Acute And Severe Asthma - Bob Lanier Md

Acute and Severe Asthma

Bob Lanier M.D.

Clinical Professor University of North Texas Guest Professor: Peking Union Medical Colle Beijing

Make sure it’s severe asthma 100 patients : severe intractable asthma 12% did not have asthma 8% had additional diagnosis ( GERD etc) 55% had reversible airways 20% had no reversablity Non-compliance with steroids common in the 55 Non-compliance not common in the 20 10% major psychiatric disease Overall 32% re- classified

Robinson DS, Barnes et al et al Eur Respir J. 2003 Sep;22(3):47883.Systematic assessment of difficult-to-treat asthma.

Definition of severe asthma • Major ( 1 or 2) • continuous high dose inhaled corticosteroids • oral corticosteroids for >50% of the previous year

Minor (2 or >) 1. Daily controller 2. SABA daily 3. FEV1 < 80% 6. 1+ Urgent visits 7. 3 or more steroid "bursts" /yr 6. Deterioration with < 25% reduction in oral or inhaled corticosteroid dose. 7. Near fatal asthma event in the past year

ATS Workshop Consensus for Definition of Severe/Refractory Asthma 2000

How big a problem ? 2 million ED visits each year in the United States2% of all ED visits – in cities asthma up to 10% of all ED visits. 5-10% of all asthma hospitalizations = ICU 0.4% patients succumb 8% mortality in admissions requiring ventilation 10% death after near fatal episode

How it begins….. Acutely as with RSV – or as genetic time bomb? Who is at risk for progression – FeV1 is only studied factor Children with decreased FeV1 = adults with (modest) decreased FeV1 (Australia and New Zealand studies 17-35 years in length)

NJH 2/3 severe asthma had onset in early childhood, 1/3 by 12 years or later. Later onset = worse 2 European suggest that late/adult onset asthma = more rapid decline

Genetic factors • No single gene Mutations in promoter region of the IL-4 gene or the promoter/coding regions of the IL-4 receptor • “non-Th2” factors- transforming growth factor (TGF)-ß1 and monocyte chemotactic protein (MCP)-1 \ promote fibrotic reactions • polymorphisms in ADAM-33 associated with rapid declines in lung function • Polymorphisms in the beta-2 receptor, arginine substitutions at position 16 (Arg/Arg) ~15% of the Caucasian population and ~25% of the African American population …….

Environmental factors >Allergy = > severe asthma Severe asthmatics in the ENFUMOSA study were less atopic than a milder asthma control group,

Role of cigarettes unclear

A cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. European Network for Understanding Mechanisms of Severe Asthma. Eur Respir J 2003;22(3):470-7

Steroid-unresponsive asthma Two types of True steroid-resistant asthma. Maybe you need a bigger Type I steroid-resistant (SR) asthma is cytokine induced and is associated dose – expression of glucocorticoid receptor beta, a less active with increased glucocorticoid receptor isoform. maybe prednisilone Type II SR asthma is due to low numbers of glucocorticoid receptors. maybe by injection – “An important distinction between these two types of SR asthma is that the glucocorticoid receptor defect in Type I, but not Type II, SR asthma - I is reversible in culture and is sustained by incubation with combination interleukin (IL)-2 and IL-4.” Type lll ? Leung DY, Spahn JD, Szefler SJ.. Steroid-unresponsive asthma Semin Respir Crit Care Med. 2002;23(4):387-98

GRE- steroid resistance cytoplasm

nuclei

Nuclear localisation (%)

Blood monocytes: asthmatic patients Effect of dexamethasone 1µM 75

Anti-GR antibody *

50

**

25

0 Mild

Steroid dependent

Steroid resistant

HOW STEROIDS WORK

Inactive steroid receptor

Primed steroid receptor

Recruit histone deacetylases Steroidtomolecules (HDACs) the site of active Cell membrane inflammatory gene transcription and inhibit the acetylation of core histones necessary Active steroid - receptor for inflammatory complex gene transcription. Dimer formation

Nucleus Gene binding

Increased anti-inflammatory activity

DNA strand

GRE

GRE

GRE

Role of Histone Deacetylase HDACs Key enzymes in chromatin remodeling complexes. Asthma = increased HAT - decreased HDAC

T

HDACs HDACs Decreased HDAC Injury HDACs HDACs Impaired HDAC (histone deacetylases)

s s ss

Transcription Acetlylation

Severe Asthma

Young-Koo Jee Presentation: KCAAI Novermber 2006

Phenotypes of severe asthma • • • • • •

Atopy Allergic symptoms Family history Hx atopic dermatitis Persistent eosinophilia Urinary cysteinyl leukotrienes

Early

Late

++++ ++++ +++ +++ ++ ++

++ ++ + + +++ +++

Adapted from the work of Sally Wenzel M.D. University of Pittsburg

Airway remodeling in Severe asthma •

Worse remodeling ( SBM) = severe with persistant eosinophila >TGF-ß + cells in the submucosa

Activates Fibroblasts –

increase collagen

•

Stimulated with TGF-ß and a Th2 cytokine, (IL-4 or IL-13) = > eotaxin-1

•

increase in collagen deposition

MMP-9,, TGF-ß

break it down.

Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma ( n=525) Omalizumab treatment resulted in significantly BACKGROUND: A recombinantexacerbations humanized anti-IgE mAb, omalizumab, forms complexes fewer asthma per subject andwithinfreelower IgE, blocking its interaction with mast cells and basophils; as a consequence, it might be effective in thepercentages treatment of asthma. OBJECTIVE: The purpose experiencing of this study was to evaluate the exacerbation efficacy and of subjects an safety of omalizumab in the treatment of inhaled corticosteroid-dependent asthma. METHODS: In thisthan phase III,placebo double-blinded, placebo-controlled 525 subjects with severe allergicreduction asthma treatment.trial,Beclomethasone requiring daily inhaled corticosteroids were randomized to receive placebo or omalizumab subcutaneously every 2 or 4 weeks, depending on baseline IgE level and body weight. Inhaled and discontinuation was significantly greater with corticosteroid doses were kept stable over the initial 16 weeks of treatment and tapered during a further 12-week treatment period. RESULTS: Omalizumab resulted in significantly fewer omalizumab treatment than treatment with placebo. asthma exacerbations per subject and in lower percentages of subjects experiencing an exacerbation than placebo treatment during thein stable steroid phasesymptoms (0.28 vs 0.54 [P =.006] and 14.6% vs 23.3% Improvements asthma and pulmonary [P =.009], respectively) and during the steroid reduction phase (0.39 vs 0.66 [P =.003] and 21.3% vs 32.3% [P =.004], respectively). Beclomethasone was significantly with function occurred alongdipropionate with areduction reduction in greater rescue omalizumab treatment than with placebo (median 75% vs 50% [P <.001]), and beclomethasone dipropionate discontinuation was more likely with omalizumab (39.6% vs 19.1% [P <.001]). beta-agonist use. Improvements in asthma symptoms and pulmonary function occurred along with a reduction in rescue beta-agonist use. Omalizumab was well tolerated, with an adverse-events profile similar to that of placebo. CONCLUSION: The addition of omalizumab to standard asthma therapy reduces asthma exacerbations and decreases inhaled corticosteroid and rescue medication use.

Busse W, Corren J, Lanier BQ, et Omalizumab is effective in the long-term control of severe allergic asthma.

Profile of responders to Omalizumab Patients who benefit most when omalizumab is Pooled analysis of two multicenter, double-blind, randomized, placebo-controlled phase III studies with omalizumab. PATIENTS: One thousand seventy allergic asthma patients symptomatic despite moderate-to-high doses (mean, 725 micro g/d) of inhaled beclomethasone dipropionate (BDP). (n = 542) orare placebo (n = 528) were administered at a 4administered asINTERVENTIONS: add-onOmalizumab therapy those weekly subcutaneous dose of at least 0.016 mg/kg/IgE (IU/mL) for 16 weeks in addition to stable BDP therapy. MEASUREMENTS AND RESULTS: Univariate logistic regression was performed to explore baseline variables predictive of best response. Various aspects of response (reduced symptom scores, reduced of rescue medication, improved lung function, improved quality of receiving high doses ofusageBDP, those with a history life [QoL]) were explored as well as a composite definition of response (response in at least one of these four aspects with no asthma exacerbation during 16 weeks of treatment). Time to onset of response as well as the ability to predict eventual response were frequent also determined for theemergency composite definition of response. A consistent pattern of predictive covariates and was seen over all of asthma treatment, definitions of response (except for QoL). For the composite definition, a history of emergency asthma treatment in the past year was the factor most predictive (p = 0.015) of best response on active treatment (response rate for those with such history was 67% for omalizumab and 42% for placebo; for those without a function. history the response rates were 63% and 54%, should respectively). Another factor those with poor lung Patients be predictive of best response on active treatment was high BDP dose (p = 0.037; response rate for those treated with >or= 800 micro g/d was 65% for omalizumab and 40% for placebo; for those treated with < 800 micro g/d, the response rates were 63% and 55%, respectively). A low FEV(1) was also predictive (p = 0.072; response those with FEV(1) or= 65% predicted, the response rates were 67% and 53%, respectively). Seventy-six percent of patients had at least one of these factors. This subgroup showed odds of being a responder (composite definition) times higher (95% confidence interval, 1.68 to 3.01) than placebo. Some 38% of patients treated with omalizumab of 122.25weeks. showed a response (composite definition) at the first evaluation time point at 4 weeks, increasing to 64% at week 16 (vs 48% for placebo; p < 0.001). Among omalizumab responders at 16 weeks, only 61% had responded at 4 weeks whereas 87% had responded at 12 weeks. CONCLUSIONS: Patients who benefit most when omalizumab is administered as add-on therapy are those receiving high doses of BDP, those with a history of frequent emergency asthma treatment, and those with poor lung function. Patients should be treated with omalizumab for a minimum duration of 12 weeks.

Bousquet J, Wenzel S, et al Predicting response to omalizumab, an anti-IgE antibody, in

patients with allergic asthma. Chest. 2004

Apr;125(4):1378-86.

How it’s dosed IgEIgEIgE IgE IgE IgE IgEIgE IgEIgE IgE IgE IgE IgE IgE

Target IgE ↓ <10 IU/mL

+ Omalizumab

Theophylline in reverse

Persistent skin testing and dosage and danger

IgE IgE

Evaluation of severe asthma and therapeutic options •

Confirmation of diagnosis

– – – •

Lung volumes and diffusing capacity Hi resolution CT scan Methacholine challenge with laryngoscopy Evaluation of confounding/exacerbating factors

– – – – – •

ph probe Sinus CT IgE level/allergen skin testing AM cortisol for patients on oral steroids Evaluation of pharmacy records for refills

(NJH Protoco) Via Sally Wenzel

Evaluation of asthma phenotype

–

Determination of age at onset/allergic phenotype • •

–

Skin testing Questions regarding asthma symptoms in response to allergic stimuli

Determination of eosinophilic phenotype • • •

Bronchoscopy at selected centers Sputum analysis Exhaled nitric oxide

Initial assessment Take a brief history and perform a rapid physical give oxygen and inhaled shortacting beta2 agonist immediately.

Take a more detailed history and do a complete physical examination once therapy has been initiated. Wheeze is an unreliable indicator of the severity of an asthma attack and may be absent in severe asthma.

Summary: Hallmarks of severe asthma • Polymorphisms in the beta-2 receptor, arginine substitutions at position 16 (Arg/Arg) ~15% Caucasian population ~25% Black • severe asthma more common in women • 25% aspirin sensitivity • Worse with later onset • Diminished perception of dyspnea • Steroid resistance ( dose response shift)