An acute exacerbation of chronic obstructive pulmonary disease (COPD) is an event of acute deterioration in a patient’s baseline clinical status that often necessitates a change in medication. Patients typically present with a worsening of their day-to-day respiratory symptoms, most commonly increasing dyspnoea, sputum volume and sputum purulence.

Exacerbations accelerate the physiological and functional decline of patients with COPD and constitute a large proportion of emergency hospital admissions in the UK.

Patients who have had previous exacerbations, a low baseline forced expiratory volume in 1 second (FEV1), secondary pulmonary hypertension and/or gastrointestinal reflux disease are at increased risk of developing an acute exacerbation of COPD.

In general, exacerbations happen because there has been a change in the underlying inflammatory process of stable disease. The triggers that cause these changes can be grouped into respiratory infections, which cause 70% of cases and non-infective causes:

• Bacterial infection - the evidence base for the role of bacterial colonisation in triggering exacerbations remains inconclusive. However, 3 potential mechanisms have been identified:
  • Acquisition of new strains of Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae
  • Alteration of lung microbiota
  • Superimposed bacteria-on-viral infections

• Viral infections - these have been definitively linked to exacerbations and cause more prolonged symptoms. Rhinovirus, influenzae and respiratory syncytial virus are most frequently detected

• Non-infective causes:
  • Eosinophilic inflammation - exacerbations caused by this show better response to systemic corticosteroid therapy
  • Environmental factors such as air pollution
  • Psychological factors such as anxiety and panic attacks

In COPD, the airways are obstructed due to inflammation and have high compliance due to emphysematous destruction. These pathophysiological mechanisms limit airflow during expiration, leading to gas trapping and lung hyperinflation. Pulmonary vasculature can also be subjected to emphysematous changes, causing pulmonary hypertension and right ventricular dysfunction.

During an exacerbation, the following processes happen:

• Increased inflammation, mucosal oedema and bronchospasm further limit expiratory flow
• Gas trapping worsens, increasing ventilation-perfusion mismatch
• The resulting hypoxia and hypercapnia trigger the neural drive to increase ventilation
• Respiratory muscles fatigue, leading to a 'neuromechanical decoupling' that reduces the ventilatory drive
• Existing cardiac dysfunction worsens due to increasing pulmonary vascular resistance

The clinical presentation of exacerbations of COPD range in severity from mild exacerbations that can be successfully managed in the community with increased short-acting bronchodilators to severe exacerbations that present with respiratory failure requiring ventilatory support. Thus, the key aim of the clinical assessment is to identify the patients who are at risk of deterioration and need to be managed in hospital.

All patients present with some form of deterioration in their respiratory status, however this needs to be characterised in terms of its variation from the patient’s baseline symptoms and the time course of its development. The modified Anthonisen criteria suggest that a diagnosis of an exacerbation of COPD can be made if there are at least 2 of the major symptoms or at least one major and one minor symptom:

• Major symptoms - dyspnoea, increased sputum volume, increased sputum purulence
• Minor symptoms - cough, wheeze, nasal discharge, sore throat, pyrexia

Signs of an acute exacerbation of COPD on physical examination include:

• Increased respiratory effort - tachypnoea, nasal flaring, use of accessory muscles, paradoxical chest wall movement
• Tachycardia – this could be due to anxiety, hypoxia and/or increased respiratory effort
• Worsening airway obstruction heard on auscultation:
  • Reduced breath sounds
  • Prolongation of the expiratory phase with wheezing
  • Crackles which could indicate an infective component

In addition, the following signs are good indicators of the patient's respiratory status:

• Indicators of hypoxia and/or hypercapnia:
  • New or worsening central cyanosis
  • Asterixis
  • Altered mentation e.g. confusion, drowsiness
• Reduced respiratory effort such as shallow breaths indicate that the patient is tiring and is at risk of progression to respiratory failure
• Hypotension could be an early of sign of haemodynamic instability indicating impending respiratory arrest

The measurement of airflow obstruction using Peak Expiratory Flow (PEF) or Forced Expiratory Volume in 1 second (FEV1) is not useful during the diagnostic process, unlike in acute exacerbation of asthma where the PEF is key in determining the severity of the presentation.

The NICE guidelines on COPD recommend that the clinical assessment of patients with a suspected exacerbation is focussed on identifying the following features that could indicate that a patient is at risk of adverse outcomes and so should be managed in hospital:

• Rapid onset of symptoms and/or severe breathlessness
• Poor baseline functional status:
  • Poor level of activity or confined to bed
  • Unable to cope at home
  • Receiving long-term oxygen therapy (LTOT)
• Presence of comorbidities:
  • Cardiac disease
  • Insulin-dependent diabetes mellitus
• Findings on physical examination that indicate hypoxia and hypercapnia:
  • SpO2 < 90% on pulse oximetry
  • Presence of cyanosis
  • Worsening peripheral oedema (which could indicate worsening renal hypoxia)
  • Acute confusion and/or impaired level of consciousness

NICE recommends that all patients admitted to hospital with a suspected exacerbation of COPD undergo the following investigations:

• Blood tests to establish a baseline:
  • Full blood count
  • Urea and electrolytes
  • Theophylline levels if the patient is on it
• Serial arterial blood gases (ABGs) to monitor for the development of Type 2 respiratory failure
  • A PaO2 of < 7 kPa and a pH level of < 7.35 are indications that the patient should continue to be managed in hospital
• Chest X-ray – overt changes such as opacification and oedema should prompt a reconsideration of the diagnosis
• ECG – helps to exclude acute ischaemia and/or comorbid cardiac dysfunction
• Microbiological investigations:
  • Sputum sample for microscopy and culture if sputum purulent
  • Blood cultures if pyrexia present

In addition, the following tests should be done if the corresponding diagnosis is suspected:

• D-dimer – pulmonary embolism
• Cardiac troponins - myocardial infarction
• Plasma brain natriuretic peptide (BNP) - heart failure

NICE also recommends that patients presenting to primary care have their oxygen saturations measured if there is a clinical suspicion of a severe exacerbation that might require hospitalisation. Sending sputum samples is not necessary if they continue to be managed in primary care.

Cardiac and respiratory causes of acute breathlessness should be considered when assessing a patient with a suspected exacerbation of COPD.

• Pneumonia
  • Similarity – clinical presentation of dyspnoea and cough productive of purulent sputum. This can be difficult to distinguish from exacerbations of bacterial origin.
  • Difference – clinical and radiological findings of lung consolidation (bronchial breathing, increased vocal resonance and opacification seen on chest X-ray)

• Pulmonary embolism
  • This is an important diagnosis to exclude as COPD is a risk factor for thromboembolism especially during exacerbations
  • Differentiating embolism from exacerbation – dyspnoea and hypoxia predominate cough and sputum production. Signs of lower limb venous thromboembolism such as calf swelling may be present

• Pulmonary oedema
  • This could be either due to a myocardial infarction or a presentation of acute-on-chronic heart failure
  • Differentiating features – sputum may be frothy rather than purulent, with characteristic X-ray changes of alveolar and interstitial oedema

The management of an acute exacerbation of COPD can be divided into 4 components.

1. Provision of respiratory support

The British Thoracic Society (BTS) recommends that prior to the availability of ABG results, all patients should be provided with supplemental oxygen titrated to achieve target saturations of 88-92%. Supplemental oxygen can be provided via either:

• A 24% Venturi mask at 2-3 L/min
• A 28% Venturi mask at 4 L/min
• Nasal cannulae at 1-2 L/min

ABG measurements should be taken upon arrival in hospital and repeated after 30-60 minutes. If the pCO2 and pH values of the ABG measurement are normal, the target oxygen saturation can be adjusted to 94-98%. However, a target of 88-92% should be maintained if the patient has:

• A history of previous Type 2 respiratory failure requiring non-invasive ventilation (NIV) or intermittent positive pressure ventilation
• Oxygen saturation below 94% when clinically stable
• Long-standing hypercapnia – raised pCO2 but with a pH of ≥ 7.35 and/or a bicarbonate level of > 28 mmol/mol

Patients with persistent hypercapnia and respiratory acidosis despite optimal medical management need to be started on NIV. The aim of NIV is to reverse the acidosis by providing pressure support for the airways during inspiration and expiration, leading to an overall improvement in gaseous exchange. BTS recommends that NIV is indicated if the following features are present 60 minutes after optimal supplemental oxygen and bronchodilation have been given:

• Acidosis - pH < 7.35
• Hypercapnia - pCO2 > 6.5
• Respiratory rate > 23

Improvement in pH and reduction of the respiratory rate within the first 4 hours are key indicators of NIV success, otherwise, escalation to invasive mechanical ventilation (IMV) should be considered, especially if the following features are present:

• Imminent respiratory arrest
• Severe respiratory distress
• Failure of NIV - persistent acidosis (pH < 7.25) and tachypnoea (RR > 35)
• Persistent or worsening acidosis (pH < 7.15)
• Depressed consciousness (GCS < 8)

Escalation to IMV may be deemed inappropriate after considering the patient’s clinical status and wishes. In such cases, if NIV is adding to the patient’s discomfort it should be discontinued and palliative care measures started.

2. Pharmacological management

• Bronchodilation
  • Short-acting beta2 agonists (SABA) and/or short-acting muscarinic antagonists (SAMA) should be used initially. These can be delivered via an inhaler or nebuliser driven by air
  • Patients’ long-acting beta2 agonists (LABA), long-acting muscarinic antagonists (LAMA) and/or inhaled corticosteroids (ICS) inhalers should be continued
  • NICE recommends that IV theophylline may be used if the response is inadequate and levels should be checked 24 hours after commencing treatment

• Corticosteroids
  • NICE recommends a 5-day course of oral prednisolone

• Antibiotics:
  • GOLD recommends that antibiotic therapy is given to patients who have all 3 of the major symptoms or have 2 major symptoms with increasing sputum purulence being one of them or require mechanical ventilation (invasive and non-invasive)
  • NICE suggests that the following factors be taken into account when prescribing an antibiotic – severity of symptoms, previous exacerbations and hospital admission history, previous culture results and risk of resistance
  • Choice of antibiotic – penicillin e.g. amoxicillin, macrolides e.g. clarithromycin and tetracyclines e.g. doxycycline are most commonly prescribed due to their effectiveness against Haemophilus influenzae and Streptococcus pneumoniae

3. Optimising the patient for discharge

NICE recommends that the following steps are taken prior to discharge:

• Measurement of spirometry
• Optimisation of maintenance bronchodilator therapy
• Satisfactory pulse oximetry and ABGs in patients who have had respiratory failure
• Confirmation that the patient has returned to their functional baseline
• Arrangement for follow-up and home care e.g. nurse visits

4. Prevention of exacerbations

The following interventions have been shown to be effective in reducing the frequency of exacerbations. While some are fundamentals of COPD care, GOLD suggests that they should be reinforced and others incorporated into patients’ long-term management where appropriate:

• Smoking cessation
• Influenza and pneumococcal vaccination
• Pulmonary rehabilitation
  • Broadly defined as an integrated programme consisting of supervised exercise training, smoking cessation, nutritional counselling and educating patients about self-management of their disease
  • A 6-8 week programme started within 2 weeks of discharge from hospital after an exacerbation has been shown to reduce readmission
• Vitamin D supplementation
  • Supplementation in severe deficiency (< 10ng/ml) reduces exacerbation frequency by 50% due to Vitamin D’s immune-modulating effects
• Augmentation of long-acting bronchodilation with anti-inflammatory therapy
  • Inhaled corticosteroids – particularly effective with blood eosinophil counts of ≥ 100 cells/µL
  • Roflumilast (phosphodiesterase-4 inhibitor) – can be used as an alternative to inhaled corticosteroids if blood eosinophil counts < 100 cells/µL or added on to the medication of patients already on a combination of LABA, LAMA and ICS if they have been hospitalised for an exacerbation in the past year
• Long-term macrolide
  • Azithromycin has been shown to be effective especially among non-smokers but is associated with an increased risk of bacterial resistance
• Mucoregulators
  • Can be used as regular therapy in patients not receiving ICS
  • N-acetylcysteine and carbocysteine are common examples