Identifying asthma-COPD overlap syndrome (ACOS)

There has been much progress over the years in how we approach the diagnosis of chronic airways disease, including asthma, chronic obstructive pulmonary disease (COPD) and bronchiectasis. Asthma and COPD are the two chronic airways diseases most frequently encountered by all healthcare practitioners, with the estimated number of COPD patients in Ireland as high as 440,000¹ and an estimated 450,000² affected by asthma.

There is an increasing recognition that these two chronic airways diseases will co-exist in a substantial minority of patients, which can pose a great challenge to clinicians. Recently, the term asthma-COPD overlap syndrome (ACOS) has been suggested to reflect the co‑existence of both pathologies in a given patient.

A welcome advance in the area has now come about via a joint initiative of the two leading producers of clinical guidelines for COPD and asthma: the Global Initiative for Chronic Obstructive Lung Disease (GOLD) and the Global Initiative for Asthma (GINA). This has resulted in the production of a practical guideline document³ focusing on the overlap state of these two diseases. The document was developed by the science committees of both GINA and GOLD. A detailed review of the two conditions was performed, and the final document proposed a sensible approach to help distinguish between the two common chronic airway conditions. 

In the situation where asthma and COPD coexist in the one individual patient, the term asthma-COPD overlap syndrome was proposed as the diagnostic term. The document outlined certain features that are consistent with ACOS. Rather than attempting to come up with an exact definition of the condition, a clinical description was provided, outlining how the ACOS is characterised by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD. 

ACOS is therefore identified by the features that it shares with both asthma and COPD. It is well accepted that asthma, COPD and now ACOS are likely in time to be further split into newly recognised discrete disease entities. This is because the phenotypic and genetic variants of all three states is becoming better understood with the future help of discerning biomarkers. This point is acknowledged in the joint GINA/GOLD guideline on ACOS. The primary objective of the approach used in the ACOS guideline is to inform clinical practice based on current evidence.

Underlying the relevance of the asthma COPD overlap state is the recognition that it results in an increased number of exacerbations, a more rapid decline in lung function and a higher mortality rate than is observed for the non-overlap state. In addition, healthcare costs are significantly higher with ACOS than with asthma or COPD alone. While estimates of the prevalence of ACOS vary greatly depending on the ACOS definition, the rigour of diagnostic criteria employed and the size of the study, it is suggested that physician-diagnosed ACOS accounts for 15-20% of chronic airways disease patients.⁴

The systematic approach recommended by GINA and GOLD for the designation of ACOS is relatively intuitive, and relies heavily on focused history-taking, supplemented by serial spirometry pre- and post-initiation of therapy. The practical guideline outlines a five-step approach to the diagnosis and initial management of the stable syndromic state (see Table 1).

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Establishing chronic airways disease

The first of the five steps is to be thinking of a chronic airways disease diagnosis in patients at risk of such disease, be it in the emergency department or a specialist clinic. Important cardiovascular conditions can be excluded by history taking and by critically evaluating previous medical records and medication lists. Once it is established that isolated symptoms or the spectrum of symptoms, which are affecting the patient’s quality of life is secondary to chronic airways disease, further investigations should follow to find out whether it is asthma, COPD or both co-existing in the one individual.

The common symptoms of chronic airways disease that the patient may present with are:⁵

• Cough (can be acute or chronic)
• Persistent sputum problems
• Episodic or persistent shortness of breath
• Poor exercise tolerance
• Wheezing
• Recurrent lower respiratory tract infections. 

Past medical history should focus on any previous use of inhalers, previous smoking (the patient may think it irrelevant when remote) of tobacco or cannabis, etc. Occupational exposures in farming, food production, manufacturing, mining etc. are relevant causes of either occupational asthma or COPD, and domestic air pollutants can be a sole cause for COPD. 

Key discriminating features that favour asthma and features that favour COPD should then be assembled and compared to potentially make the diagnosis of the ACOS overlap state.

Asthma

Asthma tends to present in the early part of life whereas COPD is rarely present before the age of 30. Patients may have used salbutamol inhalers in early life and ‘grown out of’ their asthma. Asthma can present as episodic wheezing and shortness of breath. 

There is often marked variation in the severity and nature of the symptoms during the day (better) and night (worse), more so than in COPD. Their peak expiratory flow rate tends to be lower in the mornings than in the evenings, the so-called diurnal variability of asthma. 

Certain asthma triggers should be identified by detailed history taking, including symptoms set off by dust, allergens, laughter and exercise. Hay fever and eczema are over-represented among asthma patients versus COPD. Exercise-induced symptoms can be more variable in asthma than the predictable dyspnoea on exertion seen in COPD. The symptom may even start minutes after exercise ceases. 

Some patients may give a clear history that the onset of shortness of breath and wheezing is related to temperature changes, such as moving from cold to warm rooms indoors, or going outdoors in the morning. They may experience symptoms while exposed to air conditioners in a vehicle or building. 

Infections and non-pulmonary causes such as vocal cord dysfunction and congenital heart conditions should always be considered in younger patients. Trials of salbutamol lead to quick definite improvement versus modest relief in COPD.

COPD

Chronic obstructive pulmonary disease usually presents later in life, especially after the age of 40. However, it can present earlier in patients with a major smoking history, heavy occupational exposure and in the genetic form of emphysema known as alpha 1-antitrypsin deficiency (usually lower lobe-predominant emphysema versus the typical upper lobe-predominant pattern observed in smokers). 

In the majority of cases, COPD tends to present in the sixth and seventh decades of life. Patients usually present with chronic airway symptoms which are generally progressive, they are predictably worse on exertion and the limitation is usually persistent rather than as variable as in asthma. They may have their ‘good’ and ‘bad’ days, but will not feel perfectly normal as asthma patients can at times. 

Past medical history may reveal multiple hospital admissions, courses of systemic steroids and they may or may not have symptoms/signs of cor pulmonale (dependent oedema, jugular venous distension, loud second heart sound in the left parasternal second intercostal space) depending on the stage of disease at which they seek medical attention. Their symptoms are less related to the triggers seen in asthma.

Distinguishing between asthma, COPD and ACOS

A significant proportion of chronic airways disease patients will have features of both asthma and COPD in an overlap state. The patients usually present with chronic airway symptoms after the age of 40. They may have had the same symptoms in childhood or early adulthood. They may have chronic shortness of breath on exertion and phlegm production at their baseline, but the variability in symptoms is usually marked. 

They may have had a previous physician diagnosis of asthma, they may suffer from allergies and there may be a family history of asthma. Chest radiography may reveal hyperinflated lungs. In the overlap state the patients by definition must have persistent airflow limitation with or without some reversibility. 

The clinical course over time is typically one of slowly progressive decline despite treatment. The treatment needs of ACOS patients are much higher than in asthma or COPD alone, and they tend to exacerbate more frequently than COPD patients. 

This can be reduced by appropriate pharmacological treatment, vaccination, exercise and improvement in exposures. In asthma patients, pulmonary function is usually normal but chronic severe asthma can result in fixed expiratory airflow limitation due to sub-epithelial fibrosis, and thereby mimic COPD.⁶

Investigations

A variety of investigations can aid in making a confident diagnosis. Chest x-ray, as mentioned earlier, may favour COPD, and spirometry should be performed prior to and sometime after initial therapy. Radiology has an important role in the diagnosis of ACOS. Though chest x-rays and a CT scan of the chest may be normal in the initial phases of the condition, patients with COPD may in time have evidence of hyperinflation, emphysematous change, bronchial wall thickening, and features of pulmonary hypertension may be seen as well. 

In asthma, the CT scan appearances will usually be entirely normal, though abnormal findings like air trapping, mucus plugging, subsegmental atelectasis and bronchial wall thickening may be seen. These findings may be picked up incidentally if the patient had cross sectional imaging for other reasons. Chest x-ray and CT scans of the chest may of course reveal different, less common pathologies such as bronchiectasis, lung tumours, interstitial lung disease, tuberculosis or congestive cardiac failure, which may alter the management pathway completely.

Spirometry is essential for the assessment of patients with chronic airways disease. If it is available it should be performed before the treatment is commenced and some weeks after the patient is on treatment. It may help to exclude COPD altogether and save patients from unnecessary trials of treatment. It may confirm chronic airway disease early and help in initiation of early treatment to slow down decline in lung function. 

While helpful, measuring serial peak expiratory flow rate (PEFR) is not an alternative to spirometry, as the latter is required in the diagnosis of COPD and therefore ACOS. If twice-daily PEFR performed over a two week period demonstrates >10% average diurnal variability (ie. [The day’s highest PEFR minus the day’s lowest]/[average of the two PEFRs that day], and averaged over the two weeks of values), this is consistent with asthma or ACOS. This is because both syndromes demonstrate diurnal variability in PEFR, although a normal PEFR in isolation doesn’t rule out either asthma or COPD. 

Spirometry may provide supporting evidence and in some instances may help the physician in management guidance. Normal spirometry values are inconsistent with a diagnosis of either ACOS or COPD. If the FEV1/FVC is < 0.7 it will favour the diagnosis of ACOS or COPD, though it may be transiently present in worsened asthma (and permanently present in the less common scenario of chronic severe asthma with subepithelial fibrosis). 

If there is an increase in FEV1 >12% and 400ml from baseline 15 minutes after four puffs of salbutamol there is a high probability that the patient may have asthma, but ACOS should also be considered if the history includes discriminating features of COPD and a risk factor (eg. smoking). The spirometry results should therefore be interpreted in the context of the patient history and examination findings.

The GOLD and GINA expert committees have recommended a few specialised investigations to distinguish between asthma and COPD. Formal pulmonary function testing may help in making the diagnosis confidently. The diffusing capacity test (DLCO, transfer factor) is discriminatory because in asthma it is either normal or slightly elevated, but in COPD or ACOS it will usually be reduced, reflecting the influence of emphysema. 

Arterial blood gases (ABGs) are normal in between exacerbations of asthma, whereas in COPD it is usually abnormal at baseline. The patient may or may not have evidence of chronic hypercapnia and metabolic compensation in the form of a high bicarbonate level. Allergic biomarkers such as serum total and aeroallergen-specific IgE may support the diagnosis of asthma. 

While not currently in widespread clinical use, high levels of fractional exhaled nitrous oxide (FENO) in non-smokers would be highly suggestive of eosinophilic airway inflammation typical of asthma, unlike in COPD where it is usually normal and levels are low in smokers.

Diagnosis may take time

Of course it has to be acknowledged that the diagnosis of asthma, COPD and ACOS may not be nearly as straight forward as the guidelines would have us believe. The clinician will often have to revisit the diagnosis over time until it may become clear that what starts out resembling COPD is in fact ACOS etc. It remains the case that when faced with a clinical scenario in which both asthma and COPD are equally possible, the treatment should begin in accordance with asthma management. This acknowledges the pivotal role of inhaled corticosteroids (ICS) in preventing significant clinical worsening and even death in asthma patients.⁷

In cases of diagnostic doubt, it is wise to commence ICS therapy on the first visit for a component of asthma. Then launch further investigations to confirm or refute the diagnosis, assessing response to the treatment trial, cognisant of the major challenge of poor adherence to inhaled therapy. 

Depending on the severity of the patient’s symptoms and impact on quality of life, low-dose to moderate-dose ICS should be commenced. It is important to re-emphasise that the asthma or ACOS patient should not be treated with long-acting beta-2 agonists (LABAs) alone if there are discriminating features of asthma, in line with black-box warnings about increased mortality from LABA monotherapy.⁸

If the syndromic assessment suggests that the patient has a high probability of COPD alone, appropriate symptomatic treatment should ensue with a long-acting anti muscarinic agent (LAMA), LABA or combination LAMA/LABA therapy, and not ICS alone.

In the more challenging case of an elderly patient with a smoking history, optimisation of treatment for other comorbidities should of course be consciously considered, such as congestive cardiac failure (CCF) and bronchiectasis, and might require multidisciplinary team involvement. Smoking cessation remains the most important intervention for any chronic airways disease patient irrespective of aetiology. Passive smoking should be addressed as well, and the attending clinician must bring up even a brief smoking cessation intervention with the patient and advise against smoking, in clear terms, ideally in a personalised manner.⁹

Respiratory clinical nurse specialists provide an invaluable resource for corrective instruction around inhaler technique for the many inhalational devices now on the market. In this regard barriers to the use of maintenance medication need to be proactively identified. Patient misconceptions around inhalers should be addressed, and clear instructions provided around the dosing intervals, the purpose of the inhaler and need to refill prescriptions for exhausted inhalers.

Pulmonary rehabilitation

Pulmonary rehabilitation has shown promise in reducing the number of exacerbations and hospital admissions in COPD. Unfortunately, it may not be available to the whole population, and has significant waiting times in many centres. It should certainly be arranged for COPD or ACOS patients who tend to have too many exacerbations, difficulty coping and poor functional status. Patients should also be advised to keep their influenza and pneumococcal vaccinations up to date. 

Both GOLD and GINA guidelines recommend that patients with suspected ACOS should be referred to specialist centres for further investigations and evaluation because of the worse outcomes in this subset of patients. They outline certain situations where the patient’s referral to the specialist centres should be considered, for example, if pharmacological therapy was commenced after the syndromic assessment and the patient failed to respond to the therapy, and their symptoms and lung function continue to decline.

Referral is also needed if there is diagnostic uncertainty and alternative differential diagnoses are possible such as interstitial lung disease, bronchiectasis, post tuberculous scarring, pulmonary hypertension and cardiovascular diseases. 

Another red flag is the presence of atypical symptoms alongside shortness of breath, cough and sputum. For example, if a patient has haemoptysis, significant weight loss, fever or joint symptoms, which may suggest an additional/alternative diagnosis other than asthma or COPD, prompt referral should be considered without waiting to see the response to the trial of treatment for asthma, COPD or ACOS. 

Specialist referral should also be considered when the patient has significant co-morbidities that may contribute to the symptom complex, and make the assessment of their chronic airways disease more complicated. 

In conclusion, the exercise of evaluating a patient for a diagnosis of ACOS in the syndromic approach recommended by current guidelines, will have the added benefit of more confidently assigning either a COPD or asthma diagnosis to the non-ACOS patient. This will help to get a head start over the chronic airways disease in question, which should lead to better patient outcomes.

References

1. National Clinical Programme for COPD data, [www.livingwithcopd.ie] accessed online 02 March 2015
2. National Clinical Programme for Asthma data, [www.hse.ie/asthmaprogramme/] accessed online March 2, 2015
3. Global Initiative For Asthma (GINA) & Global Initiative For Chronic Obstructive Lung Disease (GOLD). Diagnosis of Diseases of Chronic Airflow Limitation: Asthma, COPD and Asthma-COPD Overlap Syndrome (ACOS). 2014 [www.goldcopd.org/uploads/users/files/AsthmaCOPDOverlap.pdf]
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8. Kauppi P, Kupiainen H, Lindqvist A et al. Overlap syndrome of asthma and COPD predicts low quality of life. The Journal of asthma : official journal of the Association for the Care of Asthma 2011; 48:279-85
9. Pleasants RA, Ohar JA, Croft JB et al. Chronic obstructive pulmonary disease and asthma-patient characteristics and health impairment. Copd 2014;11:256-66