Chronic severe asthma: a guide to diagnosis and management
BMJ Learningد. حسين محمد جمعة
اختصاصي الامراض الباطنةالبورد العربي
كلية طب الموصل
2010
Asthma is a chronic inflammatory disorder of the airways characterised by:
• Pulmonary symptoms• Reversible airway obstruction
• Evidence of bronchial hyper-reactivity.
Asthma affects 5-20% of the population in Europe, North America, and Australia. Most patients with asthma have mild to moderate disease that you can control by prescribing regular inhaled corticosteroids and short acting inhaled beta2 agonists. But in some patients asthma stays symptomatic despite aggressive treatment with high dose inhaled corticosteroids and beta2 agonists. Patients with severe chronic asthma have the greatest impairment of their lifestyle and account for a high use of healthcare resources. Hospital admissions, unscheduled visits to the doctor, and treatment in emergency departments are common.
Chronic severe asthma.
About 5-10% of patients with asthma have serious symptoms despite high dose inhaled corticosteroids and beta2 agonists.Two to three times more common in women.
Exclude poor compliance and undertreatment before starting the diagnostic work up.
A trial of oral corticosteroids with careful supervision is usually enough to find out whether symptoms are related to poor compliance or undertreatment .
Chronic severe asthma is a serious unremitting form of asthma. Ongoing respiratory symptoms, frequent exacerbations, and persistent airway obstruction despite high dose steroids and beta2 agonists should prompt further investigation .
High dose inhaled corticosteroids combined with a long acting inhaled beta2 agonist are the mainstay of therapy in patients with chronic severe asthma. Many patients also need regular systemic steroids to minimise symptoms
Consider alternative anti-inflammatory and immunomodulatory agents to limit the chronic need for systemic steroids
Also consider a trial with biologics directed against IgE (omalizumab) in patients with the allergic form of chronic severe asthma who fail to respond to alternative anti-inflammatory and immunomodulatory therapies .
Chronic severe asthma is characterised by:
• A component of irreversible airflow obstruction and peripheral airways disease• Neutrophilic inflammation
• Intense airway remodelling
• Ongoing mediator release
• A reduced presence of atopy
An element of corticosteroid resistance or insensitivity. This notion suggests that severe asthma might be a different form of the disease with features that are distinct from mild to moderate asthma, rather than a mere increase in asthma symptoms and severity.
Most patients with severe asthma admitted to hospitals or visiting outpatient clinics are characterised by a variable combination of:
Frequent severe exacerbations
Irreversible airway obstruction
Widespread degree of dependency on systemic steroids.
The consensus of the American Thoracic Society workshop defines chronic severe asthma by the presence of
at least one major criterion and two minor criteria.
The major criteria are:
• Treatment with continuous or near continuous (≥50% of the year) oral corticosteroids
• Need for treatment with high dose inhaled corticosteroids.
The minor criteria are:
• Need for additional daily treatment with a controller medication (for example, a long acting beta agonist, theophylline, or leukotriene antagonist)
• Symptoms needing use of a short acting beta agonist on a daily or near daily basis
• Persistent airway obstruction (forced expiratory volume in one second (FEV1) <80% predicted, diurnal peak expiratory flow variability >20%)
• One or more urgent visits for asthma per year
• Three or more oral steroid bursts per year
• Prompt deterioration with ≤25% reduction in systemic corticosteroid dose
• Near fatal asthma attack in the past.
To diagnose chronic severe asthma you must have excluded other disorders and treated exacerbating factors, and the patient must be generally compliant. The current definition of chronic severe asthma is based mainly on the lack of response to appropriate treatment.
You should assess patients over at least six months before labelling them as having chronic severe asthma. Otherwise, patients with suboptimally controlled mild to moderate asthma, who may initially present with severe symptoms, may be wrongly diagnosed.
Initial investigations include:
Detailed lung function tests including:Measurement of lung volumes
Assessment of small airway function
Bronchial provocation challenge in selected patients
Plain chest radiograph
Arterial blood gases or pulse oximetry.
High resolution computed tomography (CT) of the lung and sputum cytology with a focus on eosinophils and neutrophils may be also useful.
Exclude other diseases
The diagnosis of conditions that may be mistaken for chronic severe asthma is usually obvious if you take a careful history and order the appropriate investigations. In adults, you should think of:
• Chronic obstructive pulmonary disease
• Bronchiectasis
• Congestive heart failure.
In particular, take care to exclude:
• Allergic bronchopulmonary aspergillosis
• Churg-Strauss syndrome.
If you suspect allergic bronchopulmonary aspergillosis look for the following criteria:
• A positive skin test to Aspergillus fumigatus• A total serum IgE of >1000 ng/ml or >417 kU/l
• An elevated serum IgE or IgG (or both) against A fumigatus
• Central bronchiectasis.
The diagnosis of Churg-Strauss syndrome in a patient with severe asthma may be difficult because signs and symptoms of systemic vasculitis, such as fever, weight loss, fatigue, and malaise, are non-specific. In the presence of asthma symptoms the following signs should arouse suspicion of Churg-Strauss syndrome:
• Persistent eosinophilia
• Positive serum antineutrophil cytoplasmic antibodies
• Multiorgan involvement, such as a mononeuropathy multiplex
Review the role of comorbidities
The assessment and subsequent treatment of comorbidities forms the second important part of the clinical work up for chronic severe asthma. The prevalence of chronic rhinosinusitis is high in patients with severe asthma and a thorough examination of the nose and paranasal sinuses is mandatory. Preferably, an experienced ear, nose, and throat specialist should perform this, using nasal endoscopy and CT scanning of the nasal sinuses.Recognising these features is important because concurrent management of chronic rhinosinusitis leads to substantial clinical improvement in disease control.
The same argument holds true for identifying pathological gastro-oesophageal reflux by measuring 24 hour oesophageal pH, even in the absence of reflux symptoms. Taking into consideration that poorly controlled patients are often unable or unwilling to undergo such invasive investigations, you can use a long term trial (≥three months) with proton pump inhibitors as an alternative approach. This can help.
Assess the contribution of unusual asthma triggers
The contribution of unusual asthma triggers is the third critical aspect in the diagnostic work up. Correctly recognising these triggers is important to guide management. First check for exogenous aggravating factors such as:• Cigarette smoking
• Exposure to unusual indoor allergens or irritants
• Contact with environmental chemicals
• Exposure to occupational allergens
• Use of drugs that can provoke asthma attacks (aspirin, non-steroidal anti-inflammatory drugs, beta blockers, angiotensin converting enzyme inhibitors, oestrogens).
Then check for endogenous aggravating factors such as:
• History of rhinosinusitis or previous surgery for nasal polyps• Symptoms of gastro-oesophageal reflux disease or use of antacids
• Recurrent bacterial respiratory tract infections
• Psychosocial factors
• Symptoms of hyperthyroidism
• Influence of menstruation.
Lastly look for:Side effects of treatment
Poor knowledge in skills about how best to self care.It may take several months to exclude environmental exposure to trigger factors, to explore specific psychosocial factors, and to check compliance with therapy.
Once you have completed a thorough review and you have excluded mimicking diseases, associated conditions, and trigger factors with confidence, you can establish a diagnosis of chronic severe asthma. You should now start the appropriate treatment.
Patients with chronic severe asthma may have an abnormal response to:
• Viral respiratory infections
• Exposure to allergens
• Occupational agents or environmental pollutants
• Discontinuation of corticosteroids and maintenance therapy.
These factors are known to precipitate exacerbations. Other potential causes of frequent exacerbations in patients with chronic severe asthma are:
Airway hyper-responsiveness
Air trapping
Early airway closure.
Some adults with chronic severe asthma experience a decline in lung function and develop persistent airflow limitation. This is despite appropriate therapy and in the absence of other risk factors such as smoking and environmental exposure. The airway obstruction in these patients may be indistinguishable from the limitation of airflow seen in patients with chronic obstructive pulmonary disease. In spite of the presence of "irreversible" airway obstruction, some patients still retain some response to bronchodilators.
The reasons why these patients have an accelerated decline in lung function with persistent limitation of airflow are unclear. It is possible that patients who develop persistent limitation of airflow mount a disproportionate response to ongoing inflammatory stimuli. This is characterised by refractory neutrophilic and eosinophilic inflammation of the airways, which results in tissue remodelling and more severe disease.
Many patients with chronic severe asthma need high doses of prednisolone (>30 mg) to control their symptoms. They get worse as soon as the dose of corticosteroids is tapered. The occurrence of this reduced responsiveness to inhaled and oral corticosteroids characterises a distinct subphenotype and appears to be related to a number of mechanisms including:
• Downregulation of glucocorticosteroid receptors
• Altered affinity of the ligand for glucocorticosteroid receptors
• Reduced ability of glucocorticosteroid receptor ligand complex to bind to DNA
How do I treat it?
Treatment should achieve the best possible control and quality of life with the least dose of medication, particularly systemic steroids. The choice and formulation of therapeutic agent is dictated by the severity of disease and includes:• Conventional pharmacotherapy
• Alternative pharmacotherapy
• Biologic therapies (omalizumab).
Conventional pharmacotherapy
Standard treatment for chronic severe asthma includes:
• High dose inhaled corticosteroids .
• A long acting inhaled beta2 agonist as the preferred add on therapy.
• This is often administered by a single inhaler device.
Alternative pharmacotherapy
To minimise the chronic need for systemic steroids and to reduce their side effects, an exploratory trial with existing immunomodulators should be considered. In particular, given the evidence and the reasonable safety profile, low dose methotrexate should be used as a first choice in the treatment of unremitting disease. Gold, ciclosporin, or macrolide antibacterials may be used as an alternative, but their efficacy is much lower compared to methotrexate.It is mandatory to carefully monitor symptoms and to carry out laboratory tests to avoid side effects. If adding these drugs does not lead to a substantial reduction in the need for oral corticosteroids within 24-36 weeks, withdraw them promptly.
Methotrexate
Methotrexate at low doses retains anti-inflammatory properties with little toxicity. In chronic severe asthma a number of mixed results have been reported with oral methotrexate, 7.5-30.0 mg/weekly for three to six months. In two prospective case series of 31 and 21 patients with chronic severe asthma treated with oral or intramuscular doses of methotrexate (15 mg/week) for up to 28 months, a statistically significant reduction in the baseline prednisolone dose was reported with over half of the patients being weaned off all steroid therapy.Side effects of methotrexate are common but are seldom life threatening at low dose. These include abnormal liver function and gastrointestinal symptoms (including abdominal pain, nausea, and diarrhoea), oral ulcers, and stomatitis.
These are normally transient and reversible. Treat for 12 to 28 months and monitor liver function tests, albumin levels, and full blood count.
Gold
Gold is an immunomodulatory agent that has been used commonly in the past for treating different inflammatory conditions. In the largest prospective randomised study examining the efficacy of gold in chronic severe asthma a significant overall reduction in the use of daily systemic corticosteroid dose by ≥50% was observed in patients treated with oral gold 3 mg twice per day (for six months), compared with those receiving placebo (60% versus 32%, respectively).Side effects of gold are common, but mild. Gastrointestinal upset and pruritic rash are the most common side effects, but they are self limiting when therapy is discontinued or reduced. Treatment is for six to eight months with 3 mg twice per day. Think about monitoring full blood cell count and urine dipstick for protein.
Ciclosporin
A fungal metabolite commonly used in organ transplantation, is well known for its immunomodulatory and anti-inflammatory effects. Two out of the three published prospective (≥three months) randomised trials with ciclosporin (loading dose, 5 mg/kg/day) in patients with steroid dependent asthma resulted in:
An improvement in lung function
A reduction in exacerbations needing increased steroid doses
Important cuts in the median daily use of prednisolone.
These studies didn't observe serious side effects in the low doses, but several patients experienced hypertrichosis and a worsening of pre-existing hypertension that resulted in the discontinuation of therapy. Paraesthesiae, tremor, headache, and flu-like symptoms were also common.
Although long term experience in chronic severe asthma has never been reported, its long term use in other chronic inflammatory conditions (such as ulcerative colitis) is characterised by a substantial failure rate. Treatment shouldn't extend beyond 12 months. You should monitor creatinine and potassium levels, full blood cell count, liver function tests, and albumin levels.
Macrolide antibacterials
Macrolide antibacterials, in particular troleandomycin, have been shown to decrease the need for methylprednisolone in patients with corticosteroid dependent asthma. Several studies demonstrated the clinical efficacy of troleandomycin. They showed an improvement in clinical symptoms or a reduction in methylprednisolone dosage, or both.Steroid related side effects are common with the use of troleandomycin, especially in earlier trials when patients were given doses of 1 g daily. Cushingoid features, bone loss, weight gain, fluid retention, and glucose intolerance were the most common findings.
Interestingly, in a small case series of three patients with corticosteroid dependent asthma, two of three patients discontinued prednisolone after one year of clarithromycin therapy (500 mg twice per day) and no serious side effects, bacterial resistance, or immunosuppression were reported.
In view of their sound safety profile, it is reasonable to start a patient with severe unremitting disease on clarithromycin empirically. The dose of troleandomycin is 250 mg/day for 12 to 24 months, the dose of clarithromycin is 500 mg twice per day for 12 months. Troleandomycin is not licensed for this use in the UK.
Biologic therapies (omalizumab)
In recent years new strategies have been developed. Some might be alternatives to systemic corticosteroid therapy or may have corticosteroid sparing effects. In patients who do not respond to alternative anti-inflammatory and/or immunomodulatory drugs, you could consider a trial of humanised monoclonal immunoglobulin G1 blocking antibody directed against IgE (omalizumab). These have been tested in atopic patients with chronic severe asthma with some success, but there is still limited information on their long term clinical use.Which one of the following medications should you consider to minimise some of the side effects of systemic steroids?
You should prescribe vitamin D or bisphosphonates (or both) and calcium for bone protection (particularly in postmenopausal women).
Azathioprine, a safe steroid sparing agent, may be useful for steroid refractory asthma, but large long term studies are needed before recommendations for clinical practice can be made. Analgesics do not control steroid dependent side effects. Oral hypoglycaemic drugs do not control steroid induced hyperglycaemia (rapid onset, fast acting insulin is indicated). Diuretics have no role in reducing steroid dependent side effects.
Gastrointestinal upset and pruritic rash are the most common side effects of oral gold. Abnormal liver function tests are hardly ever seen.
Abnormal liver function tests, stomatitis, and gastrointestinal symptoms (for example, abdominal pain, nausea, and diarrhoea) are common, but are generally transient and reversible with low dose methotrexate. You can minimise them by prescribing weekly folic acid supplements or by reducing the dose of methotrexate.
Injection site reaction, headache, and pharyngitis are the most common side effects of omalizumab. Important abnormalities of liver function tests have not been reported.
