The clinical management of COPD exacerbations: an update

Abstract

Clinical management of chronic obstructive pulmonary disease (COPD) exacerbations is of high importance because exacerbations reduce quality of life, increase mortality and carry high socioeconomic costs. Still, a quarter of patients with an acute exacerbation do not respond adequately to initial exacerbation treatment. Yet, research from recent years has advanced the clinical management of COPD exacerbations. Prediction of exacerbations can be improved by asking patients about their exacerbation history. The duration of oral corticosteroid treatment has been optimized, new oral- and inhalation medication has become available and important knowledge has been gathered about the risks and benefits of inhalation corticosteroids, which we will discuss in this editorial. Still, future research is needed to tailor treatment strategies for specific COPD phenotypes.

Keywords:

• Chronic obstructie pulmonary disease
• exacerbation
• disease management
• prediction
• glucocorticoids
• LABA
• LAMA
• roflumilast
• vitamin D
• asthma COPD overlap syndrome

Worsening of dyspnoea, cough and sputum production are clinical symptoms of chronic obstructive pulmonary disease (COPD) exacerbations, which reduce quality of life, increase mortality and carry high socioeconomic costs.[1] Optimal clinical management of COPD to prevent and treat exacerbations is thus of high importance. Clinical guidelines for management of exacerbations are widely available.[1] Still, a quarter of patients with an acute exacerbation do not respond adequately to initial exacerbation treatment.[2] Recently, some advances have been made in the clinical management of COPD exacerbations, which we will discuss in this editorial.

Prediction

Early recognition of exacerbations and prompt treatment (within three days) reduces the risk of hospitalization and improves the rate of recovery.[3] However, it remains a clinical challenge to predict which patients are at risk of exacerbations. Although multiple biomarkers have been found to improve prediction, the best available predictor still is a simple question: did you experience a period of persistent worsening beyond day-to-day symptoms in the past year?[4] This question can identify the so-called frequent-exacerbation phenotype, with on average two or more exacerbations per year. These patients should be treated with prednisolone earlier and receive maintenance therapy with inhalation corticosteroids (ICS).[1,3]

Treatment

Oral medication

Outpatient treatment of exacerbations consists of short acting bronchodilators, antibiotics and oral corticosteroids.[1] Until recently, the optimal duration of corticosteroid treatment was uncertain. A recent meta-analysis showed that a treatment duration of 5 days is non-inferior to a duration of 10–14 days.[5] Yet, all studies were conducted in secondary or tertiary care centres, included severe or very severe COPD patients and one study dominated the meta-analysis.[5] So, more studies in primary care and less severe COPD patients are needed.

A frequent clinical dilemma in the management of acute exacerbations is the decision to prescribe antibiotics. A recent study showed that this decision can be supported by clinical symptoms (increased dyspnoea, sputum volume and sputum purulence) combined with elevated levels of the biomarker C-reactive protein.[6] Furthermore, recent studies have suggested that chronic treatment with the macrolide antibiotic azithromycin resulted in a reduction of exacerbation rate.[7,8] Yet, only patients with recurrent exacerbations were included, which limits the generalizability. Despite these findings, macrolide long-term safety, bacterial resistance and optimal dosing schedule still remain to be determined. A promising strategy to prevent exacerbations was statin therapy. Multiple observational studies showed benefit on lung function decline, exacerbations and mortality in COPD patients. However, the recent STATCOPE trial showed that simvastatin 40 mg did not reduce exacerbation rates.[9] Along the same lines, vitamin D was thought to be beneficial in COPD patients. However, a large intervention trial showed no benefit of vitamin D supplementation on COPD exacerbations.[10] Still, in the subgroup of patients with severe vitamin D deficiency (<20 ng/L), the reduction in exacerbation rates seemed large (RR: 0.57). This suggests that vitamin D supplementation would be beneficial for patients with severe deficiency. Furthermore, treatment with N-acetylcysteine or carbocysteine potentially has a role in preventing exacerbations. Although current guidelines state that these agents may be prescribed to prevent exacerbations, more evidence is needed in this field.[1]

The oral phosphodiesterase-4 inhibitor roflumilast is the newest oral medication developed for COPD patients. In a recent clinical trial, patients were included who had severe COPD, chronic bronchitis, ≥2 exacerbations in the year before inclusion and used ICS+LABA or triple therapy (ICS+LABA+LAMA).[11] Roflumilast was thus used as add-on therapy. The study showed that moderate-to-severe exacerbations were 13.2% lower (p = 0.04) in the roflumilast group compared with placebo. This study fulfilled post-marketing commitment as stated during FDA approval in 2012. Still, we advise to be cautious prescribing roflumilast because of its side effects like diarrhea, weight loss and psychiatric symptoms. Real-world long-term follow-up data are needed to clarify its definitive role in prevention of COPD exacerbations.

New inhalation combination therapies

Both long-acting muscarinic antagonists (LAMA) and long-acting beta-agonists (LABA) have been shown to reduce exacerbation rates in the TORCH and UPLIFT trials.[12] Subsequently, the POET-COPD trial directly compared the effect of LAMA tiotropium and LABA salmeterol on exacerbation rates in patients with moderate-to-severe COPD who experience ≥1 exacerbations/year.[12] This study showed that tiotropium reduces the risk for moderate exacerbations by 14% and for severe exacerbations by 28% compared with salmeterol. This finding is supported by comparisons between the LABA formoterol and LAMA tiotropium, which showed lower exacerbation rates with tiotropium.[12] The current data support the notion that LAMA are more effective than LABA in preventing exacerbations. Still, as both LAMA and LABA have shown effectiveness, this raises the question whether combination of LABA and LAMA is even more beneficial to prevent exacerbations than either of the two alone. Co-prescription has been hampered by the need for separate inhalers. However, data on four new LABA-LAMA fixed dose combination preparations have been published recently: indacaterol/glycopyrronium, vilanterol/umeclidinium, formoterol/aclidinium and olodaterol/tiotropium. Although multiple valuable clinical endpoints have been assessed in studies, we will only discuss the results on exacerbation rates. In the SPARK trial, indacaterol/glycopyrronium reduced moderate-to-severe exacerbations by 12% compared to glycopyrronium alone and by 10% compared to tiotropium alone, although not statistically significant.[13] Moreover, only GOLD III and IV patients with previous exacerbations were included and tiotropium treatment was not blinded. In the studies with umeclidinium/vilanterol, no effect was found for exacerbation rates, although not yet powered to detect a difference in exacerbation rate.[13] Aclidinium/formoterol reduced moderate-to-severe exacerbations with 24% compared with placebo in a pooled analysis of two phase III trials.[14] Importantly, comparison was made against placebo and not to LABA or LAMA monotherapy, hampering the clinical relevance of these findings. Most recently, a trial in COPD II-IV patients compared olodaterol/tiotropium with its mono-components. A trend toward a lower exacerbation rate was found when the fixed-dose combination was compared with tiotropium alone (RR: 0.92; 95% CI: 0.78–1.09).[15] In summary, although recently published data on LABA–LAMA combination preparations are promising, more data are needed about their effect on exacerbation risk. These preparations are already approved and prescribed in clinic, so there is a large opportunity to study these preparations in real-world data to evaluate its long-term effectiveness and safety in the general population of COPD patients.

Inhalation corticosteroids

To reduce exacerbation rates, current guidelines recommend ICS for GOLD III and IV patients in combination with LABA and/or LAMA.[1] However, ICS use has also been associated with side effects, such as loss in bone density, increased dermal bruising and an increased risk of pneumonia.[16] Hence, the clinical decision to administer ICS needs to be balanced between prevention of exacerbations and these side effects. Furthermore, for patients on triple therapy (ICS+LABA+LAMA), the added benefit of ICS is uncertain. Despite this and contrary to guidelines, about 50% of COPD II patients use ICS in real-life practice.[17] In this light, the WISDOM trial provided valuable information about consequences of ICS withdrawal.[18] In COPD III–IV patients on triple therapy, the ICS fluticasone was withdrawn in a stepwise manner. Patients who withdrew ICS but continued using LABA+LAMA did not experience more exacerbations than patients who continued triple therapy (HR: 1.06; 95% CI: 0.94–1.19).[18] A difference in pneumonia risk was not yet apparent within the 12 months follow-up. Other studies showed an increased risk of exacerbations after withdrawal of ICS.[1] However, patients in this study did not use LABA+LAMA and high dose ICS was withdrawn abruptly. In summary, a stepwise reduction of ICS dose seems safe with respect to exacerbations in COPD III and IV patients who continue using LAMA+LABA combination therapy. This raises the question in which COPD patients ICS are still beneficial. The strongest evidence for a beneficial effect of ICS is in COPD patients with frequent exacerbations or with a concurrent asthma diagnosis, a patient group which has been summarized under the term ‘Asthma COPD Overlap Syndrome’ (ACOS). Among COPD patients, this still poorly defined ACOS group has an estimated prevalence of 20% and these patients have higher exacerbation risk.[19] In a recent study among 11,872 older COPD patients, ICS use was most effective in preventing COPD hospitalizations in patients with ACOS.[20] In line with this result, the combined GOLD and GINA guidelines recommend ICS treatment for ACOS patients.[19]

In conclusion, research from recent years has advanced the clinical management of COPD exacerbations. Prediction of exacerbations can be improved by asking patients about their exacerbation history. The duration of oral corticosteroid treatment has been optimized, new oral and inhalation medication has become available and important knowledge has been gathered about the risks and benefits of ICS. Still, future research is needed to tailor treatment strategies for specific COPD phenotypes such as ACOS. More importantly, the new knowledge has to be effectively transferred to both primary care and specialist clinicians to provide benefit to patients with COPD.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Notes on contributors

Tobias N Bonten

Marise J Kasteleyn

Christian Taube

Niels H Chavannes