Exacerbations of Chronic Obstructive Pulmonary Disease (COPD)

Paul G. Auwaerter, M.D.

PATHOGENS

Not all flares are infectious.

Haemophilus influenzae
Streptococcus pneumoniae
Moraxella catarrhalis
Viruses: influenza, SARS-CoV-2, rhinovirus, parainfluenza, RSV and others
Additional offenders: allergens, smoking, toxic fumes, etc.

CLINICAL

Definition: acute exacerbation of chronic obstructive pulmonary disease is an acute worsening of respiratory symptoms that demand additional therapy.
- Note: symptoms are not specific, develop a differential diagnosis.
  - Most common cause = respiratory infections (viral > bacterial or environmental factors)
- Exacerbations result in increased inflammation within the airways and mucous and more gas trapping.
  - Patients with frequent exacerbations (> 2 per year) have greater morbidity and worse health status.
Principles: Most exacerbations in COPD flares are precipitated by viral upper respiratory tract infections, but in those with chronic bronchitis, up to half of the acute exacerbations of chronic bronchitis (AECB) are caused by a bacterial infection.
- Many with increased or new purulent sputum production.
- Dominant pathogens in expectorated sputum: S. pneumoniae, H. influenzae, H. parainfluenzae and M. catarrhalis.
  - P. aeruginosa and resistant Gram-negative bacteria: associated with severe exacerbations.
Exacerbations of COPD classifications:
- Mild: treated with short-acting bronchodilators (SABDs), only
- Moderate: SABD + antibiotics +/- oral corticosteroids
- Severe: requires hospitalization or ED visit, includes respiratory failure
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:
- Exacerbation of COPD: see above.
- Chronic bronchitis: irreversible reduction in maximal airflow velocity and productive cough for most days of the month x 3 months over 2 consecutive years.
- AECB: an acute event with worsened respiratory symptoms more than usual baseline in cough, sputum, and sputum purulence in patients with chronic bronchitis.
  - Increased cough severity/frequency
  - Increased sputum volume and/or change in character
  - Worsened dyspnea
DDx: pneumonia, pneumothorax, pleural effusion, PE, CHF, cardiac arrhythmia.
Imaging:
- Obtain chest X-ray or chest CT 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 the patient is seriously ill.
Spirometry: probably not useful for acute management.
Severity: includes judgment by pulse oximetry, blood gases, and FEV-1.

TREATMENT

Supportive Care

These aspects are more important than antibiotic selection. Guidance per GOLD 2024[1].
- See the GOLD report for chronic management, including smoking cessation, etc.
Determine the need for ED evaluation or hospitalization.
- >80% of exacerbations may be handled on an outpatient basis.
- Reasons for hospital assessment:
  - Severe symptoms, e.g., worsened resting dyspnea, tachypnea, cyanosis, peripheral edema, failure to respond to existing medical therapy, comorbidities (CHF, arrhythmia), inadequate home support.
Assess the severity of symptoms: CXR, blood gases
- Supplemental oxygen as determined by oxygenation or ABG assessments.
- Consider oral corticosteroids, the need for noninvasive mechanical ventilation, IV fluids, and DVT/PE prevention. Also, determine if associated conditions are contributing, e.g., PE or CHF.
Mangement of Exacerbations:
- Short-acting inhaled beta₂-agonists +/- short-acting anticholinergics are recommended for the initial flare treatment.
- O₂: use 2-4L/min by nasal cannula; keep pulse oximeter target to 88- 92%. If need increase or pCO₂ > 45, use a Venturi mask.
  - The risk with higher O₂ administration is respiratory failure, so close monitoring is recommended if the patient is known to have a CO₂ retainer.
  - Ventilatory support: if concern for impending respiratory failure, admit to ICU or respiratory care unit.
    - Non-invasive positive-pressure ventilation requires a trained physician
- If not responding, consider systemic corticosteroids as they yield improvements in FEV₁, oxygenation and shorter LOS.
  - Prednisone 40 mg PO daily (no taper)
  - Duration: 5 days (maximum)
  - As effective as intravenous corticosteroids.
- Non-invasive mechanical ventilation should be first considered in flares of COPD who otherwise do not have a contraindication.
  - This approach lessens the need for intubation, hospital LOS and better survival.
- Monitor:
  - Fluid balance
  - Consider DVT prophylaxis
- Not recommended: methylxanthines (e.g., theophylline or aminophylline), chest PT, and mucolytic agents.
Smoking: if active, smoking cessation therapies.
- Opportune time for such intervention.

Antibacterials

There are heterogeneous reasons for AECB flare, but the key is that supportive care includes bronchodilators (albuterol, ipratropium bromide), corticosteroids, antibiotics (not all), and oxygen (see below).
- Patients may be managed as inpatient or outpatient, depending on severity.
When indicated, abx shortens the time needed for recovery, reduces relapse/treatment failure and shortens hospital length of stay (LOS).
- Abx appears to reduce short-term mortality by 77% and treatment failure by 53% per systematic review of patients with moderate or severe exacerbations (typically inpatients rather than outpatients)[9].
  - However, there is abundant conflicting data due to studies not always differentiating between acute and chronic bronchitis and COPD exacerbations or lack of chest imaging or placebo controls.
  - Key points:
    - Obtain respiratory viral panel (influenza or SARS-CoV-2, especially as treatable).
    - Consider antibiotic therapy if there is increased sputum purulence as a potential indicator of bacterial infection.
      - The presence of green or yellow sputum has a higher likelihood of indicating the presence of potentially pathogenic respiratory bacteria[3].
- Duration of antibiotic treatment: 5-day maximum
Abx indications: severe acute exacerbations with increased cough, sputum volume, and purulence.
- Studies support the use of procalcitonin to initiate abx, limiting the unneeded use of antibiotics[2].
- Antibiotic selection is optimally based on Gram stain and culture, especially for patients with frequent or severe exacerbations (e.g., ICU), to help determine if resistant organisms exist.
  - Local antibiograms should guide the choice for hospitalized patients.
Antibacterial therapy: (Note: no antibiotic use is 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. Choices may include (in alphabetical order, no preference expressed)/
  - Azithromycin 500mg, then 250mg PO once-daily x 4d (Z-pak)
  - Amoxicillin/clavulanate 875 mg PO twice daily
  - Clarithromycin 500mg PO twice daily or clarithromycin XR 1g PO once daily
  - Cefuroxime axetil 500mg PO twice daily
  - Doxycycline 100mg PO twice daily
  - Duration: 5-7 days
- Complicated flare: 1 or more risk factors--age > 65 years, FEV₁ < 50% of predicted, ≥ 2 exacerbations/year, cardiac disease. Consider sputum analysis to help guide therapeutic choice.
  - Moxifloxacin 400 mg IV/PO daily
  - Levofloxacin 500 mg IV/PO daily
- Pseudomonas or resistant Gram-negative risk factors, ICU admission: use antipseudomonal agents (e.g., ciprofloxacin, levofloxacin, piperacillin/tazobactamor cefepime)
  - Examples of patients to consider:
    - Severe COPD
    - History of Pseudomonas in sputum
    - Significant bronchiectasis
    - Frequent antibiotics courses
    - Multiple recent hospital admissions
    - Systemic glucocorticoid use
  - Obtain sputum for Gram stain and culture.
- Duration: 5-7 days
Viral Ilnness:
- If a viral infection is diagnosed, influenza or SARS-CoV-2 should be considered for treatment if the patient is hospitalized or at home.
  - See modules for details.

Selected Drug Comments

Drug	Recommendation
Amantadine	An old agent for treating and preventing influenza A, it now precludes routine use unless circulating strains are known to be sensitive.
Amoxicillin	Good activity against most S. pneumoniae performed well in the history of AECB and cheap. Due to concern about rising resistance (5-10% of S. pneumoniae, 30-40% of H. influenzae and 90-95% of M. catarrhalis), it is now not frequently employed except as amoxicillin/clavulanate.
Amoxicillin/clavulanate	Expands amoxicillin activity to cover all H. influenzae and M. catarrhalis, usually highly active vs. S. pneumoniae.
Azithromycin	It works better in patients than in the test tube (susceptibility testing). S. pneumoniae resistance rates are high, but their relevance is debated. AECB exacerbations can be treated with azithromycin, not only preferentially in smokers. However, there is an increased incidence of bacterial resistance emergence and hearing test impairments. There is also solid evidence that long-term azithromycin reduces exacerbations over one year.
Baloxivir	Single-dose drug for influenza based on the half-life of up to 91 hours. It has an FDA indication for the treatment of influenza in patients at high risk for complications and also appears to work better against influenza B than oseltamivir. It also causes less nausea or vomiting than oseltamivir. As an end-cap endonuclease inhibitor, it depresses viral shedding faster than oseltamivir.
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 but would not rely on it for severe infection.
Doxycycline	The drug has lower in vitro activities against S. pneumoniae and H. influenzae, but it has a good historical record for AECB, is well-tolerated and is 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 primary concern is abuse with the consequence of resistance and C. difficile infection. Tendon rupture is possible even with short courses, especially if patients are frequently taking systemic corticosteroids or have ESRD.
Rimantadine	It is no longer helpful since most strains are now resistant, so need to know current CDC recommendations.
Oseltamivir	Use for the treatment and prophylaxis of influenza viruses A and B. Early treatment is preferred, and it should be within 48 hours of sx onset if possible. However, use beyond this time frame is justified if the patient has a severe COLD or severe infection or is hospitalized. It is expensive. The main side effects are GI intolerance and rare cases of self-injury and confusion. See the CDC website for the latest recommendations.
TMP/SMX	Limited published data, reasonable activity vs. the major pathogen, and generally well tolerated except for hypersensitivity reactions to a sulfa moiety.
Zanamivir	Neuraminidase inhibitor (NAI) for the treatment of influenza A or B. Given by inhalation, the aerosolized form is contraindicated for persons with reactive airways and, therefore, not used in patients with COPD.

OTHER INFORMATION

Common non-bacterial causes of AECB are viral infections, allergens, and pollution.
Must r/o pneumonia (x-ray), subclinical asthma (PFTs) and respiratory failure (ABG).
Antibiotics fall into three 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: What is the role of H. influenzae and newer drugs in reducing hospitalizations and delaying the next exacerbation?
Long-term use of azithromycin or erythromycin: for those prone to exacerbations
- A placebo-controlled trial in more than 1,000 patients with chronic bronchitis showed that 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 the extensive use of antibiotics. Either azithromycin or erythromycin daily may be considered as maintenance in patients with frequent AECB.
  - Two other antibiotics had no similar effect overall, although there may be responder subgroups.
    - Moxifloxacin at 400 mg PO for 5d q 8 weeks
    - Doxycycline 100 mg PO daily
- Consider:
  - Azithromycin 250 mg PO daily or 500 mg three times per week
    - Use was associated with increased rates of bacterial resistance, prolonged QTc and impaired hearing tests.
    - No data yet exists to demonstrate benefit with > 1 year of use.
  - Erythromycin 250 mg PO twice daily

Basis for recommendation

Global Initiative for Chronic Obstructive Lund Disease (2024 Report). https://goldcopd.org/wp-content/uploads/2024/02/GOLD-2024_v1.2-11Jan24_WMV... (accessed 5/28/2024) p 80 with pharmacotherapies beyond abx 68-79 and 81; 106-108, 113
Comment: The GOLD report has been revised annually since 2011. You may go to https://goldcopd.org/ for updates to this report. Includes definitions and comprehensive treatment recommendations. Antibiotic recommendations are incorporated into the ABX module. For the overall management beyond abx, please launch and view the document for AECB.

References

Hoult G, Gillespie D, Wilkinson TMA, et al. Biomarkers to guide the use of antibiotics for acute exacerbations of COPD (AECOPD): a systematic review and meta-analysis. BMC Pulm Med. 2022;22(1):194. [PMID:35549921]
Comment: Procalcitonin appears to have the best performance (compared to CRP and others) in finding bacterial pathogens present in sputum. However, this analysis did not explore the outcomes further.
Chen K, Pleasants KA, Pleasants RA, et al. A Systematic Review and Meta-Analysis of Sputum Purulence to Predict Bacterial Infection in COPD Exacerbations. COPD. 2020;17(3):311-317. [PMID:32456479]
Comment: Since GOLD emphasizes sputum purulence for consideration of antibiotics, this group looked at six studies, all observational. Hence, the data quality is not high, and ID clinicians have long known that viral infections can cause purulence. Based on these data, it seems that there is moderate evidence to suggest that in those with AECB/COPD exacerbations, yellow or green sputum has a higher probability of likely pathogenic bacteria.
Huckle AW, Fairclough LC, Todd I. Prophylactic Antibiotic Use in COPD and the Potential Anti-Inflammatory Activities of Antibiotics. Respir Care. 2018;63(5):609-619. [PMID:29463692]
Comment: Like bronchiectasis studies, authors examine whether certain drugs (primarily macrolides) have some effect beyond anti-infective properties. Twelve trials w/ 3784 patients reviewed. The authors thought the studies with azithromycin or erythromycin had the most significant impact with improvement on clinical bases.
Vollenweider DJ, Frei A, Steurer-Stey CA, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2018;10:CD010257. [PMID:30371937]
Comment: A systematic review suggests that effects are small and inconsistent for both inpatients and outpatients. The effect of abx is best among ICU patients. Data quality is heterogeneous and limited.
Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014;189(12):1503-8. [PMID:24779680]
Comment: The role of azithromycin in the prevention of COPD remains controversial. The authors suggest that daily drug use was helpful in older patients with GOLD scores of 1 or 2 (milder disease). The drug did seem to prevent flares that required both antibiotic and steroid therapy.
Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-98. [PMID:21864166]
Comment: This randomized controlled trial in 1,142 patients with COPD given a placebo vs. azithromycin 250 mg/day. azithromycin recipients significantly reduced exacerbations (1.5/year vs. 1.8/year; p=< 0.001) and improved lung function.
Fernaays MM, Lesse AJ, Sethi S, et al. Differential genome contents of nontypeable Haemophilus influenzae strains from adults with chronic obstructive pulmonary disease. Infect Immun. 2006;74(6):3366-74. [PMID:16714566]
Comment: The authors noted authorities on COPD and 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 associated with exacerbations, supporting the thesis that these strains have greater pathogenic potential.
Rating: Important
Ram FS, Rodriguez-Roisin R, Granados-Navarrete A, et al. Antibiotics for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2006. [PMID:16625602]
Comment: This systematic review examines placebo-controlled studies not now frequently pursued by pharma (2020). These studies show that antibiotics reduce the risk of short-term mortality by 77%, treatment failure by 53% and sputum purulence by 44% if received. This supportive evidence applies to moderately or severely ill patients with COPD exacerbations and increased cough and sputum purulence with antibiotics.
Wilson R, Jones P, Schaberg T, et al. Antibiotic treatment and factors influencing short and long term outcomes of acute exacerbations of chronic bronchitis. Thorax. 2006;61(4):337-42. [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.
Murphy TF, Brauer AL, Grant BJ, et al. Moraxella catarrhalis in chronic obstructive pulmonary disease: burden of disease and immune response. Am J Respir Crit Care Med. 2005;172(2):195-9. [PMID:15805178]
Comment: The Buffalo group has studied this cohort of 104 patients with COPD for 10 years with monthly sputum cultures. In this study, they showed that M. catarrhalis was newly detected in 57 of 560 exacerbations. This was accompanied by a serologic response and clearance. They conclude that M. catarrhalis causes 10% of exacerbations.
Sethi S, Wrona C, Grant BJ, et al. Strain-specific immune response to Haemophilus influenzae in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2004;169(4):448-53. [PMID:14597486]
Comment: A longitudinal study of patients with COPD shows 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). It appears that acquiring a new strain plays a role even if it is colonized.
Murphy TF, Brauer AL, Schiffmacher AT, et al. Persistent colonization by Haemophilus influenzae in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2004;170(3):266-72. [PMID:15117742]
Comment: Analysis of sequential (monthly) sputum samples 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 cultures were an unreliable source of this agent.
Wedzicha JA. Role of viruses in exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2004;1(2):115-20. [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%.
Sethi S. Bacteria in exacerbations of chronic obstructive pulmonary disease: phenomenon or epiphenomenon? Proc Am Thorac Soc. 2004;1(2):109-14. [PMID:16113422]
Comment: The author reviews methods and conclusions of studies to determine exacerbations of COPD with two 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 with w/some exacerbations & there is an immune response that is strain-specific to support its potential role.
Nouira S, Marghli S, Belghith M, et al. Once daily oral ofloxacin in chronic obstructive pulmonary disease exacerbation requiring mechanical ventilation: a randomised placebo-controlled trial. Lancet. 2001;358(9298):2020-5. [PMID:11755608]
Comment: Results showed a benefit of ofloxacin, with a mortality decrease (4% vs 22%), reduced duration of hospitalization, and mechanical ventilation. The study raised concerns about the ethics of a placebo control with such seriously ill patients, but the accompanying editorial notes that the benefit of antibiotics had never been clearly shown.
Rating: Important
Emerman CL, Lukens TW, Effron D. Physician estimation of FEV1 in acute exacerbation of COPD. Chest. 1994;105(6):1709-12. [PMID:7911418]
Comment: The authors show PHYSICIAN ESTIMATES OF THE SEVERITY OF AIRWAY OBSTRUCTION in exacerbations of COPD correlate poorly with FEV-1 measurements.
Jørgensen AF, Coolidge J, Pedersen PA, 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. 1992;10(1):7-11. [PMID:1589668]
Comment: This was 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.
Anthonisen NR, Manfreda J, Warren CP, et al. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. 1987;106(2):196-204. [PMID:3492164]
Comment: There have been 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
Gump DW, Phillips CA, Forsyth BR, et al. Role of infection in chronic bronchitis. Am Rev Respir Dis. 1976;113(4):465-74. [PMID:1267252]
Comment: It is one of the MOST COMPREHENSIVE STUDIES EVER DONE by culture techniques. The authors followed a group of pts with chronic bronchitis & obtained quantitative bacterial cultures of sputum & viral cx at 2-week intervals. They showed that bronchitis exacerbations 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. pneumoniae). S. pneumoniae was recovered in 37% of exacerbations & 33% of control periods; for H. flu, it was 57% & 60%, respectively. The study was done when a more significant portion of the population were smokers.
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. 1975;56(4):201-7. [PMID:1198085]
Comment: The tracheobronchial tree below the larynx is usually sterile. This transtracheal aspirations study 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 exacerbations.
Pines A, Raafat H, Plucinski K, et al. Antibiotic regimens in severe and acute purulent exacerbations of chronic bronchitis. Br Med J. 1968;2(5607):735-8. [PMID:4872151]
Comment: One of the many controlled trials of tetracycline vs. placebo in 149 patients hospitalized for AECB. There was a SIGNIFICANT BENEFIT FOR TETRACYCLINE TREATMENT regarding symptom scores and peak expiratory flow rate.

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