Management of severe/difficult to treat asthma in adults
Mina Gaga MD, PhD Consultant and Head, Asthma Center and 7th Respiratory Medicine Dept, Athens Chest Hospital

Severe Asthma in Children
Andrew Bush MD FRCP FRCPCH Professor of Paediatric Respirology, Imperial College, & Honorary Consultant Paediatric Chest Physician, Royal Brompton Hospital, London, UK.

Severe asthma
Pascal Chanez, University de la méditerrannée, Dept of Respiratory Diseases, AP-HM Marseille France

When managing severe asthma, It is important to

1. Address all of the patient’s problems and to individualize the approach
2. Consider the patient’s life style and address not only pharmacotherapy but also exercise, work, diet and smoking
3. Provide education and ensure good-patient-doctor relationship
4. Follow up the patient for a long time

Chanez et al JACI 2007, Gaga et al, Curr Med Chem 2007

Summary and Conclusions (Andrew Bush MD FRCP FRCPCH Imperial School of Medicine & Royal Brompton Hospital)

• Do not forget the obvious: Wrong diagnosis, Not taking treatment, Cannot use device
• Ask the key question: What makes this asthma difficult?
• Consider environmental causes of steroid resistance
• Only then think of escalating therapy

Severe Asthma
Pascal Chanez, University de la méditerrannée,
Dept of Respiratory Diseases AP-HM, Marseille France

Severe asthma is diagnosed in patients with refractory asthma that is difficult to control despite a thorough reevaluation of the diagnosis and management and after more than 6 months of follow-up by a physician specializing in asthma.

Respiratory function measurements and reversibility and bronchial provocation tests (except when contraindicated) are essential in the reevaluation of an asthma diagnosis.

Factors that can influence asthma control, such as environmental exposures, co-morbid conditions, treatment adherence, and in particular inhalation technique must be recognized and considered appropriately before confirming the diagnosis of severe asthma.

Objective criteria are important in the follow-up evaluation of severe asthma. They must include the measurement of some disease components. During follow-up, it is recommended that patients be monitored by validated questionnaires about quality of life and asthma control and by pulmonary function measurements, airway inflammation assessment, and recording the frequency of exacerbations and healthcare system use (including whether planned or unexpected).

Severe asthma is a heterogeneous condition that includes several phenotypes. Determining the phenotype of each case of severe asthma will improve our understanding of its underlying mechanisms, natural history and prognosis, will help guide the choice of current and future treatments and will provide useful indications for new therapeutic interventions.

Chanez P, Wenzel SE, Anderson G, Anto J, Bel EH et al. Severe asthma: what are the important questions? J Allergy Clin Immunol 2007 119(6):1337-48. Epub 2007 Apr 9.

Severe Asthma in Children
Andrew Bush MD FRCP FRCPCH Professor of Paediatric Respirology, Imperial College, &
Honorary Consultant Paediatric Chest Physician, Royal Brompton Hospital, London, UK.

Most asthma in children responds to low or moderate doses of inhaled steroids. Difficult asthma is variously defined in the literature, but we would define it as ‘asthma which has not responded to 800 micrograms/day beclomethasone equivalent, plus long acting beta-2 agonist, plus leukotriene receptor antagonist’. There are two categories of ‘difficult asthma’; the first is those children who, when the basics are got right (below), the asthma becomes controlled (‘difficult to treat asthma’); and the second, true, ‘severe’ (therapy resistant) asthma. When seeing children with difficult asthma, it is important to consider:

• Is the diagnosis correct?

• Is the drug delivery device appropriate?

• Are there important environmental issues?

• Are there important psychological issues?

These are addressed in the first stage of our difficult asthma protocol, which includes a detailed, multidisciplinary assessment, and a home visit. In more than 50%, the asthma then becomes controllable. If there is still a problem, we then proceed to the second and third stages, to determine the pathological phenotype. We assess airway inflammation, bronchial responsiveness and best attainable airway calibre by measuring spirometry and reversibility, exhaled nitric oxide, and induced sputum cytology before and after an injection of depot triamcinolone, with fibreoptic bronchoscopy, bronchoalveolar lavage and endobronchial biopsy before the injection only. Pathological phenotypes we have delineated include:

• Eosinophilic inflammation, but controlled by high dose steroids

• Eosinophilic inflammation, resistant to steroids, with ongoing poor asthma control

• Eosinophilic inflammation, resistant to steroids, but with good ongoing asthma control

• Neutrophilic asthma

• Paucicellular asthma with marked airway lability

• Fixed airflow obstruction.

Different therapeutic strategies are adopted for these phenotypes.

Management of severe/difficult to treat asthma in adults
Mina Gaga MD, PhD
Consultant and Head, Asthma Center and 7th Respiratory Medicine Dept, Athens Chest Hospital

The current pharmacological approach to the treatment of difficult asthma follows a stepwise approach. Most patients with difficult asthma meet the GINA criteria for step 4 and 5, uncontrolled asthma or the U.S. National Asthma Education and Prevention Program guidelines criteria for step 4, severe, persistent asthma, and require high dose inhaled corticosteroids and long-acting inhaled β2-agonists as therapy, as well as additional medication such as theophylline, oral steroids, leukotriene-antagonists and anti IgE.

Inhaled and oral corticosteroids are extremely potent anti-inflammatory medications. They address most of the causes of airflow obstruction in asthma, including mucosal oedema, airway inflammation, increased mucus secretion and airway remodelling. They have been shown to be effective in the treatment of severe persistent and uncontrollefd asthma but many questions still remain to be defined. The optimal starting and maintenance dose of inhaled corticosteroids (ICS) in severe disease is 800-2000mcg but the dose must be individually titrated for each patient and each preparation.

Studies performed since the early 1990’s showed that although inhaled corticosteroids (ICS) are the best anti-inflammatory medications, combination treatment with ICS and long-acting β2-agonist resulted in better symptom control and fewer exacerbations compared to doubling the ICS dosing.. A recent Cochrane review examined 10 randomised, controlled studies and reported that long-acting β2-agonists have a corticosteroid-sparing effect and that their use allows reductions of up to 57% in ICS dosing. The review also states that the magnitude of ICS dose reduction requires further study

Add on medication options include methylxanthines and a recent study has demonstrated that they provide further bronchodilalory benefits when added to a medium dose of inhaled steroids in symptomatic patients, leukotriene antagonists, also less potent than LABAs in reducing symptoms and exacerbations and anti-IgE (omalizumab). Omalizumab has been shown to reduce the number of exacerbations and allow reductions in steroid dosing. Interestingly, there appears to be little effect on lung function.

To date, a combination of inhaled corticosteroids and bronchodilators is the mainstay of severe persistent asthma treatment with the additional use of other medication classes such as oral sreroids, omalizumab, methylxanthines and leukotriene antagonists are, but research into newer compounds is clearly necessary. The use of other monoclonal antibody based treatments and thermoplasty are investigated.

Références

1. Global Strategy for Asthma Management and Prevention. NIH Publication No 02-3659 Issued January, 1995. Management Segment (Chapter 7): Updated 2006 www.ginasthma.comn.

2. National Asthma Education and Prevention Program (National Heart, Second Expert Panel on the Management of Asthma, Expert panel report: guidelines for the diagnosis and management of asthma : update on selected topics, 2002, U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program, Bethesda, Md. 2003.

3. Pijnenburg MW, Bakker EM, Hop WC, De Jongste JC. Titrating steroids on exhaled nitric oxide in children with asthma: a randomized controlled trial. Am J Respir Crit Care Med. 2005 ;172:831-6.

4. A. P. Greening, P. W. Ind, M. Northfield, G. Shaw, Lancet 1994, 344 219-224.

5. Gibson P, Powell H, Ducharme F, Gibson P. Long-acting beta2-agonists as an inhaled corticosteroid-sparing agent for chronic asthma in adults and children. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD005076

6. Leckie MJ, ten Brinke A, Khan J, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000; 356: 2144–2148.

7. Walker S, Monteil M, Phelan K, Lasserson TJ, Walters EH. Anti-IgE for chronic asthma in adults and children. Cochrane Database Syst Rev. 2004;(3):CD003559.

8. Chanez P, Wenzel SE, Anderson G, Anto J, Bel EH, Gaga M et al. Severe asthma: what are the important questions? J Allergy Clin Immunol 2007 119(6):1337-48. Epub 2007 Apr 9.

9. Gaga M, Zervas E, Grivas S, Castro M, Chanez P. Evaluation and management of severe asthma. Curr Med Chem. 2007;14(9):

création: août 2007