The refractory asthma patient: Thinking outside the box to - - PowerPoint PPT Presentation

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The refractory asthma patient: Thinking outside the box to - - PowerPoint PPT Presentation

Feb 16, 2023 135 likes •648 views

The refractory asthma patient: Thinking outside the box to phenotype and give specific directed therapy Richard Martin, MD Professor of Medicine, Pulmonary Disease Section National Jewish Health Denver, Colorado

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SLIDE 1

The refractory asthma patient:
 
 Thinking “outside the box” to phenotype and give specific directed therapy

Richard Martin, MD Professor of Medicine, Pulmonary Disease Section National Jewish Health Denver, Colorado

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SLIDE 2

Learning Objectives

Upon completion of this activity, the participant should be able to:

  • Describe how to “think outside the box” when

consulted on a refractory asthma patient

  • Go through a differential diagnostic process; “all that

wheezes is not asthma”

  • Determine what tests are useful to better phenotype

refractory asthma patients

  • Describe how to use bronchoscopy to phenotype and

give specific directed therapy

  • Outline how to use novel directed therapy to improve

refractory asthmatics and use less “standard” asthma medications

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SLIDE 3

Disclosures

The following CME Committee Members/planners disclose the following:

  • Richard Martin. MD discloses he is a consultant for Teva, AZ,

Novartis, MedImmune, Merck, Genentech, Amgen, LEK, and

  • Sunovion. He is a speaker for Merck, Genentech, and the ACAAI.

He receives a royalty from UpToDate.

  • Harold Nelson, MD is a consultant for Merck, Circassia, and
  • Shionogi. He has received grant/research support from Lincoln

Diagnostics, Circassia, Rigel, and NIH.

  • Sarah Meadows, MS, CCMEP has no relevant financial

relationships to disclose.

  • The employees of CJP Medical Communications have

no financial relationships to disclose.

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SLIDE 4

REACT study: The prevalence of uncontrolled asthma (Real-world Evaluation of

Asthma Control and Treatment)

45% 55%

Controlled Asthma† Uncontrolled Asthma† (n=809) (n=1003) A US representative sample of 1812 (>18 years of age) patients with moderate-to-severe asthma.

† ACT of 5-19 = uncontrolled asthma; 20-25 =

controlled.

Peters SP, et al. JACI 2007;119:1454-61

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SLIDE 5

Limited change in asthma outcomes since 1998 - US

Asthma in America 1998 (n=1,788) Asthma insight and Management 2009 (n=2,294)

Hospitalization Limited activity

Limited work Missed work/school Acute Care

0% 10% 20% 30% 40%

% of Adult Patients

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SLIDE 6
  • 51 y/o F, never smoker
  • Asthma onset at age 30 years following a

prolonged chest cold.

  • Was under fair control with moderate dose of

combination therapy (ICS + LABA) and rescue albuterol until four years ago. Progressive worsening.

╺ Now on high dose combination and rescue

1-5 times a day for the last year

Patient History

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SLIDE 7
  • Other medications

╺ Prednisone bursts ~6 times a year (1 ED

visit/year)

╺ PPI ╺ Allergy shots (grass, trees, weeds) ╺ NSI and nasal steroids ╺ Tried montelukast and theophylline

without help. Tiotropium gave about a 5% increase in FEV1.

  • No pets, no hobbies
  • No longer working due to asthma

Patient History

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SLIDE 8

Patient R.A.—PE

  • V.S. normal, BMI 27.9 kg/m2
  • HEENT: boggy nasal turbinates. Small
  • ropharynx.
  • CV: Neg
  • Respiratory: scattered forced expiratory

wheezes

  • Rest of exam: negative
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SLIDE 9

Asthma Control Test (ACT)

x x x x x 10

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SLIDE 10
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SLIDE 11
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SLIDE 12

FeNO = 32 ppb

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SLIDE 13

Patient R.A.—Imaging

  • CXR—hyperinflation, airway wall

thickening

  • Sinus CT—Pansinusitis represented by

mild to moderate mucosal thickening. No acute change

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SLIDE 14

Discussion of case

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SLIDE 15

All that wheezes is not asthma

  • GERD
  • Laryngeal dysfunction

– VCD, polyp, tumor

  • Psychosomatic
  • Pulmonary embolism
  • PIE

– ABPA – Chronic eos.

penumonia

– Chrug-strauss

syndrome

– Loffler syndrome – Tropical pul. Eos.

  • Sarcoidosis
  • Asthma
  • AIDS
  • Angioedema
  • Bronchiolitis
  • Carcinoid syndrome
  • Central obstruction

− Tumor, aneurysm,

goiter

  • COPD
  • Cocaine toxicity
  • CHF
  • Endobronch. TB
  • Inhaled toxins

− Fire, smoke

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SLIDE 16

8 12 4

  • 4
  • 8

Predicted Baseline

Volume Flow

2 4 6 8 10 12

Vocal Cord Dysfunction

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SLIDE 17

Vocal Cord Dysfunction (VCD)
 Definition/Characteristics

  • VCD is characterized by vocal cord

closure, usually on inspiration, leading to airflow obstruction with “wheezing” or stridor.

  • VCD frequently is inappropriately

diagnosed as asthma.

  • A number of different terms have been

used to describe VCD which compounds the diagnostic difficulty. Furthermore, VCD and asthma are not mutually exclusive.

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SLIDE 18

Presentation of VCD

  • Age

– Reported in patients 3-82 years old – Most frequent 2nd - 4th decade

  • Female predominance in adults
  • Increased occurrence among health care

workers in adults

  • Among children/teenage, VCD has a

strong link to participation in competitive sports and high achievement orientation

  • Prevalence unknown, but in refractory

asthma about 10% have VCD, and 33% have both VCD and asthma

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SLIDE 19

Typical VCD Patient

  • Carries diagnosis of asthma unresponsive to

therapy

  • Episodic or recurrent wheezing/dyspnea

usually sudden in onset and cessation

  • Frequent ER visits and/or hospitalization

– Extreme case intubation or tracheostomy

  • In adults obesity is a common feature which in

part may be due to chronic oral steroid use

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SLIDE 20
  • Identify “throat” as the major site of
  • bstruction during attacks
  • Hoarseness and dysphonia
  • Tightness upper chest or neck
  • Irritants, e.g., dust, smoke, odors,

exercise can trigger an attack

  • Unlike asthmatics, VCD patients are

rarely awakened from sleep by attacks

Historical Clues (con’t.)

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SLIDE 21

Historical Clues (con’t.)

  • In children and teens

– Attacks associated with sports or

strenuous activity

– School exams

  • Physical examination cannot rule in or out

VCD versus asthma

– Since large airways are excellent

conductors of distal airway sounds, asthmatics can have laryngeal wheezing

– Conversely, patients suspected of

laryngeal stridor via auscultation can have normal vocal cord and upper airway exam

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Psychological Factors

  • No specific psychological profile

defines VCD

– Children - unusual to have

  • psychological problem besides

stress

– Adults - may have various types of

psychological processes. Past sexual abuse may be involved.

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SLIDE 23
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Normal Respiration

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SLIDE 25

Start of inspiration

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SLIDE 26

Mid Inspiration

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SLIDE 27

End Inspiration

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1

PRE POST

Flow Volume

2

Flow Volume

PRE POST

4

Flow Volume

PRE POST

3

Flow Volume

PRE POST McFadden ER, et al. AJRCCM 1996;153:942-947

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SLIDE 29

Laryngoscopy-Needed for diagnosis

  • Classic VCD presents as an anterior bowing of

the vocal cords with a small posterior opening

  • Be sure the inspiratory and expiratory phases of

respiration are precisely defined.

– Assuming the vocal cord opening (abduction)

corresponds to inspiration will lead to a missed

  • diagnosis. A hand on the chest wall will help in

determining the phase of respiration.

  • During quiet respiration the vocal cords may

function normally.

– Have the patient take three or more rapid deep breaths

to TLC and blow out to RV

– Exercise, Mch challenge, or VC stimulation may be

needed

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SLIDE 30

Adherence and technique

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SLIDE 31

Back to refractory asthma discussion

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SLIDE 32

Stepwise Approach for Managing Asthma in Individuals ≥12 Years Old

Intermittent

  • Persistent Asthma: Daily Medication
  • STEP 4

  • Medium

ICS + LABA

  • r

ICS + LTRA, theo, or zileuton STEP 5


  • High-

dose ICS + LABA


  • Consider
  • maliz-

umab STEP 6


  • High-dose ICS +

LABA + systemic steroid

  • Consider
  • malizumab
  • Each step: Patient education, environmental control, and management of

comorbidities Steps 2-4: Consider subcutaneous allergen immunotherapy for patients who have allergic asthma. NAEPP Expert Panel Report 3 (EPR-3) Guidelines, 2007. STEP 1

  • SABA prn

STEP 2 Low- dose ICS.

  • LTRA,

nedoc,

  • r theo

STEP 3 
 Low-dose ICS + LABA

  • r

Medium- dose ICS

  • r

ICS + LTRA, theo,

  • r zileuton
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SLIDE 33

Since asthma is an “airway” disorder, why not study the airway in refractory asthmatics to determine phenotypes and directed therapy?

Upper Airway (Supraglottic)

Lower Airway

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SLIDE 34

Refractory Asthma—ATS

  • Major characteristics (1 needed)

╺ Oral steroids ≥ 50% of year ╺ High dose ICS, e.g., FP > 880mcg

  • Minor characteristics (2 needed)

╺ ICS + another controller ╺ SABA ~ QD ╺ FEV1 < 80%; PEF variability >20% ╺ ≥ 1 urgent care visits/year ╺ ≥ 3 oral steroid bursts/year ╺ Deterioration with ≤ 25% decrease in steroids ╺ Near fatal asthma event

Proceedings of the ATS workshop on refractory asthma.AJRCCM 2000;162:2341-2351

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SLIDE 35

In order to give personalized specific directed therapy for refractory asthma, phenotyping that truly separates groups needs to be developed

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Phenotyping

  • The problem with most phenotyping

studies is that they are focused on those patients that need to increase steroids

╺ Exhaled nitric oxide (FeNO) ╺ Sputum eosinophils ╺ Other non-invasive surrogate

markers of lung inflammation

  • Refractory asthma patients are

already on high ICS and/or oral steroids

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SLIDE 37

Cluster Phenotypes

Mild Severe AA Fixed AA AA Late non-AA

Moore WC. 2010;181:315

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SLIDE 38

Five phenotypes defined by brochoscopic evaluation

  • Tissue eosinophilia (≥ 10 per hpf)
  • Subacute bacterial infection (SBI)
  • Laryngopharyngeal reflux – LPR (was

called GER in publication)

  • Combination
  • Nonspecific

Good, Kolakowshi, Groshong, Murphy, Martin. Chest 2012;141;599-606

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SLIDE 39

Tissue eosinophilia: >10 eos/hpf

Sole criterion + combination phenotype n= 8/58 (9%). SBI n= 2 (not Tx for eos as infection can increase # of eos)

Eosinoph ils

Good, Kolakowshi, Groshong, Murphy, Martin. Chest 2012;141;599-606

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SLIDE 40

Tissue vs. BAL eosinophils n = 58

  • R = 0.44, p = 0.001
  • However

╺ n = 13, eos on bx and 0 in BAL ╺ n = 7, eos on BAL and 0 on Bx ╺ n = 12 with 0 on either

  • Also no difference in skin test or IgE

levels between phenotypes

Good, Kolakowshi, Groshong, Murphy, Martin. Chest 2012;141;599-606

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SLIDE 41

Subacute bacterial infection

  • 25 total patients (43%)

╺ BAL neutrophils > 20% always associated

with SBI

╺ BAL neutrophils could also be < 20% with

SBI

  • Mp on Cp n = 13
  • Other bacteria n = 12
  • Sole pheontype + combination = 25/58 (43%)

Good, Kolakowshi, Groshong, Murphy, Martin. Chest 2012;141;599-606

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SLIDE 42

SBI—Organisms

# of Pts Bacteria: 3/25 patients > 1 bacteria 1 Acinetobacter 1 each Methicillin resistant/sensative Staph aureus 1 Alcaligenes xylosoxidans 1 Moraxella catarrhalis 2 Alpha hemolytic streptococci 2 Stenotrophomonas maltophilia 3 Pseudomonas aeruginosa 3 Haemophilus influenza 3 Chlamydophila pneumoniae 10 Mycoplasma pneumoniae

Good.Chest 2012; 141;599-606

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SLIDE 43

LPR (GER) phenotype

  • The SGI = 15.8 ± 3.6 in GER + test
  • = 8.9 ± 5.5 in GER − test
  • p < 0.0001
  • SGI gives a history over time of potential

micro or silent aspiration. GI studies are a snapshot in time and can be falsely + or -

  • Single cause + combination for refractory

asthma 35/58 (60%)

  • Good, Kolakowshi, Groshong, Murphy, Martin. Chest 2012;141;599-606
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SLIDE 44

Combination phenotype

  • 13 patients

╺ 9 with GER and SBI ╺ 1 with GER and Eos ╺ 3 with GER, SBI, and Eos

Good, Kolakowshi, Groshong, Murphy, Martin. Chest 2012;141;599-606

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SLIDE 45

Nonspecific phenotype

  • 6 patients

╺ Rhinosinusitis and asthma x2 ╺ Asthma x2 ╺ Harmartoma and asthma ╺ VCD and asthma

Good, Kolakowshi, Groshong, Murphy, Martin. Chest 2012;141;599-606

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SLIDE 46

Treatment

Personalized and directed

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SLIDE 47

5 10 15 20 25

GER (22) SBI (13) Tissue Eos (4) Combo (13) Non-specific (6) Pre-Bronchoscopy Post-Bronchoscopy 6 mo

ACT Score

* * *

ns

Asthma Control Test n = 58

*

(12 fundoplications)

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SLIDE 48

*

100 80 60 40 20

FEV1 % Pred

FEV1% Predicted n = 58

* * *

ns

Pre-Bronchoscopy Post-Bronchoscopy GER (22) SBI (13) Tissue Eos (4) Combo (13) Non-specific (6)

(12 fundoplications)

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SLIDE 49

5 10 15 20 25 100 80 60 40 20 ACT Score FEV1 % Pred

* ACT and FEV1—all patients

Pre-Bronchoscopy Post-Bronchoscopy

*

Good, Kolakowshi, Groshong, Murphy, Martin. Chest 2012;141;599-606

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Refractory Asthma

  • Need to document the exact phenotype so as

to treat with personalized, directed therapy

  • This will improve

╺ Asthma control ╺ Lung function

  • Further investigation is needed

╺ SGI ╺ SBI and the microbiome ╺ The exact tissue eosinophil number that is

important for treatment

╺ Nonspecific group