A Review of Asthma
Dr. Seamus Linnane
Dr. Lorraine Thong
Introduction:
Asthma is a chronic inflammatory disease of the airways. The term ‘asthma’ was first used by Hippocrates (400 BC) to describe panting and respiratory distress. He was possibly the first physician to observe the relationship between environment and respiratory diseases. The smoking of Stramonium, a herb which is an anticholinergic agent related to ipratropium and tiotropium was first introduced in India by Alexander the Great as an airway relaxant. Pliny the elder (AD 23-79), a Roman author who was thought to suffer from asthma himself observed pollen as a source of respiratory distress and recommended the use of “ephedra” (forerunner of ephedrine) in red wine as an asthma remedy.
The Burden of Asthma
Modern medicine has come a long way in understanding the pathophysiology and treatment in asthma since these ancient civilizations. Today, Ireland has one of the highest rates of asthma prevalence globally. The annual mortality rate from asthma in Ireland is estimated at 62 per annum in the year 2011 with approximately 20,000 and 50,000 attendances to the emergency department and general practice services respectively. Asthma, if effectively treated will allow patients to live a near normal life hence improving productivity and minimising the financial burden of this disease.
GINA Guidelines
The Global Initiative for Asthma (GINA) was established in 1993 to increase awareness about asthma among healthcare professionals, public health authorities and community. It also aimed to improve prevention and management through a co-ordinated worldwide effort. They focus on the 2 main principles of asthma management which are symptom control and risk reduction. The GINA guidelines propose a control-base asthma management where treatment is adjusted in a continuous cycle model ie patient assessment, treatment adjustment and treatment response review.
Diagnosing asthma is an important part of assessment that requires eliciting a history of variable respiratory symptoms and an objective measurement of variable airflow obstruction. The latter can be established with significant bronchodilator reversibility (FEV1 increases by 12% or 200 ml) on spirometry. Assessing symptom control and risk factors are essential along with identifying any treatment issues the patient may have like inhaler technique and side effects. It is also vital to identify other co-morbidities like rhinitis/rhinosinusitis, gastroesophageal reflux disease, obesity, obstructive sleep apnoea, depression and anxiety as they could contribute to respiratory symptoms hence complicating treatment. Asthma control can be assess using questionnaires like the Asthma Control Test (ACT) and Asthma Control Questionnaire (ACQ). When poorly controlled asthma is established, its imperative to examine inhaler technique and investigate compliance. Risk factors and triggers like smoking, NSAIDs and allergen exposure should be taken into consideration and removed if possible.
A step wise approach to increases in treatment should be considered when asthma is poorly controlled despite satisfactory inhaler technique and compliance. Step 1 consists of short acting beta agonist (SABA) alone if symptoms are rare in the setting of no exacerbations and normal pulmonary function tests. Inhaled corticosteroids (ICS) have been shown to have long term benefits on lung function. Step 2 consist of inhaled ICS and as needed SABA. The addition of leukotriene receptor antagonist (LTRA) may be considered at this stage. Step 3 consist of a combination of low dose ICS and a long acting beta agonist (LABA) and step 4 incorporates both agents with medium/high dose corticosteroids. The addition of LTRA, inhaled tioptropium or oral theophylline can also be considered. Patients who remain poorly controlled despite step 4 should be referred to a respiratory physician or specialist centre for consideration of add on therapy.
Patients should be reviewed regularly once treatment is commenced to monitor treatment response. The GINA guidelines recommend 1-3 month follow up after initiation of treatment and 3-12 months thereafter. The exception being pregnancy where patients should be reviewed on a more regular basis ie 4-6 weekly.
Omalizumab and Phenotyping
In recent years, asthma phenotyping has been of great importance especially when considering add on therapies. Omalizumab, an anti-IgE modulator has been a major breakthrough in severe allergic asthma. It has been FDA approved since 2003 in patients above the age of 6 years old and it is given as a 2 to 4 weekly subcutaneous injection. Allergic asthma phenotype patients can be identified clinically and confirmed via a positive skin prick test or with high serum IgE levels. Randomized clinical trials in patients with allergic asthma, have shown omalizumab reduces exacerbation rates but does not have reproducible effects on asthma quality of life scores nor on measures of lung function. Omalizumab has an established role as an add-on therapy for patients with severe refractory allergic asthma. The most common adverse reaction is injection site induration, itching, pain, and bruising. There is limited data for the use of omalizumab in patients with non-atopic asthma. Garcia G et al however demonstrated that omalizumab resulted in a statistically significant reduction in IgE receptor expression on basophils and plasmacytoid dendritic cells after 16 weeks of administration The authors also noted an increased in FEV1 in the same group of patients compared to baseline (+250 ml).
Other Novel Therapies
A deeper understanding of the pathophysiology and biochemical pathways of asthma has led to development of other novel agents. Anti-interleukin-5 (IL-5) antibodies such as mepolizumab and reslizumab have recently emerged and have been shown to be effective in severe eosinophilic asthma. A number of IL-5 targeted therapies have received marketing authorisation in Europe. Severe eosinophilic asthma is an asthma phenotype characterized by the presence of eosinophils in the airways. These patients have sputum eosinophilia or raised peripheral eosinophils of more than 400 cells/ul though different studies may quote different ranges. These monoclonal antibodies inhibit eosinophil function by binding and neutralizing IL-5 or its receptor.
Anti IL-13 antibodies have also been of interest as IL-13 stimulates the production of IgE by B-cells. Lebrikizumab, Tralokinumab and Anrukizumab are some of examples of these agents. Unfortunately clinical trials so far have been rather disappointing. The anti IL-4 agent, Dupilimab, has been shown to improved signs and symptoms of atopic dermatitis with acceptable safety profile in a phase 3 trial by Blauvelt et al in 2017.
Sublingual Immunotherapy
Sublingual immunotherapy (SLIT) has emerged from a long tradition of administering a antigen to a sensitised patient repeatedly at small doses to blunt the immune response to that allergen. Traditionally the antigen was administered via injection. Rare but devastating anaphylaxis restricted use to medically supervised settings. Sublingual immunotherapy has a much better safety profile. First doses have to be given under supervision however subsequent treatment is administered by the patient at home. Tablet preparations of grass pollen and house dust mite are available. A ragweed preparation is available in North America. A standardised bioequivalent antigen dose in tablet form is dissolved under the tongue. Initial studies were confined to allergic upper airway disease and showed improvements in symptom scores and rescue medication. SLIT has been shown to be safe in patients with concomitant asthma. Available studies show lower doses of steroid required to maintain moderate asthma and a longer time to exacerbation when steroids are withdrawn.
Conclusion
Major developments continue in our understanding of the pathophysiology of asthma. The improved understanding has opened up areas for future research into new therapies. Novel therapies are exciting and effective but expensive. Simple factors such as inhaler technique and compliance remains one of the main causes of poorly controlled asthma. The future of asthma is a combination of high tech medical progress and adherence to basic principles of management. Hippocrates would approve.