Download Allergy Grand Rounds 6/25/04

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:
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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
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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:
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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
Epithelium
Antigen
Mast Cell
Dendritic Cell
TNF
IL-1
Activation of
Endothelium
Chemical Mediators
Histamine
Leukotrienes, PGD2
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
TH2 Cell
Eosinophil
End Organ Responses
Vascular Leak
Smooth Muscle Contraction
Mucus Secretion
Mast cells as a source of TNFa
• Murine mast cells release TNFa following
triggering of FceRI
– Nature 346:274, 1990
– JEM 174:103, 1991
• Human mast cells release TNFa following
triggering of FceRI
– PNAS 88:4220, 1991
Model of IgE-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
TH2
TNF-a
Tissue
Blood Vessel
Eotaxin
Eotaxin-2
RANTES
MCP-4
Tissue
cells
Mast cell
TARC
MDC
TNF-a
PGD2
I-309
Tissue
cells
MDC
Eos
Baso
CCR3
VCAM-1
TH2
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
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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
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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
Changes in FEV1 with Enbrel
120
3.00
FEV1 (% predicted)
P=0.01
100
2.00
FEV1 %
FEV1 (liters)
2.50
1.50
1.00
0.50
0.00
WEEK 1
WEEK 12
80
60
40
20
0
WEEK 1
WEEK 12
Week 1
Week 12
P value
FEV1
1.91
2.16
0.01
FVC
2.55
2.88
0.03
Changes in Methacholine Reactivity with Enbrel
Methacholine PC20
1000
P=0.033
Log PC20
100
*
10
(1.25)
1
(0.25)
0.1
0.01
WEEK 1
Methacholine AUC
WEEK 12
Week 1
Week 12
1.45 (0.98-4.3)
10.6 (3.74-42.61)
Changes in Symptom Scores with Enbrel
Symptom
(Juniper Scale)
scoreScores
Symptom
35
P<0.001
30
25
20
15
10
5
0
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 (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
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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 TNFa
and allergic inflammation
• There is a tissue-specific pattern of
chemokines/cytokines/adhesion molecules
involved in human allergic inflammation
• This pattern is TNF-a dependent
• The primary source of TNF-a 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)