A case of refractory, severe,steroid-dependent asthma

A case of refractory, severe,steroid-dependent asthma
By: Bruce S. Bochner, M.D.

* 24 y/o AA female referred in 2/99 from southern Maryland for evaluation and management of uncontrolled asthma
* At the time, 20 weeks pregnant (G5, P4)
* Last two pregnancies were complicated by uncontrolled asthma and oral steroid use throughout the pregnancy
* H/O asthma since age 12, frequent episodes of wheezing & cough without any obvious triggers or seasonal pattern
* Review of accompanying records revealed that her FEV1 can range from 30% to 80% predicted on any given visit

* Early on, exacerbations 1x/yr, necessitating ER visits
* Initially treated with Cromolyn, Vanceril and Albuterol
* Since 1992, worsening asthma, increased ER visits and for 1998 at least 6 hospitalizations
* In 1992, found to have multiple positive skin tests, tried on ImTx w/o improvement; in fact, exacerbations of wheezing with most shots
* Frequent courses of antibiotics for bronchitis or sinusitis

* At the time of her 2/99 visit:
o Daily nocturnal symptoms
o Wheezing with minimal activity
o Normal CXR
o managed with Prednisone 30 mg qAM, Flovent 110 2 puffs BID, Serevent 2 puffs BID, Alupent 2 puffs q3h and nebs PRN, Atrovent 4 puffs BID, Accolate 20 mg BID, and Cromolyn q3h

* Drug allergy Hx: acute rashes from Penicillin, Codeine, Ceclor; Erythromycin caused GI upset
* Environ. Hx: Born and raised in MD, lives in a separate home, no pets
* Family Hx: All of her four kids (two different fathers) have asthma; current pregnancy is with a third father

* PE:
o Vitals: BP 105/66, P 112, RR 18, Wt 168 lbs, peak flow best effort 130 liters/min
o GEN: Mild Cushingoid facies, no rashes
o HEENT: Nasal exam normal, no lymphadenopathy or thyromegaly
o LUNGS: Diffuse expiratory wheezing and prolonged expiratory phase; sounds were in chest but not neck
o HEART: Normal S1, S2.
o EXTREMITIES: No peripheral edema

* SPIROMETRY
o FEV1: 1.1 liters (36% predicted), FVC: 1.62 liters (42% predicted), ratio 0.68. Post-bronchodilator FEV1 1.89 liters (79% increase), FVC 2.34 liters (44% increase)

* TREATMENT CHANGES
o At this visit, patient was switched from Flovent to Pulmicort 4 puffs bid
o The rest of her medications were continued
o Inhaler technique was observed to be correct
o Husband verified medication adherence.

* Delivered the baby on continuous nebs. Baby and Mom did fine. 5 weeks postpartum admitted to Hopkins Bayview for 5 days for worsening SOB, wheezing and leg pain
* On admission, wheezing; PEF 100 liters/min
* V/Q scan and leg dopplers normal
* FEV1 28% predicted; flow-volume loops normal
* CT scan of sinuses revealed pan-sinusitis
* 24-hr pH probe documented significant GERD
* Discharged on 24-day steroid taper with markedly improved lung function at discharge; started on antibiotics and Prilosec

* Since 2000, multiple ER visits
o two prolonged intubations in 2000 and 2001
+ 2000: complicated by full respiratory arrest and persistent doll’s eyes
+ 2001: complicated by bilateral pneumothoraces requiring chest tubes and a DVT; s/p IVC filter
* Multiple meds tried in 2000-2001 included Advair, Pulmicort respules, Theophylline, and Methotrexate. None had a significant impact on our ability to taper oral steroids.

* In 10/01, sent for an outpatient evaluation by me to National Jewish (made possible through philanthropic help from NJC, AAFA and her local church) with dx of severe, labile steroid-dependent asthma
* Diagnosis quickly confirmed when she required admission for worsening SOB and wheezing

* Skin tests positive to dust mites, grasses, alternaria
* Alpha-1 antitrypsin: normal
* CF genotyping: normal
* No peripheral blood eosinophilia
* Total IgE: 123 IU/ml
* Chest CT: no interstitial disease
* Bone densitometry: normal
* Sinus CT: mild sinusitis
* Oral steroid kinetics normal

* Seen by Drs. Barry Make and Sally Wenzel
* After stabilization with IV steroids and nebs, underwent bronchoscopy
* Found to have some collapsibility of her larynx with exhalation which they felt would be helped with CPAP
* Sleep study found sleep apnea for which CPAP was also recommended

* Bronchoscopy (on IV steroids) revealed prominent basal lamina thickening and a mild inflammatory infiltrate, primarily lymphocytic

* After 3 weeks, sent back to Baltimore on the following regimen:
o Serevent 3 puffs q12
o QVAR 6 puffs bid
o Atrovent 4 puffs qid
o Uniphyl 400 mg qhs
o Singulair 10 mg qhs
o Zyflo 600 mg qid
o Prilosec 40 mg qd
o Supplemental Calcium
o Prednisone 40 mg q am, 20 mg q afternoon
o Nasonex 1 spray bid
o CPAP

* Within 2 months, back to pre-Denver management
* 2002 to 2003
o Managed primarily with Prednisone (40-80 mg/day), Prilosec and Albuterol
o Extremely Cushingoid; now weighs 240 lbs
o Tried Xopenex w/o any additional benefit
* September 2003
o Started Xolair one vial q month (completely covered by her insurer)
o Still had ER visits but no hospitalizations while on Xolair
o Despite this, after seven months, Prenisone, q3h albuteral requirements and FEV1 remained unchanged
o She became frustrated, so we discussed other options (Enbrel) and stopped Xolair

Pathophysiology of allergic airway inflammation
Model of IgE-dependent acute and chronic allergic inflammatory reactions
Leukocyte recruitment in allergic disease
Soluble Tumour Necrosis Factor Alpha (TNF-a) Receptor (Enbrel) as an Effective Therapeutic Strategy in Chronic Severe Asthma
Respiratory Cell & Molecular Biology
Study design
* Open label, single center study
* Subjects with chronic severe asthma on oral corticosteroids, high dose inhaled corticosteroids, salmeterol, and/or theophylline
* 25 mg of Enbrel administered subcutaneous twice a week for 12 weeks
* Subjects aged 18-65 years
* FEV1 of at least 50% predicted
* Demonstrated a reversibility of at least 9%
* Lung function, methacholine response performed before and after treatment
* Asthma control symptom questionnaire completed before and after the trial
* Diary cards issued to assess peak flows and use of rescue medication

Results

* 15 subjects enrolled in the trial
* 11 female, 4 male
* Mean age of the patients: 41 yrs
* Mean duration of asthma: 24 years
* Mean dose of oral prednisolone: 12.1mg/day
* Mean dose of inhaled corticosteroids
o 2500 ľg/day of beclomethasone or equivalent
* Mean dose of nebulised albuterol: 8 mg/day

Changes in FEV1 with Enbrel

WEEK 1 WEEK 12
Changes in Symptom Scores with Enbrel
Symptom score (Juniper Scale)
Adverse effects
* Skin rashes (4)
* Injection site reactions (4)
* Respiratory tract infections (7)
* Weakly positive ANA (3)

Conclusions
Treatment with Enbrel in patients with chronic severe asthma:

* Improves lung function (FEV1, FEV1/FVC, morning and evening PEF)
* Markedly improves asthma control
* Markedly improves airway hyperresponsiveness
* Markedly reduces the need for rescue medications as all the subjects completely withdrew from their nebulised albuterol by the end of the study

* April - early June 2004
o Started Enbrel 25 mg sq twice weekly (completely covered by her insurer) after PPD was negative; husband trained on administration technique
o Two weeks later, she was admitted for an asthma exacerbation associated with nausea, fatigue, myalgias and unexplained fevers to 102° despite Enbrel and prednisone; discovered Prilosec had been stopped
o Infectious workup unrevealing; IV steroids given
o Enbrel dosing held for 2 weeks, fever resolved
o Enbrel restarted and 1 week later she was admitted for another asthma exacerbation
o Enbrel discontinued

* June 21: planned to restart Xolair but got admitted again
* Discharged June 22
* Seen June 23
o FEV1 60%; FVC 93%
o Diffuse wheezing on Prednisone 80 mg
o Restarted Xolair 300 mg q 4 weeks
o Restarted Serevent diskus 1 puff BID
* What next????

Our ongoing work on TNFa and allergic inflammation

* There is a tissue-specific pattern of chemokines/cytokines/adhesion molecules involved in human allergic inflammation
* This pattern is TNF- dependent
* The primary source of TNF- released in human allergic inflammation is the mast cell

Etanercept in late phase cutaneous allergic inflammation: study overview

* Randomized DBPC Trial
* To evaluate effects of etanercept (Enbrel) on cutaneous allergen LPR in 10 perennial allergic rhinitis/dust mite sensitive patients
* 15 visits to JHAAC over 8.5 wks
* Lead investigators: Lisa Beck, Ed Conner, Bruce Bochner

Study Purpose

* To evaluate the clinical effects of etanercept on cutaneous allergen challenge late phase responses
* To evaluate the effects of etanercept on the allergen dose response
* To characterize a variety of biomarkers in the cutaneous late phase responses
* To assess limited pharmacokinetic data of etanercept in the serum and nasal washings

DBRPC Crossover Study Design
A case of refractory, severe,steroid-dependent asthma.ppt