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 (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:– Daily nocturnal symptoms– Wheezing with minimal activity– Normal CXR– 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:– 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 S1, S2. – EXTREMITIES: No peripheral edema

• SPIROMETRY– 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– 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• 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– 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:– Serevent 3 puffs q12– 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, q3h

albuteral requirements and FEV1 remained unchanged– She became frustrated, so we discussed other options

(Enbrel) and stopped Xolair

Pathophysiology of allergic airway inflammation

TH2 Cell

Epithelium

EosinophilBasophil

TNFIL-1

Mast Cell

End Organ Responses

Vascular Leak

Smooth Muscle Contraction

Mucus Secretion

Dendritic Cell

Activation of

Recruitment of AllergicInflammatory Cells

Antigen

Chemical MediatorsHistamineLeukotrienes, PGD2Neuropeptides

Inflammatory CytokinesTNF, IL-1, GM-CSF

"Allergic" CytokinesIL-4, IL-5, IL-9, IL-13

ChemokinesEotaxins, MDC, TARC

Enzymes/Toxins

Endothelium

• Murine mast cells release TNF following triggering of FcRI– Nature 346:274, 1990

– JEM 174:103, 1991

• Human mast cells release TNF following triggering of FcRI– PNAS 88:4220, 1991

Mast cells as a source of TNF

Model of IgE-dependent acute and chronic allergic inflammatory reactions

Acute Chronic

TH2

TARCMDC

Blood Vessel

Tissuecells

EotaxinEotaxin-2RANTESMCP-4

Leukocyte recruitment in allergic disease

Eotaxin-3

Tissuecells

TH2Eos

Baso

Tissue

EosBasoCCR3

TNF-

VCAM-1

Tissuecells

MDCTNF-PGD2I-309

ALLERGEN

Mast cell

IL-4IL-5IL-9IL-13

Soluble Tumour Necrosis Factor Alpha (TNF-) 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• 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

– 2500 µg/day of beclomethasone or equivalent

• Mean dose of nebulised albuterol: 8 mg/day

0.00

0.50

1.00

1.50

2.00

2.50

3.00

FEV

1 %

0

20

40

60

80

100

120

P=0.01

Changes in FEV1 with Enbrel

WEEK 1 WEEK 12

0.032.882.55FVC

0.012.161.91FEV1

P valueWeek 12Week 1

WEEK 1 WEEK 12

FE

V1 (

liter

s)

FE

V1 (

% p

redi

cted

)

Log PC20

0.01

0.1

1

10

100

1000

(1.25)

(0.25)

P=0.033*

10.6 (3.74-42.61) 1.45 (0.98-4.3) Methacholine AUC

Week 12Week 1

Changes in Methacholine Reactivity with Enbrel

WEEK 1 WEEK 12

Met

hach

olin

e P

C2

0

Symptom Scores

0

5

10

15

20

25

30

35

WEEK 1 WEEK 12

P<0.001

12.7 ± 8.423.8 ± 7.0Symptom score

(Juniper Scale)

Week 12Week 1

Changes in Symptom Scores with Enbrel

Sym

ptom

sco

re (

Juni

per

Sca

le)

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 – 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

– FEV1 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

Baseline eval – skin testing, allergen

titration, blood, PPD, sputum, skin bx

Skin bx (16 hrs)Allergen ID titration,

blood, nasalwashing, skin

bx (2 hrs)

7 d RxEnbrel x 3vs placebo Overnight

Next day5 PM 9 AM

Skin bx (16 hrs)Allergen ID titration,

blood, nasalwashing, skin

bx (2 hrs)

OvernightNext day

5 PM 9 AM

7 d RxEnbrel x 3vs placebo(crossover)

25-30 dwashout/ recovery

10 pts c DM PAR