PATHOGENS

CLINICAL

  • Principles: most exacerbations precipitated by viral upper respiratory tract infections in COPD flares but in those with chronic bronchitis up to half of acute exacerbations of chronic bronchitis (AECB) are caused by bacterial infection.
  • Significant AECB flare: need all 3 (see below)
    • Increased sputum production
    • Increased cough
    • Increased dyspnea
  • PE: increased respiratory rate, wheezing, rhonchi, cyanosis +/- fever.

DIAGNOSIS

  • Definitions:
    • Chronic bronchitis: irreversible reduction in maximal airflow velocity and productive cough for most days of the most x 3 months over two consecutive years.
    • AECB: acute event with worsened respiratory symptoms more than usual baseline in cough, sputum and sputum purulence in patient with chronic bronchitis.
      • Increased cough severity/frequency
      • Increased sputum volume and/or change in character
      • Worsened dypnea
  • Obtain chest X-ray to R/O pneumonia, CHF, effusion, mass lesion or pneumothorax.
  • Lab: sputum Gram stain and culture, not advocated routinely for outpatients; consider for inpatient care and especially in severely ill (ICU).
  • Arterial blood gases or pulse oximetry if pt seriously ill.
  • Spirometry: probably not useful for acute management.
  • Severity: include judgment by pulse oximetry, blood gases, FEV-1.

TREATMENT

Antibacterials

  • As heterogeneous reasons for AECB flare, key is supportive care includes bronchodilators (albuterol, ipratropium bromide), corticosteroids, antibiotics (not all) and oxygen (see below).
    • May manage as inpatient or outpatient depending on severity.
  • Abx indications: severe acute exacerbations with increased cough, sputum volume & sputum purulence.
    • Evidence (Cochrane Library reviews) support antibiotic treatment for "severe exacerbations" but not more mild forms.
      • Generally not well established for outpatient care, typically reserved for inpatients.
      • Some use antibiotics in patients with 2 of 3 criteria: increased dyspnea, increased sputum volume, or increased sputum purulence.
      • Antibiotic selection is optimally made based on Gram stain and/or culture, especially for patients with frequent and/or severe exacerbations (e.g., ICU).
    • Most commonly used antibiotics for acute bronchitis is azithromycin followed by amoxicillin and clarithromycin.
  • Preferred: (Note: no antibiotic preferred for mild exacerbations). Target typical respiratory pathogens anticipated and local resistance patterns.
    • Uncomplicated flare, no risk factors: age < 65 yrs, FEV1 > 50% of predicted, < 2 exacerbations/year, no cardiac disease
    • Complicated flare: 1 or more risk factors--age > 65 years, FEV1 < 50% of predicted, ≥ 2 exacerbations/year, cardiac disease
    • Duration: 5-7 days
  • Influenza: efficacy of oseltamivir for ambulatory patients is established and should be given to high patients with COLD even if sx > 48 hrs (CDC recommendation). Check CDC website for latest recommendations: Updated Interim Recommendations for the Use of Antiviral Medications in the Treatment and Prevention of Influenza.
    • Oseltamivir 75mg twice daily x 5 days
    • Avoid zanamivir due to possible exacerbation of wheezing from inhalant powder.
    • Peramivir IV: may consider in critically ill patients, patients unable to take oral agent.

Supportive Care

  • Aspects more important typically than antibiotic selection.
  • Outpatients:
    • Corticosteroids: systemic corticosteroid can improve FEV1 and oxygenation, shorten recovery time and length of hospital stay.
      • Prednisone 30-40 mg/d PO x 5-7d
    • Inhaled bronchodilators: short-acting inhaled beta2-agonists +/- short-acting anti-cholinergic agents recommended during initial phase of acute exacerbation.
      • An example, albuterol 2.5 mg nebs four times a day (may titrate up to q 30min) or 2 puffs four times a day by metered inhaler +/- spacer when stable and/or ipratropium 0.25-0.5mg inhaled q 6h-8h.
  • Hospitalized pts:
    • Corticosteroids: methylprednisolone 125mg IV q 6h x 3d, then PO prednisone 60mg/d x 4-7d, 40mg/d x 8-11d, 20mg/d x 12-15d.
    • O2: use 2-4L/min by nasal cannula; keep pulse oximeter target to 88- 92%. If need increase or pCO2 > 45, use Venturi mask.
      • Risk with higher O2 administration is respiratory failure, so close monitoring recommended if patient is known CO2 retainer.
      • Ventilatory support: if concern for impending respiratory failure, admit to ICU or respiratory care unit.
        • Non-invasive positive-pressure ventilation; requires trained physician.
    • Aminophylline/theophylline: potentially serious side effects and not effective; no longer recommended.
  • Inhaled metered dose steroids: not generally indicated for acute therapy.
  • Not effective: chest PT, methylxanthine bronchodilators (e.g., theophylline), mucolytic agents.
  • Smoking: if active, smoking cessation therapies.
    • Opportune time for such intervention.

Selected Drug Comments

Drug

Recommendation

Amantadine

Old agent for treatment and prevention of influenza A, but now precludes routine use unless circulating strains known to be sensitive.

Amoxicillin

Good activity against most S. pneumoniae, performed well in historical of AECB and cheap. Due to concern of rising resistance (5-10% of S. pneumoniae, 30-40% of H. influenzae and 90-95% of M. catarrhalis) now not frequently except as amoxicillin/clavulanate

Amoxicillin/clavulanate

Expands amoxicillin activity to cover all H. influenzae and M. catarrhalis, usually highly active vs. S. pneumoniae.

Azithromycin

Seems to work better in patients than in the test tube (susceptibility testing). Resistance rates of S. pneumoniae are high, but relevance debated.

Cefaclor

A bad choice, poor activity against S. pneumoniae relative to other oral cephalosporins.

Cefdinir

Active against most strains of S. pneumoniae and all strains of H. influenzae and M. catarrhalis. About as active as amoxicillin vs. S. pneumoniae. Relatively expensive, well tolerated.

Cefpodoxime proxetil

Active against most strains of S. pneumoniae and all strains of H. influenzae and M. catarrhalis. Somewhat less active than amoxicillin vs. S. pneumoniae. Relatively expensive, well tolerated.

Cefprozil

Active against most strains of S. pneumoniae and all strains of H. influenzae and M. catarrhalis. Somewhat less active than amoxicillin vs. S. pneumoniae. Relatively expensive; well tolerated.

Cefuroxime and Cefuroxime axetil

Active against most strains of S. pneumoniae and all strains of H. influenzae and M. catarrhalis. Somewhat less active than amoxicillin vs. S. pneumoniae. Relatively expensive; well tolerated.

Clarithromycin

As active as azithromycin and erythromycin vs. S. pneumoniae; activity vs. H. influenzae is debated due to activity ascribed to a metabolic product, which is greater than that of the parent compound. FDA has approved for H. influenzae pneumonia.

Doxycycline

Risky choice due to low in vitro activities against S. pneumoniae and H. influenzae, but good historic record for AECB, well tolerated and cheap. This is usually a good choice for patients who aren’t very sick.

Moxifloxacin

Active against nearly all treatable pathogens except influenza virus including S. pneumoniae, H. influenzae, M. catarrhalis, most S. aureus (MSSA), most GNB, Chlamydophila pneumoniae and Mycoplasma pneumoniae. The drug is easy to take (once daily) and well tolerated. The major concern is abuse with the consequence of resistance and C. difficile infection.

Rimantadine

No longer useful since most strains now resistant, so need to know current CDC recommendations.

Oseltamivir

Use for the treatment and prophylaxis of influenza virus A and B. Early treatment preferred, should be withing 48 hrs of sx onset -- if possible but use beyond this time frame is justified if severe COLD, severe infection or hospitalized patient. Expensive. Main side effect in GI intolerance and rare cases of self-injury and confusion. See CDC website for latest recommendations.

TMP/SMX

Limited published data but reasonable activity vs. the major pathogen and generally well tolerated except for hypersensitivity reactions to sulfa moiety.

Zanamivir

Newer agent for treatment of influenza A or B. Given by inhalation, aerosolized form may not be suitable for persons with reactive airways. Should be given within 48 hrs of onset of sx if possible, but use later is justified if severe illness or hospitalized patient. Expensive. Main side effect is bronchospasm.

OTHER INFORMATION

  • Common non-bacterial causes of AECB: viral infections, allergens, pollution.
  • Must r/o pneumonia (x-ray), subclinical asthma (PFTs) and respiratory failure (ABG).
  • Antibiotics fall into 3 categories: cheap, old, and proven (TMP/SMX, doxycycline); better activity vs S. pneumoniae and H. influenzae (oral cephalosporins, amoxicillin/clavulanate); drugs w/ clout but concern for abuse and resistance (levofloxacin, moxifloxacin).
  • Main issues: role of H. influenzae and role of newer drugs to reduce hospitalizations and to delay next exacerbation?
    • A placebo-controlled trial in > 1000 patients with chronic bronchitis showed prophylactic azithromycin (250 mg/d) reduced the rate of acute exacerbations by 40%. Note that these recommendations must be interpreted with caution due to the crisis of antibiotic resistance attributed primarily to extensive use of antibiotics. Occasionally considered in patients with frequent AECB as maintenance, but not a first-line current recommendation (GOLD 2017).

Pathogen Specific Therapy

Basis for recommendation

  1. Fiore AE et al: Antiviral agents for the treatment and chemoprophylaxis of influenza --- recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 60:1, 2011  [PMID:21248682]

    Comment: Recommendation is for oseltamivir for patients with risk for severe disease due to influenza regardless of the duration of flu symptoms. this includes patients with COLD.

  2. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. http://www.goldcopd.org (accessed 5/18/17)

    Comment: This group is supported by the NHLBI and WHO, and it’s regularly updated guidance comprises a definition of COPD and chronic bronchitis as well as a basis for recommendations in this module.

References

  1. Han MK et al: Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med 189:1503, 2014  [PMID:24779680]

    Comment: Role of azithromycin for prevention in COPD remains controversial. Authors here suggest that daily use of drug was most helpful in older patients and with GOLD scores of 1 or 2 (milder disease). Use of the drug did seem to prevent flares that required both antibiotic and steroid therapy.

  2. Vollenweider DJ et al: Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 12:, 2012  [PMID:23235687]

    Comment: Review of trials of abx v. placebo RCTs only (2068 pts), found benefit in patient in ICU while those on non-ICU hospitalizations and outpatients were not consistent. Of note, these trials ranged in years from 1957 to 2012. There was no apparent impact on mortality or LOS in hospital for those patients.

  3. Albert RK et al: Azithromycin for prevention of exacerbations of COPD. N Engl J Med 365:689, 2011  [PMID:21864166]

    Comment: This is a randomized controlled trial in 1,142 patients with COPD given placebo vs. azithromycin 250 mg/day. azithromycin recipients had a significant reduction in exacerbations (1.5/year vs. 1.8/year; p=< 0.001) and improved lung function.

  4. Albertson TE, Louie S, Chan AL: The diagnosis and treatment of elderly patients with acute exacerbation of chronic obstructive pulmonary disease and chronic bronchitis. J Am Geriatr Soc 58:570, 2010  [PMID:20398122]

    Comment: Recommended antibiotics for exacerbations of COLD: amoxicillin, ampicillin, pivampicillin, trimethoprim/sulfamethoxazole and doxycycline. "Second line agents:" amoxicillin/clavulanic acid, second and third generation cephalosporins and fluoroquinolones. The latter are described as better versus resistant bacteria but risk driving resistance.

  5. Dimopoulos G et al: Comparison of first-line with second-line antibiotics for acute exacerbations of chronic bronchitis: a metaanalysis of randomized controlled trials. Chest 132:447, 2007  [PMID:17573508]

    Comment: First line agents (ampicillin, TMP-SMX and doxycycline) vs. 2nd line (amox-CA, macrolides, quinolines and 3d gen cephalosporins). First line agents were inferior (RR 0.5).

  6. Mensa J, Trilla A: Should patients with acute exacerbation of chronic bronchitis be treated with antibiotics? Advantages of the use of fluoroquinolones. Clin Microbiol Infect 12 Suppl 3:42, 2006  [PMID:16669928]

    Comment: The authors make a case for fluoroquinolones as preferred antibiotics for exacerbation of COPD because: Purulent sputum is a good indicator of large bacterial load. Fluoroquinolones penetrate mucous well, they are bactericidal and they reduce bacterial load better than beta-lactams or macrolides. (Nevertheless, clinical trials don't show these advantages).

  7. Fernaays MM et al: Differential genome contents of nontypeable Haemophilus influenzae strains from adults with chronic obstructive pulmonary disease. Infect Immun 74:3366, 2006  [PMID:16714566]

    Comment: The authors, noted authorities on COPD, examined genetic differences between 59 H. influenza strains implicated in exacerbations of COPD and 73 that merely colonized the lower airway in these patients. They noted gene patterns that were associated with exacerbations supporting the thesis that these strains have greater pathogenic potential.
    Rating: Important

  8. Wilson R et al: Antibiotic treatment and factors influencing short and long term outcomes of acute exacerbations of chronic bronchitis. Thorax 61:337, 2006  [PMID:16449273]

    Comment: Patients with AECB were randomized to treatment with moxifloxacin or placebo. Clinical cure was significantly associated with antibiotic treatment (OR 1.5) and negatively associated with age >65, and bronchodilator use. The conclusion was that the benefit of moxifloxacin was seen primarily in those >65 yrs.

  9. Chodosh S: Clinical significance of the infection-free interval in the management of acute bacterial exacerbations of chronic bronchitis. Chest 127:2231, 2005  [PMID:15947342]

    Comment: Author discusses a new goal with antibiotics for AECB: delay in the time to the next exacerbation or the infection - free - interval (IFI).

  10. Murphy TF et al: Moraxella catarrhalis in chronic obstructive pulmonary disease: burden of disease and immune response. Am J Respir Crit Care Med 172:195, 2005  [PMID:15805178]

    Comment: The Buffalo group has studied this cohort of 104 pts with COPD for 10 years with monthly sputum cultures. In this study they showed M. catarrhalis was newly detected in 57 of 560 exacerbations. This was accompanied by a serologic response and clearance. They conclude M. catarrhalis causes 10% of exacerbations.

  11. Sethi S et al: Strain-specific immune response to Haemophilus influenzae in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 169:448, 2004  [PMID:14597486]

    Comment: Longitudinal study of patients with COPD showing some exacerbations are associated with an immune response to a newly acquired strain of H. influenzae. (This supports the role of H. flu as a pathogen in exacerbations).

  12. Murphy TF et al: Persistent colonization by Haemophilus influenzae in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 170:266, 2004  [PMID:15117742]

    Comment: Analysis of sequential (monthly) samples of sputum from patients with COPD defined a group with a less than six month lapse with negative cultures for H flu. The subsequently recovered strain was identical to the initial isolate suggesting it was always there and that sputa culture are unreliable sources of this agent.

  13. Sethi S: Bacteria in exacerbations of chronic obstructive pulmonary disease: phenomenon or epiphenomenon? Proc Am Thorac Soc 1:109, 2004  [PMID:16113422]

    Comment: The author reviews methods and conclusions of studies to determine exacerbations of COPD with 2 categories: 1) Conventional: sputum culture, serology & placebo-controlled trial; 2) New: Bronchoscopic sampling, molecular epi of sputum isolates, immune response & markers of airway inflammation. Most exciting are the new methods which include studies showing a new strain of H. influenzae is associated w/some exacerbations & there is an immune response that is strain specific to support its potential role.

  14. Wedzicha JA: Role of viruses in exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc 1:115, 2004  [PMID:16113423]

    Comment: Viruses implicated in 168 cases in 83 patients are: All viruses - 66 (40%), Rhinovirus - 59% (of the 66), RSV - 29%, Coronavirus -11%, influenza - 16%.

  15. Seemungal T et al: Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 164:1618, 2001  [PMID:11719299]

    Comment: Study of 168 exacerbations - viruses found in 67 (40%) - most common were rhinovirus and RSV.

  16. Nouira S et al: Once daily oral ofloxacin in chronic obstructive pulmonary disease exacerbation requiring mechanical ventilation: a randomised placebo-controlled trial. Lancet 358:2020, 2001  [PMID:11755608]

    Comment: Results showed a benefit of ofloxacin with mortality decrease (4% vs 22%) & reduced duration hospitalization & mechanical ventilation. The study raised concerns about ethics of a placebo control with such seriously ill pts, but the accompanying editorial notes that the benefit of antibiotics had never been clearly shown.
    Rating: Important

  17. Snow V et al: Evidence base for management of acute exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 134:595, 2001  [PMID:11281744]

    Comment: Position paper of ACP for managing exacerbations of chronic bronchitis. Indications to Rx: Increased dyspnea, increased cough AND increased sputum purulence. Agents recommended: Amoxicillin, doxycycline, TMP-SMX.

  18. Gonzales R, Steiner JF, Sande MA: Antibiotic prescribing for adults with colds, upper respiratory tract infections, and bronchitis by ambulatory care physicians. JAMA 278:901, 1997  [PMID:9302241]

    Comment: This review of antibiotic prescribing patterns shows that exacerbations of chronic bronchitis account for 5-10% OF ALL ANTIBIOTIC SCRIPTS in the U.S. This is a big market.

  19. Emerman CL, Cydulka RK: Use of peak expiratory flow rate in emergency department evaluation of acute exacerbation of chronic obstructive pulmonary disease. Ann Emerg Med 27:159, 1996  [PMID:8629745]

    Comment: The authors show the ADVANTAGES OF MEASURING FEV-1 AND/OR PEFR for baseline evaluation and response to treatment. Both require patient effort

  20. Emerman CL, Lukens TW, Effron D: Physician estimation of FEV1 in acute exacerbation of COPD. Chest 105:1709, 1994  [PMID:7911418]

    Comment: The authors show PHYSICIAN ESTIMATES OF THE SEVERITY OF AIRWAY OBSTRUCTION in exacerbations of COPD correlate poorly with FEV-1 measurements

  21. Jørgensen AF et al: Amoxicillin in treatment of acute uncomplicated exacerbations of chronic bronchitis. A double-blind, placebo-controlled multicentre study in general practice. Scand J Prim Health Care 10:7, 1992  [PMID:1589668]

    Comment: One of many controlled trials of amoxicillin vs. placebo, this one with 262 outpatients with AECB. Analysis by symptom score and peak expiratory flow rate showed NO ADVANTAGE FOR ANTIBIOTICS.

  22. Wiedemann HP, McCarthy K: Noninvasive monitoring of oxygen and carbon dioxide. Clin Chest Med 10:239, 1989  [PMID:2661121]

    Comment: The data support use OF PULSE OXIMETRY to evaluate oxygenation except when O2 saturation is < 70%

  23. Anthonisen NR et al: Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med 106:196, 1987  [PMID:3492164]

    Comment: There are many trials of antibiotics, but this is THE BEST AND MOST QUOTED TRIAL. Anthonisen et al, studied 362 exacerbations and showed that antibiotics have a significant benefit, but only when the exacerbation is relatively severe with at least 2 of the major 3 symptoms--increased cough, sputum, and sputum purulence. Clinical success was noted in this group for 75% of antibiotic recipients vs. 63% of placebo recipients. This is close, but the number of patients was sufficiently high to push it over the p=0.05 threshold for statistical significance.
    Rating: Important

  24. Gump DW et al: Role of infection in chronic bronchitis. Am Rev Respir Dis 113:465, 1976  [PMID:1267252]

    Comment: One of the MOST COMPREHENSIVE STUDIES EVER DONE. Authors followed a group of pts with chronic bronchitis & obtained quantitative bacterial cultures of sputum & viral cx at 2-week intervals. They showed that exacerbations of bronchitis were often due to viral infection (positive cultures in 32% of exacerbations vs. <1% in periods of stability), sputum bacterial culture showed no significant changes in either frequency of recovery or counts of the big 2--H. flu & S. pneumo). S. pneumo was recovered in 37% of exacerbations & in 33% of control periods; for H. flu, it was 57% & 60%, respectively

  25. Bjerkestrand G, Digranes A, Schreiner A: Bacteriological findings in transtracheal aspirates from patients with chronic bronchitis and bronchiectasis: a preliminary report. Scand J Respir Dis 56:201, 1975  [PMID:1198085]

    Comment: The tracheobronchial tree below the larynx is normally sterile. This study using transtracheal aspirations shows that about one-third of patients with chronic bronchitis have COLONIZATION OF THE LOWER AIRWAYS by the same bacteria implicated as the major causes of AECB--H influenzae and S. pneumoniae. This presumably accounts for the common observation that sputum cultures show the same bacteria during stability and during exacerbations.

  26. Pines A et al: Antibiotic regimens in severe and acute purulent exacerbations of chronic bronchitis. Br Med J 2:735, 1968  [PMID:4872151]

    Comment: One of many controlled trials of tetracycline vs. placebo in 149 patients hospitalized for AECB. There was SIGNIFICANT BENEFIT FOR TETRACYCLINE TREATMENT in terms of symptom scores and peak expiratory flow rate.

  27. Saint S et al: Antibiotics in chronic obstructive pulmonary disease exacerbations. A meta-analysis. JAMA 273:957, 1995 Mar 22-29  [PMID:7884956]

    Comment: A META-ANALYSIS OF ANTIBIOTIC TRIALS, which shows a slight advantage to these drugs compared to placebo. The benefit was measured in duration of symptoms and in peak expiratory flow rates, but the advantage of antibiotics was tiny and was statistically significant only because the numbers were large.
    Rating: Important

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Last updated: June 3, 2017

Citation

TY - ELEC T1 - Chronic Bronchitis, Acute Exacerbations ID - 540124 A1 - Auwaerter,Paul,M.D. AU - Bartlett,John,M.D. Y1 - 2017/06/03/ PB - Johns Hopkins ABX Guide UR - https://www.unboundmedicine.com/medline/view/Johns_Hopkins_ABX_Guide/540124/all/Chronic_Bronchitis__Acute_Exacerbations ER -