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The phenotypes of acute exacerbations of COPD

Presented by Prof Maarten van den Berge, Netherlands

SUMMARY

There are different exacerbation subtypes within COPD. Recognition of the exacerbation subtype is important as it may have an impact on treatment decisions. Comorbidity and severity of disease must also be considered. It is not always easy to accurately diagnose an exacerbation or to objectively grade its severity.

What are exacerbations?

Exacerbation is considered as an acute worsening of the patient’s usual pattern of respiratory symptoms beyond normal day-to-day variability.  These include increased dyspnoea, worsening of cough, increased sputum volume and sputum purulence. Thinking about severity, a moderate exacerbation is usually treated with prednisolone and/or antibiotics and severe cases need hospitalization and may lead to death.

Triggers of exacerbation

Of the different subtypes of exacerbations, viruses is the most important factor, but due to limited testing, there is limited data of its role. Triggers may also be bacteria, eosinophilic type 2-inflammation and other factors.

Exacerbations are not unannounced

The term acute exacerbation is misleading, says prof. van der Berge, as it has been shown that the worsening of the symptoms starts already seven days before the actual event1.  This timepoint could be an excellent opportunity to intervene particularly in the case when the subtype of the exacerbation is known. For example, patients with higher eosinophilic count have a higher risk for exacerbations2,3. In these cases, treating the patient with corticosteroid containing inhalation therapy could help avoid escalation. Eosinophils are increased during exacerbations in a certain subset of patients, not in all4

Systemic corticosteroids and antibiotics in treating COPD exacerbations

Comparing outcomes for patients suffering from exacerbation, where standard of care (all receive prednisolone and antibiotics) with biomarker-based treatment, study results support the latter. Results from the original study5 by the OXFORD-group, published in 2012, was confirmed in 20246. In the biomarker arm, patients received antibiotics plus either prednisolone or placebo. Lung function, health status and symptoms were similar in both groups. However, symptom recovery was slower in the patients who received prednisolone if their eosinophilic count was low. The conclusion was that prednisolone should only be given to the right phenotypes of exacerbations to avoid harming the patients. If the patient already has taken prednisolone, this will impact biomarker count, and this should be checked.

Antibiotics or not?

An old (but landmark) study published in 1987 showed that exacerbating patients treated by antibiotics vs. placebo had a better outcome7. The same study identified three exacerbation subtypes:

  1. Increased dyspnea, sputum volume and sputum purulence
  2. Two of three above mentioned symptoms present
  3. One of the above symptoms present AND upper respiratory infection, fever, increased wheeze or cough or increased respiratory or heart rate

Antibiotics were beneficial only in the first subtype exacerbations.

Exacerbation severity  

Exacerbation severity is divided in three categories:
Mild: events that result in change of COPD medications for>2 days.
Moderate: Events requiring treatment with antibiotics and/or systemic corticosteroids
Severe: Events that result in hospitalization or ER visit8.  

Severity of COPD exacerbations: The Rome proposal

The severity of an exacerbation relies exclusively on a patient’s perception of increased respiratory symptoms and physician’s perception regarding the treatment options, both subjective. The symptoms can be mimicked by other clinical conditions. Lack of measurable pathophysiological variables is another challenge. Published in 2021, the Rome proposal suggests a new approach of diagnosing COPD exacerbations and their severity. The assessment should include ruling out other clinical causes of symptoms (e.g. heart failure, pneumonia or pulmonary embolism9).

Post-exacerbation vulnerability

Risk of coronary symptoms of heart failure increases during and shortly after an COPD exacerbation. The risk of acute coronary syndrome increases almost 10-fold, and the risk of heart failure increases 27-fold during the first seven days. It is not fully understood what the causes behind these increases are10.

The bottom line

Understanding and recognizing the exacerbation subtype is important as it provides guidance for treatment decisions.


Pekka Ojasalo

Medical Advisor

References

  1. van den Berge M, Hop WC, van der Molen T, van Noord JA, Creemers JP, Schreurs AJ, Wouters EF, Postma DS; COSMIC (COPD and Seretide: a Multi-Center Intervention and Characterization) study group. Prediction and course of symptoms and lung function around an exacerbation in chronic obstructive pulmonary disease. Respir Res. 2012 Jun 6;13(1):44. doi: 10.1186/1465-9921-13-44. PMID: 22672621; PMCID: PMC3494574.
  2. Pascoe S, Barnes N, Brusselle G, Compton C, Criner GJ, Dransfield MT, Halpin DMG, Han MK, Hartley B, Lange P, Lettis S, Lipson DA, Lomas DA, Martinez FJ, Papi A, Roche N, van der Valk RJP, Wise R, Singh D. Blood eosinophils and treatment response with triple and dual combination therapy in chronic obstructive pulmonary disease: analysis of the IMPACT trial. Lancet Respir Med. 2019 Sep;7(9):745-756. doi: 10.1016/S2213-2600(19)30190-0. Epub 2019 Jul 4. Erratum in: Lancet Respir Med. 2021 Dec;9(12):e114. doi: 10.1016/S2213-2600(21)00516-6. PMID: 31281061.
  3. Rabe KF, Martinez FJ, Ferguson GT, Wang C, Singh D, Wedzicha JA, Trivedi R, St Rose E, Ballal S, McLaren J, Darken P, Aurivillius M, Reisner C, Dorinsky P; ETHOS Investigators. Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD. N Engl J Med. 2020 Jul 2;383(1):35-48. doi: 10.1056/NEJMoa1916046. Epub 2020 Jun 24. PMID: 32579807.
  4. Saetta M, Di Stefano A, Maestrelli P, Turato G, Ruggieri MP, Roggeri A, et al. Airway eosinophilia in chronic bronchitis during exacerbations. Am J Respir Crit Care Med 1994;150:1646–1652
  5. Bafadhel M, McKenna S, Terry S, Mistry V, Pancholi M, Venge P, Lomas DA, Barer MR, Johnston SL, Pavord ID, Brightling CE. Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial. Am J Respir Crit Care Med. 2012 Jul 1;186(1):48-55. doi: 10.1164/rccm.201108-1553OC. Epub 2012 Mar 23. PMID: 22447964; PMCID: PMC3400995.
  6. Ramakrishnan S, Jeffers H, Langford-Wiley B, Davies J, Thulborn SJ, Mahdi M, A’Court C, Binnian I, Bright S, Cartwright S, Glover V, Law A, Fox R, Jones A, Davies C, Copping D, Russell RE, Bafadhel M. Blood eosinophil-guided oral prednisolone for COPD exacerbations in primary care in the UK (STARR2): a non-inferiority, multicentre, double-blind, placebo-controlled, randomised controlled trial. Lancet Respir Med. 2024 Jan;12(1):67-77. doi: 10.1016/S2213-2600(23)00298-9. Epub 2023 Nov 2. Erratum in: Lancet Respir Med. 2023 Dec;11(12):e98. doi: 10.1016/S2213-2600(21)00351-9. PMID: 37924830.
  7. Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. 1987 Feb;106(2):196-204. doi: 10.7326/0003-4819-106-2-196. PMID: 3492164.
  8. GOLD 2024 report
  9. Celli BR, Fabbri LM, Aaron SD, Agusti A, Brook R, Criner GJ, Franssen FME, Humbert M, Hurst JR, O’Donnell D, Pantoni L, Papi A, Rodriguez-Roisin R, Sethi S, Torres A, Vogelmeier CF, Wedzicha JA. An Updated Definition and Severity Classification of Chronic Obstructive Pulmonary Disease Exacerbations: The Rome Proposal. Am J Respir Crit Care Med. 2021 Dec 1;204(11):1251-1258. doi: 10.1164/rccm.202108-1819PP. PMID: 34570991.
  10. N M Hawkins, C F Vogelmeier, S O Simons, E Garbe, N Manito, K Swart, P Ekwaru, N Kossack, I Hernandez, H Mullerova, A Randhawa, L Van Burk, J Sanchez-Covisa, K Rhodes, C Nordon, EXACOS-CV Study Group, Increased risk of decompensated heart failure, acute coronary syndrome, arrythmias and ischemic stroke following exacerbation of COPD: results from a multi-database cohort study, European Heart Journal, Volume 44, Issue Supplement_2, November 2023, ehad655.2617, https://doi.org/10.1093/eurheartj/ehad655.2617

ID 8699-18.06.2024