8/2/2019 ASMA DIFICIL ERJ
1/62
EL DISCURSO MAS CORTO por Bryan Dyson, ex Presidente deCoca ColaQue cosa extraa es el hombre,nacer no pide,vivir no sabe,y morir no quiere
"Imagina la vida como un juego en el que ests malabareando cinco pelotas en el aire. Estas son: -
Tu Trabajo,- Tu Familia,- Tu Salud,- Tus Amigos y - Tu Vida Espiritual, Y t las mantienes todas stas enel aire.
Pronto te dars cuenta que el Trabajo es como una pelota de goma. Si la dejas caer, rebotar yregresar. Pero las otras cuatro pelotas: Familia, Salud, Amigos y Espritu son frgiles, como de cristal. Sidejas caer una de estas, irrevocablemente saldr astillada, marcada, mellada, daada e incluso rota.Nunca volver a ser lo mismo. Debes entender esto: apreciar y esforzarte por conseguir y cuidar lo msvalioso.
Trabaja Eficientemente en el horario regular de oficina y deja el trabajo a tiempo.
Dale el tiempo requerido a tu familia y a tus amigos.Haz ejercicio, come y descansa adecuadamente.Y sobre todo.....crece en vida interior, en lo espiritual, que es lo ms trascendental, porque es eterno.
8/2/2019 ASMA DIFICIL ERJ
2/62
Thank you for viewing this presentation.
We would like to remind you that thismaterial is the property of the author. It is
provided to you by the ERS for yourpersonal use only, as submitted by the
author.
2008 by the author
8/2/2019 ASMA DIFICIL ERJ
3/62
Why isnt his Asthma
getting better, Doctor?
Andrew Bush
Andrew Bush, Cara Bossley, Pippa HallRoyal Brompton Hospital,
London UK
8/2/2019 ASMA DIFICIL ERJ
4/62
8/2/2019 ASMA DIFICIL ERJ
5/62
Most screened were not taking their medication or did not have asthma!
JACI 2008; 122: 1138-44
Does azithromycin work in severeasthma?
8/2/2019 ASMA DIFICIL ERJ
6/62
Stepwise Approach to Asthma
Is the diagnosis correct?
Is the drug delivery device appropriate?
If the child is still not right:
Is it Difficult to Treat or Severe, therapyResistant
8/2/2019 ASMA DIFICIL ERJ
7/62
Case Study 1
Dr Cara Bossley
Paediatric Respiratory SpRRoyal Brompton Hospital
8/2/2019 ASMA DIFICIL ERJ
8/62
MC 14 year old boy
Brittle asthma and allergic rhinitis
Asthma since 1 year, worse over past 3 years
Productive cough
Flixotide (500mcg/day), salmeterol (100mcg/day), theophylline
(250mg/day)
FEV1 57%, no reversibility
No improvement with high dose oral steroids
8/2/2019 ASMA DIFICIL ERJ
9/62
What would you do next?
1. Increase the dose of inhaled corticosteroid
2. Start anti-IgE therapy
3. A series of investigations to check thediagnosis is correct
4. Refer to ENT surgeons for advice
5. None of the above
8/2/2019 ASMA DIFICIL ERJ
10/62
What would you do next?1. Increase the dose of inhaled corticosteroid
2. Start anti-IgE therapy
3. A series of investigations to check the diagnosis is
correct
4. Refer to ENT surgeons for advice
5. None of the above
The productive cough, poor response to steroids andabsence of bronchodilator reversibility arepointers that the diagnosis could be incorrect
8/2/2019 ASMA DIFICIL ERJ
11/62
8/2/2019 ASMA DIFICIL ERJ
12/62
What would you do now?
1. Give a course of oral prednisolone
2. Give a course of oral augmentin
3. Give a course of intravenous cefuroximeand gentamicin
4. Give a course of oral rifampicin
5. Commence omeprazole and domperidone
8/2/2019 ASMA DIFICIL ERJ
13/62
What would you do now?
1. Give a course of oral prednisolone
2. Give a course of oral augmentin
3. Give a course of IV cefuroxime and gentamicin
4. Give a course of oral rifampicin
5. Commence omeprazole and domperidone
Due to the poor lung function and severity ofinflammation and infection seen on bronchoscopya 2 week course of IV antibiotics was given
8/2/2019 ASMA DIFICIL ERJ
14/62
What further investigationsshould be done?
1. Exercise tolerance test
2. Psychological testing
3. Milk scan
4. Nasal nitric oxide testing
5. Blood sugar testing
8/2/2019 ASMA DIFICIL ERJ
15/62
What further investigationsshould we do?
1. Exercise tolerance test
2. Psychological testing
3. Milk scan
4. Nasal nitric oxide testing
5. Blood sugar testing
Nasal nitric oxide testing can be performed asa screening test for primary ciliarydyskinesia which can be a cause of chronicproductive cough and rhinitis
8/2/2019 ASMA DIFICIL ERJ
16/62
Diagnosis: PRIMARY CILIARYDYSKINESIA
Nasal NO
30ppb (normal >200ppb)
Ciliary studies
8/2/2019 ASMA DIFICIL ERJ
17/62
8/2/2019 ASMA DIFICIL ERJ
18/62
Normal cilia PCD: Absent outer dynein arms
8/2/2019 ASMA DIFICIL ERJ
19/62
Progress
Did very well after intravenous antibiotics
Regular physiotherapy
Stopped theophylline
Halved flixotide dose (500 to 250mcg/d)
Spirometry improved; FEV1 57% rising to 94%
Symptomatically much better
8/2/2019 ASMA DIFICIL ERJ
20/62
Summary
Ongoing poorly controlled symptoms despite highdose inhaled corticosteroids and add-on therapy
Chronic productive cough
Non-atopic
Low lung function, with no evidence of bronchodilator
reversibility or steroid responsiveness
Other diagnoses must be considered
Difficult asthma alternative
8/2/2019 ASMA DIFICIL ERJ
21/62
Difficult asthma alternativediagnoses; our experience
(n=102) One vascular ring
Two had bronchiectasis
idiopathic primary ciliary dyskinesia
One Jobs syndrome
One severe sinus diseasecorrected by sinus surgery
bronchiectasis
Vascular ring
8/2/2019 ASMA DIFICIL ERJ
22/62
Co-morbidities Immune abnormality
10/74 (14%) 5/12 non-atopic patients vs
5/62 atopic children (p=0.04)
41/55 (75%) gastro-oesphagealreflux disease
4/99 (4%) airway malacia
5/99 (5%) enlarged adenoids
1/99 (1%) narrow right mainbronchus Tracheomalacia
Enlarged adenoids
8/2/2019 ASMA DIFICIL ERJ
23/62
Alternative / Additional diagnoses
Royal London Hospital
57 difficult asthma children, 9 alternative diagnosis
3/57 (5.2%) bronchiolitis obliterans
2/57 (3.5%) functional dyspnoea
1 hyperventilation
1 vocal cord dysfunction
1/57 (1.8%) interstitial pneumonitis
2/57 (3.5%) over reporting of symptoms
Pediatr Pulmonol, 2001:31:114-120
8/2/2019 ASMA DIFICIL ERJ
24/62
8/2/2019 ASMA DIFICIL ERJ
25/62
Definitions-1
Problematic Severe Asthma = A new concept in the literature Presentation label
Symptoms >3 times per week despite high dose ICS(>800 mcg BDP equivalent), LABAs, LTRAs &Theophyllines (?)
Multiple severe exacerbations or a single PICUadmissionBrittle (chronically chaotic peak flow Type 1,
catastrophic exacerbations out of the blue Type 2)Daily or alternate day prednisolonePersistent airflow limitation
Comprises two (four) categories: Difficult asthma Severe, therapy resistant asthma (Not asthma at all wrong diagnosis) (Asthma plus co-morbidities)
8/2/2019 ASMA DIFICIL ERJ
26/62
Definitions-2
Difficult to treat asthma = becomes easier when the basics are got right
(adherence, environment, etc.)
NOT candidates for novel therapies
Severe, therapy resistant asthma = treatment still extremely difficult despitegetting
the basics right
Would be potentially suitable for cytokine specifictherapies
8/2/2019 ASMA DIFICIL ERJ
27/62
The Protocol
Visit two: FOB
Assess symptoms,
use of rescue medication
Spirometry & reversibilityInduced sputum, eNO
FOB, BAL, biopsy
Visit three: Decision time
Assess symptoms, diary card,use of rescue medication
Spirometry & reversibility
Induced sputum, eNO
Develop treatment plan
IntramuscularTriamcinolone
4 weeks
Visit one: MDT Assessment
Drug delivery device
Assess symptoms, use of
rescue medicationSpirometry & reversibilityInduced sputum, eNO
Home visit: environment
School visit: bullying?
Assess compliance
Psychological assessment
1-2 months
8/2/2019 ASMA DIFICIL ERJ
28/62
What does a home visitachieve?
Psycho-social issues re-addressed Anecdotally, more likely to open up
74% referrals were after home discussions
Adherence
Smoking
Allergens
8/2/2019 ASMA DIFICIL ERJ
29/62
Case Study 2
Pippa Hall
Childrens Respiratory NurseRoyal Brompton Hospital
8/2/2019 ASMA DIFICIL ERJ
30/62
Child B - History
16 year old female
Referred from local Paediatrician
Ongoing persistent symptoms despitebeyond guideline treatment
Psychological issues
9 hospital admissions in past 12 months including an admission to PICU
8/2/2019 ASMA DIFICIL ERJ
31/62
Treatment at Referral
Regular Medication
Symbicort 400/12mcg (x3 puffs) BD
Montelukast 10mg OD
Uniphylline 400mg BD
Omalizumab 300mg 2 weekly Triamcinolone 80mg (i/m) monthly
Rescue Medication
11 courses of high dose oral steroids in last year
Short acting beta agonist (SABA) use >3 times daily
8/2/2019 ASMA DIFICIL ERJ
32/62
Investigation Results
FEV1: 73% predicted
BDR: 26%
FeNO50: 16ppb
Asthma Control Test (ACT): 15/25
Skin Prick Tests: all negative
Total IgE: 454
8/2/2019 ASMA DIFICIL ERJ
33/62
What would you do now?
1. Prescribe alternate day prednisolone
2. Prescribe daily prednisolone3. Prescribe oral methotrexate
4. Trial of subcutaneous terbutaline
5. None of the above
8/2/2019 ASMA DIFICIL ERJ
34/62
What would you do now?
1. Prescribe alternate day prednisolone
2. Prescribe daily prednisolone3. Prescribe oral methotrexate
4. Trial of subcutaneous terbutaline
5. None of the above
8/2/2019 ASMA DIFICIL ERJ
35/62
How did we assess adherence?
1. Asked the child how often they took themedication
2. Asked the parents how often they gave
the medication3. Checked GP and hospital prescriptions
4. Checked in the home for availability of
in-date medications5. Shouted at everyone until a confession
was made
8/2/2019 ASMA DIFICIL ERJ
36/62
How did we assess adherence?
1. Asked the child how often they took themedication
2. Asked the parents how often they gave themedication
3. Checked GP and hospitalprescriptions
4. Checked in the home foravailability of in date medications5. Shouted at everyone until a confession was
made
8/2/2019 ASMA DIFICIL ERJ
37/62
How much in fact had beencollected?
1. 75 100%
2. 50 75%3. 25 50%
4.
8/2/2019 ASMA DIFICIL ERJ
38/62
How much in fact had beencollected?
1. 75 100%
2. 50 75%3. 25 50%
4.
8/2/2019 ASMA DIFICIL ERJ
39/62
Interventions
Patient education Importance of regular inhaled medication
discussed
Parental supervision of medication Parental involvement encouraged
Simplification of medication regime Montelukast stopped
8/2/2019 ASMA DIFICIL ERJ
40/62
Investigations Continued
Adherence Poor understanding of Turbohaler use
GP prescription uptake
8/2/2019 ASMA DIFICIL ERJ
41/62
Outcome After 6 months
SABA use:
8/2/2019 ASMA DIFICIL ERJ
42/62
Conclusion
Poor adherence to treatment was the maincontributor to ongoing poorly controlled
symptoms
In our cohort of difficult asthmatics1: Prescription uptake was
8/2/2019 ASMA DIFICIL ERJ
43/62
Did they take medications?
55 (77%) had a complete setof in-date, accessiblemedication
44 (62%) had a goodtechnique
34 (48%) medication issuescontributed to poor control
0
510
15
20
2530
35
40
45
Nos.
%
80
Prescription Records
8/2/2019 ASMA DIFICIL ERJ
44/62
The Buck Stops Where?
Pediatrics 2008; 122: e1186-92
8/2/2019 ASMA DIFICIL ERJ
45/62
Case Study 3
Pippa Hall
Childrens Respiratory Nurse Specialist
Royal Brompton Hospital
8/2/2019 ASMA DIFICIL ERJ
46/62
H h ld h hild b d
8/2/2019 ASMA DIFICIL ERJ
47/62
How should the child be assessedfor sensitivity to allergens?
1. Skin prick testing
2. Histamine challenge
3. Total serum IgE
4. Specific IgE in serum
5. Inhalant allergy challenge
H h ld h hild b d
8/2/2019 ASMA DIFICIL ERJ
48/62
How should the child be assessedfor sensitivity to allergens?
1. Skin prick testing
2. Histamine challenge3. Total serum IgE
4. Specific IgE in serum
5. Inhalant allergy challenge
8/2/2019 ASMA DIFICIL ERJ
49/62
Investigation Results
FEV1: 61% predicted
BDR: 48%
FeNO50: 120ppb
Asthma Control Test (ACT): 7/25
Skin Prick Tests: +ve grass, cat, dog
8/2/2019 ASMA DIFICIL ERJ
50/62
Home Visit
Adherence
Chaotic medication regimen noted in thehome
Smoke Exposure
Step father smokes outside (no evidenceof smoke inside)
Allergen Exposure
4 cats at home
8/2/2019 ASMA DIFICIL ERJ
51/62
Changes Following Home Visit
Medication
Simplified medication regimen SMART
Smoke Exposure
Step father to attempt to give up smoking
Allergen Exposure
Cats removed from the home
Wh t h d t th hild
8/2/2019 ASMA DIFICIL ERJ
52/62
What happened to the childs
asthma after removal of the cats?
1. Became completely symptom free
2. Dramatically improved control
3. Stayed the same
4. Got worse
5. The child became psychoticallydepressed at the loss of a pet
Wh t h d t th hild
8/2/2019 ASMA DIFICIL ERJ
53/62
What happened to the childs
asthma after removal of the cats?
1. Became completely symptom free
2. Dramatically improved control3. Stayed the same
4. Got worse
5. The child became psychoticallydepressed at the loss of a pet
8/2/2019 ASMA DIFICIL ERJ
54/62
6 months After Home Visit
SABA use: < once daily
FEV1: 85% predicted
BDR: 15%
FeNO50: 68ppb
ACT: 16/25
No hospital admissions or courses of high dose
oral corticosteroids
8/2/2019 ASMA DIFICIL ERJ
55/62
Conclusions
Removing allergens in the home andsimplifying medication regimen improved
patient outcomes
8/2/2019 ASMA DIFICIL ERJ
56/62
Allergen avoidance?
HDM n=31 sensitised
Avoidance:
5 (16%) reasonable
15 (48%) some 11 (36%) none
Pets n=30 owners, 17 sensitised Avoidance: n=2
8/2/2019 ASMA DIFICIL ERJ
57/62
Subclinical Allergen
Exposure
Low dose allergenchallenge (no decline inFEV1)
Worsening AHR,sputum eosinophiliawith no acutedeterioration
ERJ 1998; 11: 821-7
http://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeg8/2/2019 ASMA DIFICIL ERJ
58/62
Dose-response curves for inhibition of PHA stimulation.
White = no IL-2 or 4; Black = IL-2 & IL-4
IL-2 & IL-4 decrease sensitivity to the anti-proliferative effects of
dexamethasone
Persistent Asthmatics
http://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeg8/2/2019 ASMA DIFICIL ERJ
59/62
Lancet, April 2008
A: Because the wrong question has been askedin the wrong population!
http://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeg8/2/2019 ASMA DIFICIL ERJ
60/62
Cochrane review: Problems
Combined adult and children
Intervention duration 3 weeks - 2 years
Wide variety of types and scope of interventions Mattress-only studies included
Minority showed intervention successful Most did not reduce HDM burden
Unsuitable candidates Not all had clinical allergy
Demanding intervention did they have a problem?
Should have adjusted for season/ virus infections in small trials
How many really severe asthmatics?
http://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeg8/2/2019 ASMA DIFICIL ERJ
61/62
Viruses, Asthma, Allergens
84 children, 3-17yr
Acute exacerbation ofasthma vs. stable asthma vs.controls
SPT, RASTs, home allergenlevels
Viral PCR on nasal lavage
Thorax 2006; 61: 376-82 02
4
6
8
1012
14
16
18
20
OR(mv)
+ - + + + Sensitized- - + - + Exposed- + - + + Virus
P
8/2/2019 ASMA DIFICIL ERJ
62/62
Summary and Conclusions
Do not forget the obvious Wrong diagnosis Not taking treatment Cannot use device
Ask the key question: What makes this asthmadifficult?
Consider environmental causes of steroid resistance
Only then think of escalating therapy
http://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeghttp://ajrccm.atsjournals.org/content/vol170/issue4/images/large/200308-1143OCf1.jpeg