tient might be offered short-term use of codeine or is “not recommended, regardless of duration of hydrocodone-containing preparations or inhaled cough.” 42 According to the 2006 guidelines of corticosteroids if the cough is persistent, although the American College of Chest Physicians (ACCP) data from trials to support their use are lacking.
for treating acute bronchitis, routine treatment Dr. Wenzel reports receiving consulting fees from Pfizer and Replidyne and research support from Pfizer. No other potential with antibiotics is not justified, antitussive agents conflict of interest relevant to this article was reported.
n engl j med 355;20 www.nejm.org november Downloaded from www.nejm.org at HENNEPIN COUNTY MEDICAL CENTER on October 23, 2009 . Copyright 2006 Massachusetts Medical Society. All rights reserved. Refe renc e s
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