KMA Annual Meeting 2010 - Allergy - Wheeze, Crackle, POP: When its not Asthma/COPD

Uof L Division of Pulmonary, Critical Care, and Sleep Disorders MedicineUof L Division of Pulmonary, Critical Care, and Sleep Disorders Medicine

Wheeze, Crackle, Pop: When it’s not Asthma/COPD

Rodney J. Folz, MD, PhDChief, Division of Pulmonary, Critical Care and

Sleep Disorders MedicineUniversity of Louisville School of Medicine

KY Society of Allergy, Asthma & Clinical Immunology2010 KMA Annual Meeting

Sept 22, 2010

Uof L Division of Pulmonary, Critical Care, and Sleep Disorders Medicine

Disclosures

• Funding From:• NIH

• American Heart Association

• Pfizer

• Merck

• Boehringer Ingelheim

• BioMarcks

• GlaxoSmithKline

• Cystic Fibrosis Foundation


Case 1

• 60 yo WF referred for 2nd opinion with chronic cough, asthma, and mild bronchiectasis.

• CC– chronic cough

• Waxed and waned

• Minimally productive

– recurrent pneumonia every couple of years, bronchitis over 34 yrs

– allergic rhinosinusitis and placed on immunotherapy

– bronchoscopy 6 years ago

• Allergic rhinits– Significantly improved with allergy shots

and medications

• Mild asthma dx 15 years ago– Well controlled, improved with allergy

shots and ICS/LABA.

• Mild recurrent sinusitis– Normal sinus CT

• Allergies:– PCN, Sulfa, Ceftin, flagyl

– Lactose intolerant

– Ink, cats, dust, mold allergies


Case 1

• Meds:– montelukast

– ICS/LABA

– Albuterol

• FH: +recurrent bronchitis (mother)

• SH:– Homemaker

– hobbies: print makeup with some exposure to solvents acetones/solvents

• PE: + bibasilar expiratory crackles


Adult Combined Skin Tests


Case 1

Mild obstruction


Typical Flow‐Volume CurveNormal vs severe obstruction

Normal Severe obstruction

Patient


Case 1

• Findings:– Coarse lung markings within the base

– Prominent right cardiophrenic fat pad


Case 1

• Findings:– Scattered parenchymal abnormalities

– Mild left base bronchiectasis


Case 1

• Immunoglobulin levels– IGG 1180

– IGA 152

– IGM 100

– IGE 246 (High)

• CBC, CMP, TSH, UA normal

• Fungal serologies: neg

• A1AT: 170


What would you do at this point?

Active Diagnoses:

• Allergic rhinosinusitis

• Asthma / cough

• Prior pneumonia

• Recurrent bronchitis – mild

• Mild bronchiectasis

DDx for Bronchiectasis• Pneumonia, recurrent

• Acquired airway obstruction (foreign body, TB, airway adenoma, amyloid, ABPA, impaction, etc)

• Congenital airway obstruction (bronchial cyst, sequestration,

• Immuno deficiencies

• Chronic granulomatous disease

• Ciliary defects

• Recurrent aspiration

• Inhalation toxic fumes/dusts

• Cystic fibrosis


Pilocarpine Iontophoresis ‐ “Sweat Chloride”


CFTR Genotyping


Overview of Cystic Fibrosis

• Most common “lethal” genetic disease in Caucasian population– 1:3,300 Caucasian– 1:29 Carriers mutant CFTR gene (more in other countries

e.g. N Ireland, Australia)

• Lower incidence in other populations– 1:9,500 Hispanic– 1:15,300 African‐American– 1:32,100 Asian

• ~30,000 patients in U.S.• Close to 50% of those with CF are now adults


History and Epidemiology

• 1938: “Cystic Fibrosis of the Pancreas” described by Andersen

• 1950’s: Excessive salt loss in sweat recognized in heat wave by di Sant’Agnese

• 1980’s: Specific ion transport abnormalities described (Boucher, Knowles, others)

• 1989: CFTR cloned by Collins, Tsui groups• 1990’s: New treatment strategies, gene therapy• 2000’s: Pathophysiology, gene modifiers, standards of care, quality improvement, novel treaments


Median Survival

CFF registry data


Adult with CF are increasing

CFF registry report 2007


Rodman et al., AJRCCM 171:621-626, 2005

Frequency histogram for age at diagnosis for those >40 years

Median age at diagnosis = 13

years


CF Genetics

• Monogenetic, autosomal recessive

• Carriers are asymptomatic

• Affected gene– Cystic Fibrosis Transmembrane

conductance Regulator” or CFTR.

• >1600 individual CFTR mutations identified

• The ΔF508 mutation accounts for 2/3 of CF alleles worldwide


MSD - Membrane spanning domainNBD - Nucleotide binding domainR - Regulatory domain

CFTR Function


CF Mutation Frequency


The Diagnosis of CF

• 71% diagnosed in 1st year of life

• 8% diagnosed after age 10

• 2% have Non Classic CF, which may not be recognized until adulthood

• Diagnosis requires both:– 1 or more typical phenotypic features and

– evidence of CFTR malfunction


With permission: N Eng J Med 347; 439-442: 2002


Overview: diagnostic criteria contd..

Laboratory evidence of CFTR dysfunction.

Elevated sweat chloride (>60 mmol/L)

Mutations in CFTR on both alleles

Characteristic bioelectric abnormalitiesnasal PCD – research

Immunoreactive trypsinogen (IRT)newborn screening


UofL / Kosair Cystic Fibrosis CenterPEDIATRIC PROGRAM

502‐629‐8830

• Nemr Eid, MD– Pediatric Program Director

• Martha Eddy, RN– Peds CF coordinator

• 502‐629‐7455 (office)

• 502‐629‐7540 (fax)

• Dietitian

• Social Worker

• Respiratory Therapists

ADULT PROGRAM

502‐852‐5841

• Rodney Folz, MD, PhD– Adult Program Director

• Kay Burris, RN– Adult CF coordinator

• 502‐852‐1080 (office)

• 502‐852‐1359 (fax)

• Dietitian

• Social Worker

• Respiratory Therapists


Case #2

• CC:– 35 yo WF c/o referred for wheezing and cough, much worse following

“exposure” to noxious fumes.

• PMH:– Asthma, 15+ years

– Recurrent hoarseness, SOA

– Multiple chemical sensitivities to fumes, odors, fragrances.

– MVR

– Recurrent URIs dating back 15+ years

– Tobacco use, 1‐2 ppd for 15 years. Significant second hand tobacco smoke exposure as a child.

• FHx: CAD, DM, HTN, COPD, asthma


Case #2

• HPI:– In USOH and claims while at a grocery store parking lot was exposed to strong fumes from an acetic acid container spill nearby.

– Examined in ED. CXR nl. ABG: pH 7.42, pCO2 38, pO2 102

– 10 days later underwent spirometry testing:• 19% (610 ml) improvement in FVC

• 10% (260 ml) improvement in FEV1

– Had several “asthma exacerbations” treated with ICS/LABA, oral corticosteroids.

– 6 months later underwent Challenge testing.


MCh Case Studies

Post Bronchodilator

Spirometry pre and post albuerol

1. Is this asthma?2. Is this RADs?


Several Questions

• Is this asthma?

• Is this RADs?


Exposures known to cause RADS


Minimally acceptable criteria ‐Spirometry

• Have the patient assume the correct posture.

• Attach the nose clip, place mouthpiece in mouth and instruct patient to close lips around the mouthpiece and breathe quietly.

• Instruct the patient to inhale completely and rapidly with little or no pause (< 1 sec) at TLC.

• Instruct patient to exhale maximally until no more air can be expelled.

• Repeat instructions as necessary, coaching vigorously during the expiratory maneuver.

• Repeat for a minimum of 3 acceptable maneuvers, no more than 8 are usually required.

• Check test repeatability and perform more maneuvers as necessary.


Between maneuver repeatability criteria for spirometry

• After a minimum of 3 acceptable FVC maneuvers have been obtained:– The 2 largest FVCs are within 0.15 liters of each other.

– The 2 largest FEV1s are within 0.15 liters of each other.

• If both of these criteria are not met, continue testing until – Both of criteria are met with additional acceptable maneuvers, OR

– A total of 8 maneuvers have been performed, OR

– The patient cannot or should not continue.


MCh Case Studies


PostPre

Spirometry did not meet ATS standards


Should we order MCh Challenge Testing?

baseline diluent MCh 1 mg/dl Albuterol #1 Albuterol #2

80%

Questions:1. Is this a positive Mch challenge test?2. Does this patient have bronchial hyperreactivity?3. Does this patient have asthma or RADS?


Asthma: Four Domains

1. Symptoms

2. Variable airway obstruction

3. Airway hyperresponsiveness

4. Airway inflammation

• No one domain is essential for the diagnosis.

• Primary care mostly uses symptoms to diagnose asthma can lead to incorrect diagnoses

• Increasing awareness of different asthma phenotypes and associated response to treatments.


Measurements ofBronchial Hyperresponsiveness (BHR)

1. Methacholine Challenge Testing (MCT)

2. Exercise Induced Bronchoconstriction (EIB)

3. Challenge testing can also be performed at specialized centers using:• Allergens

• Histamine

• Drugs

• cold air

• occupational sensitizers

• Eucapneic hyperventilation


MCT indications

• When asthma is a serious possibility and traditional methods unable to establish the diagnosis.– Wheezing, chest tightness,

dyspnea, cough following:• Cold air exposure

• Exercise

• URI

• Work place exposure

• Allergen exposure

• Determine relative risk of developing asthma

• Response to therapy

• Clinical research trials


Contraindications for MCT


Technician Training Qualifications

• Be familiar with this guideline and knowledgeable about specific test procedures

• Be capable of managing the equipment including set‐up, verification of proper function, maintenance, and cleaning

• Be proficient at spirometry

• Know the contraindications to MCT

• Be familiar with safety and emergency procedures

• Know when to stop further testing

• Be proficient in the administration of inhaled bronchodilators and evaluation of the response to them

• 4 days of hands on training

• Minimum of 20 supervised tests


Safety Considerations ‐ Patients

• Patient– Acute bronchospasm

– Hypoxia

– V/Q mismatch

• 1000 COPD patients ‐MCT• 25% cough

• 21% dyspnea

• 10% wheezing

• 6% dizziness

• 2% headache

• 2/3 no symptoms

• 700 histamine challenge• 20% cough, chest tightness, or

flushing

• Delayed effects are rare

• No deaths

• However, there have been fatalities reported with

– antigen challenge

– distilled water challenge.


Safety Considerations ‐ Technician

• Technician– Minimize exposure to aerosol

– 2 exchanges per hour

– Extra precautions or avoidance in technicians with asthma.

– Use of HEPA cleaner.

English Wright Nebulizer

DeVilbiss model 646 nebulizer


Safety Considerations

• Technician– Survey of 600 allergy specialists:

• 20% report symptoms

• 2 cases of asthma in nurses who use MCh

English Wright Nebulizer

DeVilbiss model 646 nebulizer


Factors that influence MCT results

• Excellent sensitivity

• Mediocre positive predictive value

• BHR is also seen in:• COPD – tobacco induced

• CHF

• CF

• Bronchitis

• Allergic rhinitis

• Sarcoidosis

• Bronchiectasis

• Siblings of asthmatics


Environmental factors that enhance bronchial hyper‐responsiveness and their duration of effect


Agents that decrease bronchial hyper‐responsiveness and their duration of effect


MCh Dosing Protocols2 Methods

• 2 min tidal breathing– Recommended by the Canadian Thoracic Society.

– Uses doubling doses of MCh

• 0.03, 0.06, 0.125, 0.25, 0.5, 1, 2, 4, 8, 16 mg/dl

– Perform 2 minutes of tidal breathing from FRC

• 5 breath dosimeter– Standardized by NIAID

– Uses quadrupling doses of MCh

• 0.0625, 0.25, 1, 4, 16 mg/dl

– Perform 5 inhalations from FRC


Advantages / Disadvantages

• 2 min tidal breathing– Allows more precise steps– More commonly used by

clinical research protocols.– May shorten overall time by

starting at 1 mg/ml if no history of asthma

– May omit next dose if < 5% drop in FEV1

• 5 breath dosimeter– Quicker method– Reduced MCh exposure to

technician


Interpretation strategies

• Factors to consider when interpreting PC20– Pretest probability of asthma

– Presence or degree of baseline airway obstruction

– Quality of patient’s spirometry maneuvers

– Symptoms reported by patient at end‐of‐test

– Degree of recovery after bronchodilator


Interpretation StrategiesCategorical Method Decision analysis


MCh Case Studies

• EH

• 65 yo WF

• 20 py

• Referred for– chronic cough

• Normal PFTs

• BMI 29

• BH

• 60 yo WF

• Never smoke

• Referred for– chronic cough and dyspnea

• Normal spirometry

• BMI 32


MCh Case Studies

• EC

• 63 WF

• Never smoke

• Referred for:– SOB, DOE

• BMI 33

• PH

• 43 WF

• Never smoke

• Referred for:– Sarcoidosis, cough

• BMI 33


Methacholine challenge

baseline diluent MCh 1 mg/dl Albuterol #1 Albuterol #2

80%

Poor QualityStudy:1. Started at 1 mg/dl MCh.2. Constricted with first dose albuterol.3. Second dose albuterol had opposite effect.


Case Presentation

14 yo WF presents with:Intermittent cough a/w exerciseIntermittent chest tightness a/w exerciseSeasonal allergiesOtherwise completely healthyAntihistamines and Singulair not helpful

14 minutes treadmillHeart rate 200 bpm

Does this patient have Exercise-Induced Bronchoconstriction (EIB)?


EIB ‐ Indications

1. Evaluation of breathlessness during or after exertion

2. When EIB would impair a person (with a history suggestive of asthma) to perform demanding work

1. Lifeguard

2. Firefighter

3. military or police

3. Determine effectiveness and optimal dosages of medications used to treat EIB

4. Evaluate effects of antiinflammatory therapy


EIB ‐Mechanism

• The major factors that determine the severity of EIB are:• the pulmonary ventilation reached and sustained

• water content and temperature of inspired air

• The stimulus for airway narrowing is• Rapid loss of water

• The mechanisms involved are:• Thermal and /or osmotic effects of dehydration and cooling

• Stimulates release of inflammatory mediators » Histamine

» cysteinyl leukotrienes)


EIB ‐ Contraindications


EIB – patient prep

• Wear comfortable clothes and gym shoes

• Light meal

• Avoid vigorous exercise for > 4 hours– Prior exercise exerts protective effect.

– 50% of EIB are refractory to second challenge with 60 minutes.


Treadmill versus Cycle Ergometers


Exercise Challenge Testing Protocol

• Patient breathes dry air in air conditioned room.

• Target 4‐6 minutes of near‐maximum exercise, total duration 6‐8 minutes.

• Advance exercise to reach 80‐90 Max HR in 2‐3 minutes. (220 – age).

• Alternatively target work rate in watts» (53.8 X FEV1) – 11.07

• Valid test requires:• Exercise intensity sustained for 4‐6 min

• Reach target HR within 4 minutes

• Monitor HR, O2 Sats, EKG


Assessing Response

• FEV1 is primary outcome variable.

• Assess at 5 min, 10 min, 20 or 30 min.

• Decrease from baseline FEV1 of 10% is a generally accepted as an abnormal response.

• A fall of 15% appears more diagnostic of EIB.

• Healthy subjects generally increase FEV1.

• Nadir FEV1 occurs most often within 5‐10 minutes.


Case Presentation

14 yo WF presents with:Intermittent cough a/w exerciseIntermittent chest tightness a/w exerciseSeasonal allergiesOtherwise completely healthyAntihistamines and Singulair not helpful


Does this patient have Exercise-Induced Bronchoconstriction (EIB)?


Case Presentation

• 14 yo WF presents with:

• Intermittent cough

• Intermittent chest tightness

• Seasonal allergies

• O/W completely healthy

• Antihistamines and Singulair not helpful



EIB therapeutic options

• Improve control of underlying concomitant asthma.

• Patient education.

• Improve cardiovascular fitness.

• Breath through scarf or mask to warm/humidify air.

• Prophylactic SABA

• Prophylactic mast cell stabilizers.

• Antileukotriene agents

• Diet enriched with omega‐3 fatty acids


Thank you for your attention

KMA Annual Meeting 2010 - Allergy - Wheeze, Crackle, POP: When its not Asthma/COPD

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