Acute exacerbation of chronic obstructive pulmonary disease - Prevention

Primary prevention

Given the detrimental impact of COPD exacerbations on the patient, every effort should be made to prevent their occurrence. Previous exacerbation history is a key risk factor for future exacerbations.[1][54] People with a high burden of symptoms and history of frequent exacerbations (Global Initiative for Chronic Obstructive Lung Disease [GOLD] group D) are at particular risk of future exacerbations and mortality.[1][78] However, multiple factors impact the risk of subsequent exacerbations and relevant factors vary among individual patients. Following COPD exacerbation, every effort should be made to both identify and intervene in potentially modifiable factors to reduce risk of subsequent exacerbation events.

Trigger avoidance, smoking cessation, and immunization

Avoiding smoke and smoking cessation are the best measures not only to prevent the onset of COPD but also to prevent progression of the severity of COPD.[79][80] Smoking cessation can also reduce risk of exacerbations,[81] and smoking cessation counseling and treatment is recommended for people with COPD.[82] Patients should also be advised to avoid other potential triggers such as airborne pollutants. More severe COPD is associated with both more frequent and more severe exacerbations.[54][83] There is evidence that influenza vaccination is effective in preventing complications of COPD,[84][85][86] particularly among people with severe airflow obstruction.[87] Yearly influenza vaccine is recommended for adults with COPD.[82] The benefits of pneumococcal vaccination in reducing overall morbidity from COPD (including exacerbations) is less clear,[82][88] but the vaccine does reduce the risk of pneumococcal pneumonia.[87] An updated Cochrane review concluded that pneumococcal vaccination in people with COPD reduced the chance of an acute exacerbation and provided some protection against community-acquired pneumonia.[89] Pneumococcal vaccinations, PCV13 (13-valent conjugated pneumococcal vaccine) and PPSV23 (23-valent pneumococcal polysaccharide vaccine), are recommended for all patients over 65 years of age. The PPSV23 is also recommended for younger patients with COPD who have comorbidities such as chronic heart or lung disease.[1][82] The indications and benefits of vaccination against influenza virus, and Streptococcus pneumoniae, should be discussed with the patient.[84][85][90]

Pharmacotherapy

Once the patient has stabilized following treatment for an exacerbation, the patient’s maintenance medications should be reviewed and consideration should be given to adjusting the medications following exacerbations, with the goal of reducing the risk and/or severity of future episodes,[82] and use of medications according to evidence-based guidelines.[1] The use of long-acting beta-2 agonists and long-acting anticholinergic medications has been associated with a decreased frequency of exacerbations.[91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107] The long-acting anticholinergic agent tiotropium bromide may be more effective than the long-acting beta-2-agonist salmeterol in preventing exacerbations,[108] particularly among people with moderate-severity airflow obstruction.[109] The novel Respimat mist delivery system for tiotropium must, however, be used with caution, given that its use has been associated with a higher mortality rate.[110] The once-daily long-acting inhaled beta-2 agonist indacaterol is also effective in improving health status and reducing symptoms and exacerbations in COPD.[111][112][113] Another once-daily beta-2-agonist, olodaterol, has been approved for use in some countries, including the US.[114] Aclidinium bromide, a novel long-acting muscarinic antagonist, is also an effective bronchodilator that improves lung function, reduces symptoms, and reduces severe exacerbations requiring hospitalization.[115][116][117] Neither class of agent poses substantial increased risk of adverse cardiovascular events.[105] Combination dual-class bronchodilator therapy confers greater benefits on lung function than either individual class (long-acting beta-2-agonist or long-acting anticholinergic) alone.[118] However, it remains unclear whether a combination of dual-class bronchodilator therapy is more effective than long-acting antimuscarinic agents alone for reducing exacerbations.[119] [ ] Novel combinations of a long-acting beta-2 agonist with a long-acting muscarinic antagonist (i.e., vilanterol/umeclidinium)[120][121] are currently under investigation, but their efficacy in reducing the frequency and/or severity of exacerbations is as yet unknown.[122] Inhaled corticosteroids have been shown to decrease the frequency of exacerbations and decrease healthcare utilization for respiratory illnesses.[123][124][125][126][127] Inhaled corticosteroids should not be used as monotherapy in COPD; their use should be considered as additional therapy for people with exacerbations not controlled with long-acting bronchodilators alone.[1]
The combination of inhaled corticosteroids and long-acting beta-2 agonists appears more effective than either agent alone to decrease the frequency of episodes in people with more severe COPD.[92][128][129] In patients with moderate to severe COPD, treatment with salmeterol plus fluticasone propionate reduces the rate of exacerbations and slows the progressive worsening of FEV1.[130][131][132] Importantly, withdrawal of the inhaled corticosteroid component of combination therapy led to deterioration in lung function and worsened symptoms among patients who had two or more exacerbations in the previous year.[133] A subsequent large parallel group study among patients with severe COPD and history of previous exacerbation showed similar risk of moderate or severe exacerbation among people who withdrew the inhaled corticosteroid from triple combination treatment gradually over a 12-week period, compared with controls who did not; inhaled corticosteroid withdrawal was, however, associated with a greater reduction in trough FEV1 at 18 weeks of follow-up.[134] Also, an increased risk of pneumonia has been reported following long-term use of inhaled corticosteroids and inhaled corticosteroid/beta-2 agonist combination therapy.[92][135][136][137][138][139] This increased risk of pneumonia is not accompanied by a clear increase in mortality risk.[139] Currently, there are limited but encouraging data on the concurrent use of inhaled corticosteroids, long-acting beta-2 agonists, and long-acting anticholinergic medications.[97][125][140][141][142][143][144][145][146] While long-acting beta-2 agonists, anticholinergics, and inhaled corticosteroids are all helpful, the optimal choice of medications to reduce exacerbations while minimizing potential adverse events remains somewhat uncertain,[135][147][148] and the impact of triple-class therapy as compared with dual-agent combination therapy or anticholinergic therapy alone on long-term outcomes such as mortality or hospitalizations is as yet unclear.[146][149] Novel combination therapies including fluticasone/vilanterol and indacaterol/glycopyrronium bromide are emerging, and their impact on exacerbations of COPD is currently being studied.
Treatment of patients with intermittent doses of macrolide,[150][151] the fluoroquinolone moxifloxacin,[152][153] phosphodiesterase inhibitors[154][155] such as roflumilast, or statins[156][157][158] can also decrease the frequency, severity, and/or duration of COPD exacerbations. The short-term use of prophylactic antibiotics can reduce the rate and number of exacerbations of COPD or chronic bronchitis,[159] and preventative treatment with macrolides can lead to healthcare cost savings.[151] Daily azithromycin therapy was most effective in reducing exacerbations requiring both antibiotic and steroid treatment, and risk reduction was greatest among people of older age and milder GOLD grade; notably, no significant reduction of exacerbation risk was found among current smokers.[160] The impact of long-term use of intermittent (e.g., three-times weekly) macrolides or other prophylactic antibiotics on the development of antibiotic-resistant pathogens and related COPD exacerbations is as yet unknown but is of potential concern. Phosphodiesterase-4 (PDE4) inhibitor therapy is commonly associated with gastrointestinal upset, abdominal pain, weight loss, and other side effects; individual patient tolerance of these agents varies. Importantly, existing studies suggest that the PDE4 inhibitor roflumilast reduced exacerbations among patients with severe airflow obstruction with clinical features of chronic bronchitis (including sputum production and cough), but not among those with a predominance of emphysema without chronic bronchitis features.[161][162]
Oral mucolytics such as N-acetylcysteine may offer benefit in exacerbation reduction, particularly among people with moderate to severe COPD and or history of two or more exacerbations in the previous 2 years, but their role remains controversial.[82][163][164]
Alpha-1-antitrypsin augmentation therapy may reduce the frequency of exacerbations for selected people with documented alpha-1-antitrypsin deficiency as the etiology of their COPD.[165]
Beta-blockers are often withheld from patients with COPD due to concerns regarding precipitation of exacerbations and bronchospasm. However, cardiovascular disease is a common comorbidity of COPD, and many patients have cardiovascular indications for beta-blocker therapy. Current data suggest that cardioselective beta-blockers are not only safe and effective in patients with COPD, but may reduce exacerbation risk and mortality.[166][167] Therefore, beta-blockers should not be withheld from patients with COPD who have cardiovascular indications for their use.
Some data suggest that an oral Haemophilus influenzae vaccine may help reduce recurrent exacerbations of chronic bronchitis in selected patients;[168] however, one Cochrane review analysis demonstrated that oral H influenzae vaccine did not significantly reduce the number or severity of exacerbations.[169]
Oral Haemophilus vaccines are not formally recommended in existing guidelines.[30] Prophylactic antibiotics to prevent exacerbations are also not recommended.
Although retrospective studies suggested that statins might decrease the rate and severity of exacerbations, one large prospective randomized controlled trial of simvastatin versus placebo did not show a reduction in exacerbation rates or time to first exacerbation among people with history of COPD exacerbation requiring emergency department visit or hospitalization in the year prior to study enrollment.[170]

Secondary prevention

Pulmonary rehabilitation and disease-management programs

Patients nonadherent with their medication regimens may develop worsening of signs and symptoms associated with COPD. It is important to discuss and determine adherence with medications in patients presenting with acute exacerbations.[303] Failure to adhere to prescribed medications may be associated with increased healthcare costs.[304] Moreover, healthcare providers do not always adhere to existing guidelines for management of stable COPD or acute COPD exacerbations.[305] This, in turn, may impact COPD exacerbation outcomes.
Also, patients with COPD are less physically active than healthy adults and low physical activity levels are associated with a faster rate of decline in lung function and increased hospitalizations for COPD exacerbations over time.[296][306][307] Pulmonary rehabilitation programs provide exercise reconditioning and education focused on health-enhancing behaviors that can improve patients’ physical activity levels and knowledge regarding management of their disease.[233][308] As such, patients’ participation in pulmonary rehabilitation programs can play an important role in prevention of subsequent exacerbations,[296][303][309] particularly when undertaken within a month following an exacerbation.[82][241]
Outpatient follow-up of patients within 30 days of hospital discharge following acute exacerbations also helps prevent readmissions and relapse of disease.[300] Action plans can help patients recognize worsening symptoms, initiate earlier treatment, and reduce overall impact of exacerbations.[82][310] [ ] Enrollment of patients in disease-management and integrated care programs can also be effective in reducing emergency visits and/or hospitalizations for COPD exacerbations.[232][274][275] However, their use remains somewhat controversial given that some trials have not shown any increase in time to hospital readmission,[311] and one randomized controlled trial had to be stopped early due to a noted increase in mortality in the patient group randomized to comprehensive care management compared with the control group receiving guideline-based routine clinical care.[87][277] Self-management programs offered immediately after acute exacerbations are associated with positive effects on patients’ knowledge, but based on existing evidence it is not possible to draw firm conclusions regarding their efficacy for other outcomes.[312] Education with case management that includes direct access to a healthcare specialist at least monthly is recommended by evidence-based guidelines for patients with previous or recent exacerbations to reduce subsequent severe exacerbations requiring hospitalization.[82] The benefits of disease management programs likely vary depending on program content and structure, the healthcare system in which they are implemented, and the patient population being studied. The role of hospital-at-home programs in the management of COPD exacerbations is being studied.[87][279]
Tele-health has been used for home-based disease monitoring and management intervention.[313] Randomized controlled trials have suggested that the use of nurse-centered tele-assistance may decrease the occurrence of exacerbations of COPD, urgent care visits, and hospitalization.[313] The use of such programs may be cost-saving.[280] Other analyses have suggested that home tele-monitoring may prolong the time free of hospitalizations or ER visits,[87] but the total number of hospitalizations may not be affected and another randomized controlled trial showed no clear beneficial effects.[281] Heterogeneity of existing studies precludes development of any firm generalizable conclusions regarding the role of tele-health in the prevention or treatment of exacerbations,[314] and as such it is not currently recommended for exacerbation prevention.[1][82]

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