ReferenceReference

Optimal Management of Severe/Refractory Asthma

Clinical Medicine Insights: Circulatory, Respiratory and Pulmonary Medicine 2011:5 37–47

Optimal Management of Severe/Refractory Asthma

Clinical Medicine Insights: Circulatory, Respiratory and Pulmonary Medicine 2011:5 37–47

1.Definition

2.Diagnosis

3.Risk factors.

4.The Pathology of Refractory Asthma

5.Treatment

.A chronic inflammatory disorder of the airways

.Many cells and cellular elements play a role

.Chronic inflammation is associated with airway hyper responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing particularly at night or in the early morning

.Widespread, variable, and often reversible airflow obstruction

GINA 2011

Refractory Asthma” should be defined on the basis of

.med-ication requirements,

.asthma symptoms ,

.frequency of asthma exacerbations, and

.Degree of airflow limitation.

According to American Thoracic Society workshop consensus for definition of severe/refractory asthma: (published in 2000).

Definition requires that at least one major criterion and two minor criteria are met.provided that:

1.other disorders have been excluded, 2.exacerbating factors have been treated, and

3.patient is generally compliant.

1.Treatment with continuous or near continuous (≥50% of

year) oral corticosteroids.

2.Need for treatment with high-dose inhaled corticosteroids.

Drug Dose (puffs/d) Dose (μg/d)

a. Beclomethasone

dipropionate >40 puffs (42

μg/inhalation

>20 puffs (84

μg/nhalation

>1,260

b. Budesonide >6 puffs >1,200

c. Flunisolide >8 puffs >2,000

d. Fluticasone

propionate >8 puffs (110 μg/), . 4

puffs (220 μg/) >880

e. Triamcinolone

acetonide >20 puffs >2,000

1.Need for additional daily treatment with a controllermedication (e.g long-acting β agonist, theophylline, or

leukotriene antagonist.(

2 .Asthma symptoms needing short-acting β2 agonist use on a daily or near-daily basis.

3 .Persistent airway obstruction (FEV1 >80% predicted, diurnal peak expiratory flow variability >20%)

4 .One or more urgent care visits for asthma per year.

5.Three or more oral steroid bursts per year.

6 .Prompt deterioration with ≤25% reduction in oral or intravenous corticosteroid dose

7 .Near-fatal asthma event in the past

.Misdiagnosis may be as high as 10%

.exposure to factors that may contribute to a poor response to conventional therapy (risk factors).

.Nonadherence with oral steroid therapy has been reported at30%, and

.in some cases there is a significant psychological factors to patients’ symptoms and percetion of their asthma.

1.Chronic Obstructive Pulmonary Disease (COPD)

2.Bronchiectasis and cystic fibrosis

3.Primary bronchiolar disorders

4.Congestive heart failure

5.Upper airway obstruction

6.Aspiration or inhaled foreign body

Fatal or near fatal asthma

Severe asthma

Steroid-dependent and/or resistant asthma

Difficult to control asthma

Poorly controlled asthma

Brittle asthma (either Type 1 or Type 2, depending on the stability of the patient's maximum speed of expiration, or peak expiratory flow rate (PEFR). Type 1 is characterized by sustained, chronic variability of PEFR, while type 2 is distinguished by sudden unpredictable drops in PEFR where asthma symptoms are otherwise well controlled and the function of the lungs is not substantially impaired)

Irreversible asthma

1exacerbating factorsGastro-oesophageal reflux (GERD) is commonly associated with chronic asthma both in adults and children.Environmental exposures

1.Tobacco smokea.In uterob. Environmental

2 .Allergen sensitization3 .Viral infections

4 .Occupational agents5 .Air pollutants

6 .Stress

Systemic diseasesCarcinoid syndromeChurg-Strauss syndrome and others vasculitides

DrugsB-blockersNonsteroidal anti-inflammatory drugs

Chronic infectionsMycoplasmaChlamydiaFungi (especially Aspergillus species)

Bronchopulmonary allergic aspergillosis is very important, if left untreated it can lead to bronchiectasis

Psycological factors

Comorbidity,The coexistence of:

Chronic rhinitis, nasal polyposis, and sinusitis contribute to asthma severity.Endocrine factors:

Severe asthma is two to three times more common in women than in men

Due to a genetic polymorphism of the oestrogen receptor which affecting disease severity

ThyrotoxicosisObesity

4.The Pathology of Refractory AsthmaPathological features of severe/ refractory asthma:

1.persistent inflammation :Although chronic asthma is associated with airway eosinophilia but when the disease adopts a severe phenotype the inflammatory profile commonly changes to the presence of neutrophils alone or in combination with eosinophils.

the neutrophils also seem to be in an activated state with their numbers correlating with indices of airway damage and reduced corticosteroid responsiveness with increased expression of TNFα and interferon-γ.

.In addition, neutrophils have been seen in increased numbers

in patients dying of status asthmaticus

.Studies of sputum samples from patients undergoing emergency room

.visits for status asthmaticus, as well as studies of bronchialwashes from patients intubated for status asthmaticus, alsosupport the concept that the neutrophil may be an importantinflammatory cell in more severe forms of asthma

Figure 3: Possible cellular targets for TNFα in severe corticosteroid refractory asthmaICAM=interstitial cell adhesion molecule. VCAM=vascular cell adhesion molecule. MAPK=mitogen-activated protein kinase. TNFα is stored in granules and is releasedin large amounts from mast cells and macrophages as a result of immunological stimulation. In the airways, TNFα elicits a general infl ammatory response mainlythrough enhanced release of pro-infl ammatory and chemotactic mediators and upregulation of adhesion molecules. These series of events will ultimately lead tochronic eosinophilic and neutrophilic infi ltration and irreversible airway remodelling. TNFα also has a potent direct e ect on the ffairway smooth muscles leading to an increase in airway hyper-responsiveness . Adapted from Clin Sci 2005; 109: 135–42 with permission of Portland Press.

www.thelancet.comVol 368 August 26, 2006

.The mass of airway smooth muscle appears to be clearly increased in severe/refractory asthma as opposed to mild to moderate asthma or COPD

.Thickness of the basement membrane, though of unknown pathophysiological relevance, has been shown to be increased in severe/refractory asthma as compared to mild asthma and COPD

Figure 2: Infl ammatory and remodelling responses in asthma with activation of the epithelial mesenchymal trophic unitEpithelial damage alters the set point for communication between bronchial epithelium and underlying mesenchymal cells, leading to myofibroblast activation, anincrease in mesenchymal volume, and induction of structural changes throughout airway wall.

)Adapted from J Allergy Clin Immunol 2003; 111: 215–25, with

permission of Elsevier(.

In fatal asthma and sever asthma these inflammatory and remodelling processes are found not only in large but also small

airways .

Extensive small-airway involvement in severe disease has important implications for inhaled drug delivery and might explain the increased efficacy of the hydrofl- uoroalkane formulations of corticosteroids and available drugs.

Evidence-based Management of Severe/Refractory Asthma:

it is important to:) 1 (confirming the diagnosis of asthma,

) 2 (evaluate and treat confounding or exacerbatingfactors, and

) 3 (optimized the “standard” asthma pharmacotherapy

-To prevent chronic and troublesome symptoms,

-To normalize pulmonary function,

-To maintain normal activity levels,

-To prevent exacerbations

-To improve health-related quality of life and

-To provide optimal pharmacotherapy with minimal or no adverse effects.

A personalized self-treatment written Asthma Actionplan guided by symptoms or peak flow meter shouldbe developed in collaboration with the educator andthe respirologist.The action plan should include instructions:

regarding the maintenance medication scheduledoses of rescue therapy for increased symptoms,and when and how to seek urgent or emergency care.

such as yearly influenza vaccines

and pneumococcal polysaccharide vaccine

GERD

Obesity and OSA

5.smoking cessation

6.Adherence

especially to corticosteroid therapy

7. Psychological disturbances control

at home such as dust mites,

cats, cockroaches and other domestic pets should be

reviewed.

and ABPA treatment

Levels of Asthma Control(Assess patient impairment)

Assessment of Future Risk (risk of exacerbations, instability, rapid decline in lung function, side effects)

Shaded green - preferred controller options

TO STEP 3 TREATMENT, SELECT ONE OR MORE:

TO STEP 4 TREATMENT, ADD EITHER

Mainstay pharmacotherapy for severe/refractory

asthma is combination of inhaled corticosteroids

)ICS( and one or two controller agents such as longacting ß2-agonists (LABA), leukotriene modifiers ororal theophylline. Recently, tiotropium bromide was demonstrated to be effective as an add-on controllertherapy to ICS in uncontrolled asthma

several alternative options have been evaluated intreating severe/refractory asthma. Cochrane review ofrandomized controlled trial determined that there wasinsufficient evidence to support the use of azathioprine,

chloroquin, cyclosporine, gold or methotrexate in thetreatment of chronic asthma as a steroid sparing-agent.

For most of these agents the side-effect profile is notpreferable

Macrolide antibiotics have shown immunomodulatory effects in neutrophilic lung diseases such as panbronchiolitis in East Asians and cystic fibrosis.

More recently, clarithromycin was demonstrated

to modulate IL-8 and neutrophil accumulation in

refractory asthmatics in a randomized trial.

A randomized placebocontrolled trial by Denning and colleagues on severe asthmatics with fungal sensitization demonstrated by skin prick or specific IgE testing showed treatment

with oral itraconazole (200 mg twice a day) over a 32 week period increased asthma related quality of life .

Immunoglobulin E (IgE) plays a pivotal role inthe molecular pathway responsible for the allergic response.Omalizumab which is a humanized recombinant monoclonal anti-IgE antibody was shown to reduce emergency room visits and exacerbations, when added to high dose ICS and LABA therapy.Also several studies evaluating Omalizumab have demonstrateda clinical effect on markers of airway inflammation,asthma symptom severity, inhaled corticosteroid use ,

and quality of life in patients with moderate to severe asthma

Bronchial thermoplasty

.Bronchial thermoplasty is a bronchoscopic procedure where controlled radiofrequency energy is delivered to the airways through the catheter, heating the smooth muscle through the catheter, heating the smooth muscle walls of the airway to approximately 149˚ walls of the airway to approximately 149˚ F (F (65 degrees Celsius) in order to reduce the airway smooth muscle mass and attenuate bronchoconstriction.

.More than 5 years ago, dog experiments revealed that:

Bronchial thermoplasty might have therapeutic benefits for asthma subjects by reducing airway hyperresponsiveness.

This has now been tested in asthmatic subjects in randomized controlled trials(A well

powered, sham controlled, double-blind multi-center

Study(

The earlier trials performed on moderately severe and severe asthmatic subjects were disappointing due to the notable adverse effects of the treatment and the lack of any effect on airway hyperresponsiveness

Thus, bronchial thermoplasty can not be offered to severe/refractory asthmatics as it has neither proven to be effective nor safe.

While the National Institue for Health and Clinical Excellence (NICE) issued a consultation document on bronchial thermoplasty for severe asthma, which states that evidence on the safety of bronchial thermoplasty is adequate in the short- and medium-term, although patients may experience exacerbation of symptoms after the procedure .

) Campbell, 2011.(

In summary, although available data are promising, more research is needed to ascertain what role, if any, bronchial thermoplasty should play in the treatment of patients with asthma

Figure 4: Algorithm of possible strategies and recommendations for managing patients with difficult to control asthma despite maximum

combination treatment

1 .Titrate down oral steroids (administer the lowest amount of oral steroid to control/stabilise symptoms)2. Consider adding a steroid sparing drug (eg, azathioprine, methotrexate)3. Add treatment for steroid-induced adverse e ects (eg, ffosteoporosis)4. If uncontrolled, consider alternative therapeutic options (eg, omalizumab, etanercept, high dose IVIG)5. Frequent periodic re-evaluations.

Reference:Stephen T Holgate and Riccardo Polosa; The mechanisms, diagnosis, and management of severe asthma in adults Lancet 2006; 368: 780–93-+

Other references:1.Smita Pakhale, Sunita Mulpuru and Matthew Boyd; Optimal Management of

Severe/Refractory Asthma. Clinical Medicine Insights: Circulatory, Respiratory and Pulmonary Medicine 2011:5 37–47

2.National Institute for Health and Clinical Excellence (NICE). Bronchial Thermoplasty for severe asthma - consultation document. London, UK: NICE; July 2011. Available

at :http://guidance.nice.org.uk/IP/675/DraftGuidance

3.D.L. URSO, D. VINCENZO, F. PIGNATARO, P. ACRI*and G. CUCINOTTA*; Diagnosis and treatment of refractory asthma European Review for Medical and Pharmacological Sciences 2008; 12: 315-320

4.Stephen T Holgate and Riccardo Polosa; The mechanisms, diagnosis, and management of severe asthma in adults Lancet 2006; 368: 780–93

5..Proceedings of the ATS Workshop on Refractory Asthma Current Understanding, Recommendations, and Unanswered Questions AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 162 2000