A case of refractory severe steroiddependent asthma Please

A case of refractory, severe, steroid-dependent asthma Please help! 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 (G 5, P 4) • 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 FEV 1 can range from 30% to 80% predicted on any given visit

• Early on, exacerbations 1 x/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 Im. Tx 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: – Daily nocturnal symptoms – Wheezing with minimal activity – Normal CXR – managed with Prednisone 30 mg q. AM, Flovent 110 2 puffs BID, Serevent 2 puffs BID, Alupent 2 puffs q 3 h and nebs PRN, Atrovent 4 puffs BID, Accolate 20 mg BID, and Cromolyn q 3 h

• 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: – Vitals: BP 105/66, P 112, RR 18, Wt 168 lbs, peak flow best effort 130 liters/min – GEN: Mild Cushingoid facies, no rashes – HEENT: Nasal exam normal, no lymphadenopathy or thyromegaly – LUNGS: Diffuse expiratory wheezing and prolonged expiratory phase; sounds were in chest but not neck – HEART: Normal S 1, S 2. – EXTREMITIES: No peripheral edema

• SPIROMETRY – FEV 1: 1. 1 liters (36% predicted), FVC: 1. 62 liters (42% predicted), ratio 0. 68. Post-bronchodilator FEV 1 1. 89 liters (79% increase), FVC 2. 34 liters (44% increase) • TREATMENT CHANGES – At this visit, patient was switched from Flovent to Pulmicort 4 puffs bid – The rest of her medications were continued – Inhaler technique was observed to be correct – 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 • FEV 1 28% predicted; flow-volume loops normal • CT scan of sinuses revealed pan-sinusitis • 24 -hr p. H 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 – 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 Ig. E: 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: – – – Serevent 3 puffs q 12 QVAR 6 puffs bid Atrovent 4 puffs qid Uniphyl 400 mg qhs Singulair 10 mg qhs Zyflo 600 mg qid Prilosec 40 mg qd Supplemental Calcium Prednisone 40 mg q am, 20 mg q afternoon Nasonex 1 spray bid CPAP

• Within 2 months, back to pre-Denver management • 2002 to 2003 – Managed primarily with Prednisone (40 -80 mg/day), Prilosec and Albuterol – Extremely Cushingoid; now weighs 240 lbs – Tried Xopenex w/o any additional benefit • September 2003 – Started Xolair one vial q month (completely covered by her insurer) – Still had ER visits but no hospitalizations while on Xolair – Despite this, after seven months, Prenisone, q 3 h albuteral requirements and FEV 1 remained unchanged – She became frustrated, so we discussed other options (Enbrel) and stopped Xolair

Pathophysiology of allergic airway inflammation Epithelium Antigen Mast Cell Dendritic Cell TNF IL-1 Activation of Endothelium Chemical Mediators Histamine Leukotrienes, PGD 2 Neuropeptides Inflammatory Cytokines TNF, IL-1, GM-CSF "Allergic" Cytokines IL-4, IL-5, IL-9, IL-13 Chemokines Eotaxins, MDC, TARC Enzymes/Toxins Recruitment of Allergic Inflammatory Cells Basophil TH 2 Cell Eosinophil End Organ Responses Vascular Leak Smooth Muscle Contraction Mucus Secretion

Mast cells as a source of TNF • Murine mast cells release TNF following triggering of Fce. RI – Nature 346: 274, 1990 – JEM 174: 103, 1991 • Human mast cells release TNF following triggering of Fce. RI – PNAS 88: 4220, 1991

Model of Ig. E-dependent acute and chronic allergic inflammatory reactions Acute Chronic

Leukocyte recruitment in allergic disease Tissue cells IL-4 IL-5 IL-9 IL-13 ALLERGEN TH 2 TNF- Tissue Blood Vessel Eotaxin-2 RANTES MCP-4 Tissue cells Mast cell TARC MDC TNF- PGD 2 I-309 Tissue cells MDC Eos Baso CCR 3 VCAM-1 TH 2 Eos Baso Eotaxin-3

Soluble Tumour Necrosis Factor Alpha (TNF-a) Receptor (Enbrel) as an Effective Therapeutic Strategy in Chronic Severe Asthma Babu KS, Arshad SH, Howarth PH, Chauhan AJ, Bell EJ, Puddicombe S, Davies DE, Holgate ST Respiratory Cell & Molecular Biology Southampton University Hospital Southampton, UK JACI 2003 (abstract)

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

Study Design • • Subjects aged 18 -65 years FEV 1 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. 1 mg/day Mean dose of inhaled corticosteroids – 2500 µg/day of beclomethasone or equivalent • Mean dose of nebulised albuterol: 8 mg/day

Changes in FEV 1 with Enbrel FEV 1 (liters) FEV 1 (% predicted) P=0. 01 WEEK 12 Week 12 P value FEV 1 1. 91 2. 16 0. 01 FVC 2. 55 2. 88 0. 03

Changes in Methacholine Reactivity with Enbrel Methacholine PC 20 P=0. 033 * WEEK 1 Methacholine AUC WEEK 12 Week 12 1. 45 (0. 98 -4. 3) 10. 6 (3. 74 -42. 61)

Changes in Symptom Scores with Enbrel Symptom score (Juniper Scale) P<0. 001 WEEK 1 Symptom score (Juniper Scale) WEEK 12 Week 1 23. 8 ± 7. 0 Week 12 12. 7 ± 8. 4

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 (FEV 1, FEV 1/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 – Started Enbrel 25 mg sq twice weekly (completely covered by her insurer) after PPD was negative; husband trained on administration technique – 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 – Infectious workup unrevealing; IV steroids given – Enbrel dosing held for 2 weeks, fever resolved – Enbrel restarted and 1 week later she was admitted for another asthma exacerbation – Enbrel discontinued

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

Our ongoing work on TNF 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 10 pts c DM PAR 7 d Rx Enbrel x 3 vs placebo Overnight Allergen ID titration, blood, nasal washing, skin bx (2 hrs) Baseline eval – skin testing, allergen titration, blood, PPD, sputum, skin bx 25 -30 d washout/ recovery Next day 5 PM 7 d Rx Enbrel x 3 vs placebo (crossover) Next day 5 PM Allergen ID titration, blood, nasal washing, skin bx (2 hrs) 9 AM Skin bx (16 hrs) Overnight 9 AM Skin bx (16 hrs)