Insect Sting Allergy and Venom Immunotherapy

Insect Sting Allergy and Venom Immunotherapy
By: David B.K. Golden, M.D.
Johns Hopkins University, Baltimore


History of Reaction to Insect Stings (Skin Test Positive Patients)

No reaction
Large Local
Cutaneous Systemic
Anaphylaxis

Severe swelling 24 hrs after a sting should be treated with:
A. Antibiotics C. Antihistamine E. Epinephrine
B. Prednisone D. Venom immunotherapy

Venom immunotherapy:
A. Is not necessary (“He’ll outgrow it”) B. Is dangerous
C. is only partially effective D. Is forever E. None of the above

Diagnosis of Insect Sting Allergy (Indications for Venom Immunotherapy)
Symptoms and Signs of Insect Sting Anaphylaxis in Adults and Children
Symptoms or Sign
Cutaneous only
Urticaria/angioedema
Dizziness/hypotension
Dyspnea/wheezing
Throat tightness/
Hoarseness
Loss of consciousness

Epidemiology of Venom Allergy
* History of systemic reaction in 0.5%-3.0% of the population
* Positive venom skin test or RAST in 15%-25% of the population.
* Transient positive skin test or RAST may occur after uneventful sting.
* Presence of IgE venom antibody not necessarily predictive of clinical reactivity.

Correlation of Yellow Jacket Venom
RAST and Skin Tests
History Positive Patients with Negative Venom Skin Tests
Possible explanations:
Not true allergic reaction (no objective signs)
Allergy “outgrown”
Mastocytosis (~1 % of insect allergic patients)
Not detected:
Diagnostic Venom Test Reactivity after Systemic Sting Reaction
Venom Skin Test / RAST in History Positive Patients
Total history positive patients screened:
Diagnosis of Insect Allergy in Patients With Positive History (Systemic)
Skin test positive
ST negative /
Low Risk Sub-Groups of Patients With Positive Venom Skin Tests
Insect Sting Allergy in Children
Summary Of Sting Reactions
Natural History of Large Local Reactions
Repeat Systemic Reaction In Sting Allergic Patients
Risk of Systemic Reaction in
Untreated Skin Test Positive Patients
Controlled Trial of Venom Immunotherapy
Venom Immunotherapy Treatment Protocols
Dose Response of Venom Immunotherapy
Premedication During Venom Immunotherapy
Venom-IgE and Skin Test During
and After Venom Immunotherapy
Discontinuing Venom Immunotherapy:
Reported Studies and Criteria
Discontinuing Venom Immunotherapy

Insect Sting Allergy and Venom Immunotherapy.ppt

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Allergy Grand Rounds

Allergy Grand Rounds
By:Sarbjit S. Saini, M.D.
JHAAC

Chief complaint
* 13 yr old male referred in June 2004 for evaluation of severe chronic urticaria
* Referred by pediatric allergist in VA
* Significant illnesses:
o include Type I DM for 2.5 yrs
o ADHD
o mood disorder

History of Present Illness-I
History of Present Illness-II
History of Present Illness-III
Other atopic history
* No history of eczema or food allergy
* Allergic rhinitis symptoms
* Exercise-related asthma age 9 treated with prn albuterol prior to activity
* Reported qhs cough, but denied wheezing
Medications
* Zoloft, 50 mg qd**
* Oxcadazepine (Trileptal) 300 mg/600 mg **
* Adderall 30 mg bid
* Quetiapine (Seroquel) 200 mg qd
* Fexofenadine 180 mg qd ( off 1 wk)
* Cetirizine 10 mg qd ( off 1 week)
* Cyclosporine 100 mg bid (off 1 wk)
* Humulin 7 U/4 U, Humulin R 5 U/ 4 U
* Epipen, Albuterol

Past Medical History
* Type I DM for 2.5 yrs
* ADHD
* Mood disorder, possible bipolar
o exacerbated by steroids
o suicidal ideation due to urticaria
* Chicken pox as child
* Salivary gland surgery
* Normal birth history, negative history of other infections
Family History
* Younger Sister with eczema
* PGM with asthma
* Paternal cousins with asthma
Environmental Hx
* Apt dweller x 5 yrs
* Dog since 1999
* 3 hamsters

Social Hx
* 7th grader
* Lives with mom and sister
Physical Exam
* T-99.7, HR-121, BP-109/75, HT-5, WT-125,RR-22
* General: no obvious pubertal signs,central obesity, moon facies
* HEENT: “allergic shiners”,erythematous nasal mucosa, prominent turbinates
o Normal TMs, oropharynx, neck
* Resp: CTA, normal I:E ratio, CV: nl S1, S2 tachy
* Abdomen: benign Ext: no joint swelling
* Skin: urticaria on face, arms, feet, back, chest; no pigmentation

Recent labs
* CBC-WBC 7.3 HCT-41.2, Plts-331
* HbA1C-8.6 (4-6) Jan 2004
* Negative studies: ANA, H. Pylori Ab,anti-thyroid peroxidase antibodies, WESR
* Normal C3, C4, CH50; TSH, thyroxine, T3 and T4
* RASTS- negative for crab, lobster, fish garlic and insulin

Cyclosporine related labs
* Jan 2004 reduced Hct-12.1 HB- 37.2
o CsA: 37 ng/ml trough
* March 2004 Normal studies
* June 2004
o CsA: 46 ng/ml trough
o CBC, Mg, Cr, K normal
Impression/ Recommendations
* Severe CIU/angioedema h/o significant steroids requirements
o No clear drug (insulin), food or systemic etiology
o Avoiding NSAIDs
* Consider alternate diagnoses:
o Hx of autoimmunity with Type I DM
o Rheumatologic?-joint symptoms, bruising
o Obtain a skin Biopsy to verify urticaria vs. other
+ Consider immunofluorescence

Follow-up on Recommendations
* Rheum evaluation: Repeated ANA, RF, dsDNA, ANCA, Urine and SPEP- all normal
o showed IgA of < 20, no other etiology for joints
* October 04 -Csa 100 mg qd and fexofenadine with good control
* Prednisone used only single day since 6/2004
* No skin biopsy to date- attempted
* Glucose under better control
CU in children : association with thyroid autoimmunity
* 187 CU pts (6- 18 yr) followed 7.5 yrs
* Tests: CBC, sed, Chem, Antibodies to Hep B, HSV, EBV,CMV, mycoplasma, ASO, ANA, C3, C4, Thyroid function and antibodies,Ua, chest and sinus X-rays, food skin tests, ice cube test
* Results: 8/187 antithyroid Ab (4.3%), all girls
o 3x -1.27% rate seen in pediatric population
o Much less than 14 to 33% range in adults
o 5 +ANA, 4 + family Hx of autoimmunity
Cyclosporine in Urticaria
* CBC, Mg, K, renal function q 2 wks for first 3 months, CsA levels
* Gingival hypertrophy
* BP monitoring
* Dose: 2-6 mg/kg/d similar to RA and psoriasis (2.5 mg/kg/day)
* Tx dose 8 mg/kg/d; trough levels 100 ng/ml

CsA and Urticaria-RDBCT
* 30 subjects, severe CIU unresponsive to H1 tx and positive ASST ( +HRA)
o 4mg/kg CsA (n=20) or placebo (n=10) for 4 wks
o All subjects followed for up to 20 wks, all on daily 20 mg cetirizine
* Outcome: +< 25% of baseline UAS, relapse > 75% of UAS
* Results: 8/19 + at week 4, 6 relapse wk 6
o Noted reductions in HRA and ASST

CsA in CIU:Adults
* Open trial in 35 CIU with 3(0-3)
o Low dose CsA 3 mos, 68% response (13/19) with few SEs1
* DB trial :40 pts CsA 5 mg/kg x 8 wks, then 4 mg/kg x 8 wks vs. cetirizine 10 mg/d2
o All cetirizine crossed to active CsA
o 3 pts reduced CsA for Cr rise
o On tx- 22 had relapse, 10 resolved spon 12 with H1
o Off tx- 16/40 in remission at 9 mos

Immunosuppression in Adolescents: Cyclosporin
* 80% of liver, kidney, cardiac Tx > 5 yr survivors on CsA
* Nephrotoxicity: 4-5 % in cardiac and liver
o 10% in RA dosed > 4 mg/kg avg 19 mos
* HTN (20-30%)
* Hyperlipedemia (10% of cardiac)
* Post-tx lymphoproliferative disease:5-17%
* Cosmetic-Gingival hyperplasia, hirsutism

Allergy Grand Rounds.ppt

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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

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