Asthma Management Considerationsin Allergic Respiratory Disease

Peter Socrates Creticos, M.D.

World Allergy Congress - CancunDecember 5, 2011

Dr. Creticos is engaged in current research with the following entities: - Greer Labs - Merck/Schering-Plough Corporation - Stallergenes - AHRQ

Dr. Creticos has enduring consulting agreements with the following entities: - Merck Research - Sanofi-Aventis - Greer Labs

Dr. Creticos has participated on ad-hoc SABs with the following entities: - Dynavax Technologies Inc. - Sanofi-Aventis - Genentech/Novartis - AstraZeneca - GlaxoSmithKline - Schering-Plough - Circassia - FDA - Stallergenes - Biomay

Chief Complaint: 20 year old female referred by primary physicianfor evaluation and management of worsening “hay fever” and seasonal asthma

History: • Perennial nasal congestion with distinct seasonal exacerbations punctuated by sneezing/itchy watery eyes/rhinorrhea/ postnasal drip with cough

- describes moderate-severe symptomatology in Spring-Summer (mid-April to late June) and Fall (late August-October)

- Triggers: cut grass/ragweed/dust/cats/ perfume/cigarette smoke

History Continued: - Has tried various nasal steroids/antihistamine- decongestants/leukotriene antagonists with only partial relief

- notes she does not “like to use” nasal steroids because they cause nasal bleeding

- tried nasal antihistamine (azelastine) but could not tolerate taste

- previously tried allergen immunotherapy in early teens but discontinued shots after six months due to repeated LLRs and one systemic reaction (hives and chest tightness occurring within 10 minutes of injection)

History Continued:

• By early teens, she began to appreciate EIA with spring training and fall soccer season

- c/o mild/intermittent wheezing/chest tightness/cough which respond to albuterol prn (only required with exercise)

- no nocturnal asthma/no inhaled steroid or oral steroid use/no ER visitation or hospitalization for asthma

- since being placed on montelukast (Singulair) + fexofenadine (Allegra) for control of rhinitis, she feels that her asthma has become less bothersome

- Triggers: pollen/exercise/viral infections/cats

History Continued:

• In college (Va) her episodes of asthma have worsened and become more frequent, with symptoms that correlate with peaks of pollen seasons (May; late September) x past 3 years + more persistent/prolonged exacerbations with soccer

- she now finds herself using albuterol 4-5 times during practice and frequently throughout days when not playing soccer

- now notes nocturnal asthma occurring 1-2x per week and she had an ER visit in mid-September

- she has been referred for evaluation and management considerations

Allergy Profile:

No known food/drug/bee sting sensitivity; eczema as toddler (worsened in early teens;now quiescent); tolerates NSAIDs

Past History:

Episodes of sinusitis occur ~ 1-2 x/year (Fall/early winter) - correlates with worsening rhinitis with yellow-greenishnasal discharge/facial discomfort/pain

- usually requires one-two (7-10 days) courses of antibiotics to bring resolution

Family History:

Father & mother in good health (dad with asthma +hay fever); 12 yr old sister w/ allergic rhinitis

Environmental History:

Born in Maryland; resides 75-year old stone-timber home x 20 yrs; FHA/CAC/WWC/non-encased mattress/foam pillows; Pets: 1 cat (bedroom at home)

At college, moved out of sorority house to 2-story apt w/ no air conditioning, old carpeting, and rabbit

Work History/Social History:

College junior; does not smoke or use alcohol/drugs; competitive soccer player

Review of Systems:14 systems queried: other positives includeheartburn/menstrual cramps

Physical: Well-developed white female; no acute distress; oriented x 3; BP: 118/68; pulse: 68; RR: 12; Hgt: 5 6”; Wt: 124; PEFR: 410/430 (445)

HEENT: Conjuctiva clear; tympanic membranes intact; nares with mild edema (30%) of nostrils bilaterally with pale mucosa; no erosions/ulcerations/polyps; oral mucosa unremarkable except for minimal drainage over the posterior pharynx; no adenopathy; Sinuses: non-tender;

Physical Continued:

Neck: supple without thyroid enlargement/no bruits; Chest: normal to percussion/ausculation; no wheezing/rales/rhonchi; normal fremitus/egophony; CV: regular rate withoutmurmur/gallop/click; Abdomen: soft/non-tender/no palpable masses/no organomegaly; no bruitsExtremities: no edema/normal pulses; Skin: no lesions; Musculoskeletal: intact; Neuro: intact.

PFTs: FEV1: 79%; FVC: 91%; FEV1/FVC ratio: 87% [Interpretation: mild obstructive indices]

PEFR (pre-exercise): 410/450 L/min (91%)PEFR (post-exercise): 320/450 L/min (71%)Response to bronchodilator: 28%

Skin Test Evaluation:

Primary (puncture) skin test reactivities:positive to trees (maple/oak/pecan); grasses (timothy/bermuda); weeds (ragweed); cat; dust mites

Secondary (intradermal) skin test reactivities: positive to additional trees (ash/poplar/elm); rabbit

Assessment:

1) Seasonal allergic rhinitis/conjuctivitis a) trees/grass (spring); ragweed (fall)

2) Perennial allergic rhinitis a) dust mites/cat/rabbit

3) Persistent asthma a) allergic component b) exercise-induced component

4) Episodic sinusitis a) responds to antibiotics

5) Past history of eczema

Plan/Treatment Strategies:

1) Discuss environmental control and provide literature to patient

2) Optimize rhinitis management plan: add nasal steroid to existing regimen [LTα (Singulair: 10 mg tab once daily) +/- fexofenadine (Allegra: 180 mg tab prn)]

3) Optimize asthma management plan: a) initiate ICS + LABA/LAA combination agent; b) vs initiate ICS + maintain LTα; c) vs consider omalizumab (anti-IgE);

d) re-attempt immunotherapy (?)

4) Develop EIA-management plan

5) Instruct & provide peak flow meter to patient

Plan continued:

6) Rhinitis and Asthma Management plans reviewed and provided to the patient

7) Medication instructions reviewed/ samples provided/principal side effects of medicines discussed

8) Risks/benefits of immunotherapy reviewed with patient; treatment options outlined

Clinical Consideration:

Risks of Long-acting Beta-agonists in Asthma Therapy

Citation:

Age & Risks of FDA-approved Long-acting ß2-Adrenergic

Receptor Agonists; AW McMahon, MS Levenson, BW McEvoy,

et al. Pediatrics 128: 1147-54, 2011

Findings:

In a meta-analysis of 110 controlled clinical trials (61,000 subjects; age >4) a composite event incidence of 6.3 events per 1000 patient-years was observed [95%CI: 2.2-10.3] for using LABA vs not using LABA

-- the incidence was observed to be age-dependent, with the largest difference in children [ages (4-11): 30.4 events per 1000 patient years (95%CI: 5.7- 55.1)]

In the patient subgroup receiving concomitant ICS (n: 36,210) the risk declined [0.4 events per 1000 patient-years (95%CI: -3.8 – 4.6)]

Conclusion:

Serious asthma-related events associated with LABA use was observed to be greatest amongst children

Clinical Consideration:

Use of Leukotriene Antagonists as Controller Therapy in Asthma Management

Citation:

Leukotriene Antagonists as First-Line or Add-on Asthma

Controller Therapy DP Price, SD Musgrave, L Shepstone, et al.

N Engl J Med 364: 1695-1707, 2011

Methods:

Two “real world” multicenter clinical trials were conducted to evaluate the effectiveness of a LTRA as compared with either an ICS for 1st-line asthma-controller therapy or a LABA as add-on therapy in patients already receiving inhaled glucocorticoid therapy

Patients (age: 12-80) with impaired asthma-related QOL(Mini AQLQ score < 6) or inadequate asthma control (ACQ score >1) were randomly assigned to 2-year open-label therapy

Findings:

Mean MiniAQLQ scores increased by 0.8-1.0 over the initial 2-year period of assessment in both clinical trials

- equivalence in treatment effect, based on differences in MiniAQLQ scores between the two treatment groups, was met at 2 months [MiniAQLQ 95%CI: -0.3 – 0.3] - at 2 years, MiniAQLQ scores approached equivalence, with an adjusted mean difference between groups of -0.11 [95%CI: -0.35 – 0.13] in 1st-line controller therapy, and -0.11 [95%CI: -0.32 – 0.11] in the add-on therapy clinical trial

Exacerbation rates and ACQ scores did not differ significantly between the two groups

Conclusion:

■ Study results at 2 months suggest that LTRA therapy was equivalent to an inhaled corticosteroid as first-line controller therapy and to a LABA as add-on therapy in a diverse population of primary care asthma patients

▲ However, sustained equivalence was not observed at the 2-year endpoint of the clinical trials

Clinical Consideration:

Tiotropium Bromide Step-Up Therapy for Adults with Uncontrolled Asthma

Citation:

Tiotropium Bromide Step-Up Therapy for Adults with Uncontrolled Asthma SP Peters, SJ Kunselman, N Icitovic, et al.

N Engl J Med 363: 1715-1726, 2010

Methods:

Three-way, double-blind, triple-dummy crossover trial involving 210 patients with asthma

-- the study design evaluated the addition of tiotropium bromide to an inhaled glucocorticoid, as compared to doubling the dose of the inhaled corticosteroid, or simply adding a LABA to an inhaled corticosteroid

* Tiotropium bromide is a long-acting anticholinergic agent approved in the U.S. for the treatment of chronic obstructive pulmonary disease but not asthma

Findings:

The use of tiotropium resulted in significant improvement in the primary outcome [PEF] as compared to doubling the dose of an inhaled glucocorticoid [mn diff: 25.8 L/min (p<0.001)]

-- superiority was also shown for most secondary outcomes measured (DSS/ePEF/ACDs/ pre-BD FEV1)

The addition of tiotropium was also non-inferior to the addition of salmeterol for all assessed outcomes and more effectively increased the pre-bronchodilator FEV1[difference of 110 ml (p=0.003)]

Conclusion:

When added to an ICS, tiotropium improved symptoms and lung function in inadequately controlled asthmaticsand its effects appeared to be comparable to that observed with the addition of a LABA