Introduction

Last year, 66% of Indians reported asthma exacerbations¹

Due to asthma, 78% of Indians missed work or school in previous year¹

In the Asia-Pacific region, Indians had the longest average absence from work or school of 16.5 days¹

Productivity of Indians decreased by 50% in the previous year due to asthma¹

Approximately 15.0 million outpatient visits, 2 million emergency room visits and 5,00,000 hospitalizations occur in the US each year due to acute asthma³

Frequency of high exacerbations are linked with poor quality of life and irreversible decline in lung function^1,3,4

Defining the Problem

The Global Initiative for Asthma Management (GINA) guidelines describe asthma exacerbations as follows: “Exacerbations of asthma (asthma attacks or acute asthma) are episodes of progressive increase in shortness of breath, cough, wheezing or chest tightness, or some combination of these symptoms and are characterized by decreases in the expiratory airflow that can be quantified and monitored by measurement of lung function (peak expiratory flow [PEF] or forced expiratory volume in 1 second [FEV1])”.

However, this description lacks a clear definition and several clinical trials have used different definitions of an asthma exacerbation. Hence, the American Thoracic Society (ATS) and the European Respiratory Society (ERS) jointly released a consensus document in 2009 with an aim to standardize the definition of asthma exacerbations as per their severity.

However, these definitions have been developed with respect to clinical trials and may not necessarily be valid in clinical practice. Further information regarding these definitions can be found in Am J Respir Crit Care Med. 2009; 180:59–99 available at http://www.thoracic.org/statements/resources/allergy-asthma/ats-ers-asthma-control-and-exacerbations.pdf

What Exactly Happens in an Asthma Exacerbation?

The hallmark feature of an asthma exacerbation is the surge in the inflammation in the airways. The classical notion is that the cause of the exacerbation is usually attributable to allergens such as dust mites, pollen, etc., leading to predominant eosinophilic inflammation. However, there is data that inflammation in asthma exacerbations is heterogeneous and could involve predominant neutrophils due to viral infections. In fact, viral infection is the most dominant trigger for an asthma exacerbation for both adults and children.

Evolution of an Exacerbation in the Airways

Asthma is a chronic inflammatory disease with variable episodic attacks. Chronic inflammation in asthma is associated with sub-epithelial fibrosis, smooth muscle hyperplasia/hypertrophy, mucous gland hyperplasia and neo-vascularization. On the entry of an allergen or some other trigger, there is a substantial increase in this chronic inflammation (Figure 1). This acute inflammation in asthma is associated with bronchoconstriction, plasma exudation/oedema, vasodilatation and mucous hypersecretion, all of which are the pathophysiological features of an asthma exacerbation. The clinical result of these events is that the patient experiences increased breathlessness, coughing, wheezing and chest tightness. The severity of the exacerbation is dependent on the extent of this acute inflammation and, hence, it is essential to treat this acute inflammation.


Exacerbations therefore, are a consequence of acute-on-chronic inflammation induced by the triggers, viral infections, dust, pollen, etc.

Clinical Evolution of an Exacerbation (Figure 2)

The analysis of the 425 exacerbations in the FACET* trial revealed the following:

Knowing the rate of change in the PEF and the symptoms as an exacerbation develops might help to determine whether the exacerbations can be identified at an early stage. This would enable treatment to be started earlier — thereby reducing the severity of the exacerbation, and this is the idea behind the SMART regimen (Figure 2).
{*FACET: The Formoterol and Corticosteroids Establishing Therapy trial was a double-blind, randomized, parallel-group trial with 852 patients, who had been on inhaled corticosteroids [ICS] before the start of the study, receiving either low-dose budesonide (100 mcg), low-dose budesonide plus formoterol (12 mcg), high-dose budesonide (400 mcg), or high-dose budesonide plus formoterol (12 mcg) twice daily along with a short-acting beta2-agonist (SABA) as rescue medication. The primary endpoint was the incidence and the rate of severe and mild exacerbations. The study concluded that in patients who have persistent symptoms of asthma despite treatment with ICS, the addition of formoterol to budesonide may be beneficial in improving asthma control.}

Impact of Exacerbations

Exacerbations not only impact the quality of life in patients but are also detrimental to the lung function over the long term. There have been reports of accelerated loss in lung function to the extent of 30.2 ml per year-decline in the FEV1 after one severe exacerbation annually (a follow-up of 11 years).
Exacerbations activate pathways of inflammation and remodelling, resulting in deterioration of lung function. Accelerated loss of lung function, in turn, puts patients at increased risk of recurrent exacerbations, resulting in a vicious cycle that may promote the exacerbation-prone phenotype (Figure 3).

At Risk for Exacerbation: The Likely Candidates

Patients who are at risk for exacerbations include the following:

Classifying the Severity of an Exaberation

Classifying the severity of asthma exacerbations is important as it also helps identify the correct treatment approach. The following approach (Table 1) has been proposed by the GINA guidelines.
In addition to the GINA guidelines, a more concise approach has been proposed by the National Asthma Education and Prevention Program (NAEPP): Expert Panel Report 3, the asthma management guidelines for the United States of America (USA).
This can be accessed at: http://www.nhlbi.nih.gov/guidelines/asthma/11_sec5_exacerb.pdf

Table 1: Classifying the severity of asthma exacerbations

Treatment and Management

Treating an asthma exacerbation early is the most effective management strategy and, for this, it is essential that patients learn to understand the signs and symptoms for taking appropriate action. A mild exacerbation, although considered just outside the normal variation of day-to-day symptoms, can be easily treated at home (Figure 4):

Figure 4: Home treatment of a mild asthma exacerbation

A moderate exacerbation requires an emergency room visit, while a severe exacerbation may result in hospitalization. A life-threatening exacerbation where respiratory failure is imminent could possible require an admission into the intensive care unit.

Figure 5 describes the approach that the GINA guideline recommends for managing asthma exacerbations in acute-care settings such as the emergency room or hospital or intensive care unit.

Figure 5: Management of asthma exacerbations in acute-care settings

Oral corticosteroids are usually as effective as those administered intravenously and are preferred because this route of delivery is less invasive and less expensive.

If vomiting has occurred shortly after administration of oral corticosteroids, then an equivalent dose should be re-administered intravenously. In patients discharged from the emergency department, intramuscular administration may be helpful, especially if there are concerns about compliance with oral therapy. Oral corticosteroids require at least 4 hours to produce clinical improvement.

Daily doses of systemic corticosteroids equivalent to 60–80 mg methylprednisolone as a single dose, or 300–400 mg hydrocortisone in divided doses, are adequate for hospitalized patients, and 40 mg methylprednisolone or 200 mg hydrocortisone is probably adequate in most patients.

Preventing Asthma Exacerbation

The age old wisdom of “Prevention is better than Cure” holds true even in the case of asthma exacerbations. Indeed, preventing asthma exacerbation is an important component of establishing asthma control and is one of the key recommendations of the various asthma guidelines.

The most effective and proven strategy to reduce the risk of asthma exacerbations is the regular use of ICS. The regular use of combination of ICS and long-acting beta2-agonists (LABAs) also confers additional benefit in terms of reducing the risk of asthma exacerbations.

One of the strategies to reduce the risk of asthma exacerbations, which has emerged in the recent years, is using a budesonide/formoterol combination as the single maintenance and reliever therapy (SMART). The basic principle behind SMART is the pharmacological properties of formoterol such as fast onset of action and dose–response effect, which enables the budesonide/formoterol combination to be used as maintenance as well as reliever.

Large-scale, randomized, blind clinical studies in patients with asthma, aged 12 years or older, have highlighted the benefits of the budesonide/formoterol maintenance and reliever therapy, which has shown a consistent decrease in the rate of asthma exacerbations (Figure 6).

Additionally, the other therapeutic options to reduce the risk of asthma exacerbations, which are currently being studied, are monoclonal antibodies such as omalizumab (directed against immunoglobulin E), mepolizumab (directed against interleukin-5) and bronchial thermoplasty. Though the initial clinical studies have shown some positive results, it could be some time before these treatments become easily available for the reduction of asthma exacerbations.

Summary

References

1. Respirology. 2013; 18(6):957–967
2. Pol Arch Med Wewn. 2010; 120 (12):511–517
3. Clin Exp Allergy. 2009; 39(2):193–202
4. Prim Care Respir J. 2007; 16(1):22–27
5. Global Initiative for Asthma Management (GINA) Guidelines–Update 2012
6. J Allergy Clin Immunol. 2008; 122:662–668
7. Am J Respir Crit Care Med. 2009; 180:59–99
8. Curr Opin Allergy Clin Immunol. 2011; 11:181–186
9. J Allergy Clin Immunol. 2011; 128:1165–1174
10. Pharmacol Ther. 2011; 131(1):114–129
11. Am J Respir Crit Care Med. 1999; 160(2):594–599
12. Am Fam Physician. 2011; 84(1):40–47
13. J Allergy Clin Immunol. 2011; 128:257–63
14. Pulm Pharmacol Ther. 2010; 23(2):88–96