Format 2015: asthma severe or difficult

Severe or Difficult Asthma ?
 Introduction
 Is it asthma?
 Comorbidities
 Compliance /Adherence
 Severe Asthma: definition & phenotyping
 Severe Asthma: pathogenesis
 Severe Asthma: environment
 Severe Asthma: genetics & gender
 Prognosis & Natural History: Difficult/Severe
 Assessment
 Treatment problems
 Therapy: what can be done
 Questions?
 Summary & Conclusions
Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it
Carlo Capristo
University of
Napoli, Italy

Although the majority of
asthma patients can be
effectively treated with
currently available medications,
a substantial subset exists who
remain difficult-to-treat.
These patients account for a
relatively large proportion of
resource expenditure.
Difficult Asthma
Severe or Difficult Asthma ?

Severe asthma in childhood: assessed in 10 year olds in
a birth cohort study. Lang A, Carlsen KH, Allergy 2008;63:1054.
Children enrolled in the
prospective birth cohort;
the Environment and Childhood
Asthma Study in Oslo;
reinvestigated at the age of
10 years (n = 1019).
Severe asthma was defined as
poorly controlled asthma despite
treatment with ≥ 800 µg budesonide
or equivalent and LABA or LTRA
Point Prevalence at age 10 yrs
of Current Severe Asthma
all
children
5 –
4 –
3 –
2 –
1 –
0
0.5%
4.5%
asthmatics

Severe asthma in childhood: assessed in 10 year olds in
a birth cohort study. Lang A, Carlsen KH, Allergy 2008;63:1054.
Children enrolled in the
prospective birth cohort;
the Environment and Childhood
Asthma Study in Oslo;
reinvestigated at the age of
10 years (n = 1019).
Severe asthma was defined as
poorly controlled asthma despite
treatment with ≥ 800 µg budesonide
or equivalent and LABA or LTRA
all
children
5 –
4 –
3 –
2 –
1 –
0
0.5%
4.5%
asthmatics
However, there may be
disparate underlying problems
including:
1) wrong diagnosis,
2) poor adherence to
therapy,
3) adverse environmental
conditions and
4) comorbid conditions,
5) as well as genuine
therapy-resistant asthma
Point Prevalence at age 10 yrs
of Current Severe Asthma

Indeed, when the Childhood Asthma Research and Education
(CARE) Network attempted to compare montelukast vs
azithromycin as add-on therapy for children remaining
symptomatic despite prescribed treatment
with ICS and LABA,
Azithromycin or montelukast as inhaled corticosteroid-sparing agents in moderate-to-severe
childhood asthma study. Strunk RC, J Allergy Clin Immunol 2008;122:1138–1144.
Disparate Underlying Problems: how much is true?
the trial had to be abandoned as futile since only
55 (19%) out of 292 children could be randomised,
the main reasons for exclusion being:
wrong diagnosis or
failure to adhere to standard therapy

Problematic severe asthma: a proposed approach to
identifying children who are severely resistant to
therapy. Konradsen JR, Pediatr Allergy Immunol 2011;22:9-18.
54 school-aged children with problematic
severe asthma (PA) vs age-matched peers with
controlled persistent asthma (CA).
PA defined as insufficient asthma control
despite level 4 treatment*, according to GINA.
difficult to treat
because of
aggravating factors.
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
39%
61%
Of the 54 children
initially considred with
Problematic Asthma, % with
Real
therapy
resistant
asthma
*
33/54
21/54

Problematic severe asthma: a proposed approach to
identifying children who are severely resistant to
therapy. Konradsen JR, Pediatr Allergy Immunol 2011;22:9-18.
54 school-aged children with problematic
severe asthma (PA) vs age-matched peers with
controlled persistent asthma (CA).
PA defined as insufficient asthma control
despite level 4 treatment*, according to GINA.
difficult to treat
because of
aggravating factors.
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
39%
61%
Of the 54 children
initially considred with
Problematic Asthma, % with
Real
therapy
resistant
asthma
*
33/54
21/54
The protocol included
1) questionnaires,
2) spirometry,
3) methacholine provocation,
4) exhaled FENO and nasal air,
5) blood sampling for
inflammatory biomarkers and
atopy,
6) computerized tomography of
sinuses and lungs

Problematic severe asthma can be divided up into
difficult-to-treat asthma and severe therapy-resistant
asthma. Hedlin G, ERJ 2010;36:196
Wrong diagnosis
“Not asthma at all”

Wrong diagnosis
“asthma plus” and “difficult asthma”
in which the problems can be
addressed if the basics are right

Wrong diagnosis
when factors that
make the child
difficult to treat
cannot be identified.
“asthma plus” and “difficult asthma”
in which the problems can be
addressed if the basics are right

Wrong diagnosis
this is the group that
may be eligible for
toxic steroid-sparing
agents, such as
cyclosporin, or novel
molecular-based
therapies, such as
anti-immunoglobulin-E
or anti-IL-5
Such children would not be candidates for innovative therapies,
unless these problems have been solved and asthma severity persists.

Difficult Asthma
ERS/ATS Guidelines, ERJ 2014;43:343-373
the evaluation of children with
difficult-to-control asthma have to address:
1) that the patient with ‘‘difficult asthma’’ has asthma,
2) the appropriate assessment of confounding factors and
comorbidities,
3) the determination of phenotypes which may
be useful in optimising therapy.

The patient has asthma ?
Clinicians should maintain a degree of
scepticism regarding the diagnosis and
establish whether the patient’s history and
evaluation truly represent asthma.
Misdiagnosis of non-asthmatic conditions
as uncontrolled asthma has been reported
to be as high as 12–30%.
Robinson DS, Eur Respir J 2003; 22: 478–483.
Aaron SD, CMAJ 2008;179: 1121–1131.
-

Systematic assessment of difficult-to-treat asthma.
100 patients with a
respiratory physician
diagnosis of
difficult-asthma
investigated in a single
tertiary respiratory unit
No
asthma
% patients with
60 –
50 –
40 –
30 –
20 –
10 –
0
12%
PEF-FEV1 reversible > 15%
or diurnal variation > 15%
YES
55%
NO
20%
?
13%

No
asthma
60 –
50 –
40 –
30 –
20 –
10 –
0
12%
YES
55%
NO
20%
?
13%
% patients with
diagnosis of
difficult-asthma

No
asthma
60 –
50 –
40 –
30 –
20 –
10 –
0
12%
YES
55%
NO
20%
?
13%
A major psychiatric
component was detected
in 10% of patients
% patients with
diagnosis of
difficult-asthma

% patients with
60 –
50 –
40 –
30 –
20 –
10 –
0
32%
alternative or additional diagnoses,
psychiatric illness or
nonconcordance with therapy
diagnosis of
difficult-asthma

Overdiagnosis of asthma in obese and nonobese adults.
Aaron SD, CMAJ 2008;179:1121–1131.
496 adults with a doctor
diagnosis of asthma
(242 obese and 254 nonobese).
diagnosis of current asthma
excluded in those who did not
have evidence of acute
worsening of asthma
symptoms, reversible airflow
obstruction or bronchial
hyperresponsiveness, despite
being weaned off asthma
medications
of obese subjects
40 –
30 –
20 –
10 –
0
31.8%
Asthma was excluded in
Dyspnoea Asthma

Investigation of young children with severe recurrent
wheeze: any clinical benefit?
Saglani S, Eur Respir J 2006;27:29–35.
47 children aged 3 mo - 5 yrs
with severe recurrent wheezing,
chest computed tomography scan,
blood tests,
nasal ciliary brushings,
fibreoptic bronchoscopy,
bronchoalveolar lavage (BAL),
endobronchial biopsy
pH probe.
+ pH
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
67%
% children
atopic
39%
abnormal
bronchoscopy
79%
(37/47)

blood tests,
pH probe.
% children
abnormal
bronchoscopy
79%
(37/47)
structural abnormalities
[13 out of 37 (36%)],
excessive mucus
[20 out of 37 (54%)]
macroscopic inflammation
[10 out of 37 (27%)].
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00

80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
blood tests,
pH probe.
% children
abnormal
bronchoscopy
79%
(37/47)
structural abnormalities
[13 out of 37 (36%)],
excessive mucus
[20 out of 37 (54%)]
macroscopic inflammation
[10 out of 37 (27%)].
Including:
1) enlarged tonsils and adenoids
causing dynamic airway
obstruction during quiet
breathing (not previously
appreciated during multiple
physical examinations),
2) laryngo-, tracheo- or
bronchomalacia,
3) foreign body
4) external, pulsatile tracheal
compression.

blood tests,
pH probe.
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
asthma
*41%
Predominantly GOR
(abnormal pH study
and BAL fat-laden
macrophages and
normal biopsy)
*23%
Predominantly infection
(significant bacterial
growth and
neutrophilia in BAL)
*13%
% children

blood tests,
pH probe.
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
asthma
*41%
Predominantly GOR
(abnormal pH study
and BAL fat-laden
macrophages and
normal biopsy)
*23%
Predominantly infection
(significant bacterial
growth and
neutrophilia in BAL)
*13%
No definite diagnosis
*23%
% children

As confirmation of reversible airflow
limitation is part of the diagnosis of
asthma, spirometry with both inspiratory
and expiratory loops, assessed following
pre- and post-bronchodilator
administration should be obtained
Standards for the diagnosis and care of patients with
chronic obstructive pulmonary disease (COPD) and
asthma. ATS Am Rev Respir Dis 1987; 136: 225–244.
UAO=upper
airway obstruction

UAO=upper
airway obstruction
•Fixed upper airway obstructions
demonstrate plateaus of flow
during both forced inspiration
and forced expiration.
•Causes of fixed upper airway
obstruction include:
goiters, endotracheal neoplasms,
stenosis of both main bronchi,
postintubation stenosis, and
performance of the test through a
tracheostomy tube or other fixed
orifice device.

UAO=upper
airway obstruction
•Variable extrathoracic
obstructions demonstrate
reduction of inspired flows during
forced inspirations with
preservation of expiratory flows.
•Causes of this type of upper airway
obstruction include: unilateral and
bilateral vocal cord paralysis, vocal
cord adhesions, vocal cord
constriction, dysfunction,
laryngeal edema, and
upper airway narrowing associated
with obstructive sleep apnea.

UAO=upper
airway obstruction
Variable intrathoracic constrictions
expand during inspiration, causing an
increase in airway lumen and resulting
in a normal-appearing inspiratory limb
of the flow-volume loop.
During expiration, compression by
increasing pleural pressures leads to
a decrease in the size of the airway
lumen at the site of intrathoracic
obstruction, producing a flattening
of the expiratory limb of the
flow-volume loop.
Causes of variable intrathoracic
lesions include malignant tumors,
vascular rings, tracheomalacia.

UAO=upper
airway obstruction
A diagnosis of asthma can
only be made when a clear
and dramatic response to
asthma medication is
demonstrated.
This may be evidence of
‘‘reversibility’’, that is an
increase of >12% in FEV1 in
response to inhaled
β2-agonists (in those who
can perform lung function
tests reliably), or, more
commonly, a dramatic
response to inhaled or oral
corticosteroids.

UAO=upper
airway obstruction
Without such a
response, it is not
possible to label a
patient as having
asthma.
The patient does not have
asthma
or
the patient has asthma
together with a respiratory
problem that is not being
addressed.

Diagnostic accuracy of the bronchodilator response
in children. Tse SM, JACI 2013;132:554
Background
The bronchodilator response (BDR) reflects the reversibility of
airflow obstruction and is recommended as an adjunctive test to
diagnose asthma.
The validity of the commonly used definition of BDR, a 12% or greater
change in FEV1 from baseline, has been questioned in childhood.
Objectives
We examined the diagnostic accuracy of the BDR test by using 3 large
pediatric cohorts (1041 children with mild-to-moderate asthma from
the Childhood Asthma Management Program (CAMP), and control
subjects (nonasthmatic and nonwheezing) chosen from Project Viva
and Home Allergens, 2 population-based pediatric cohorts.

 1041 children with
mild-to-moderate
asthma from the
Childhood Asthma
Management Program
(mean age, 8.9 years).
 250 control subjects
(non -asthmatic and
non-wheezing).
Mean bronchodilator
response: % increase in FEV1
Asthmatics
10.7%
Controls
15 –
10 –
05 –
00
2.7%

 1041 children with
mild-to-moderate
asthma from the
Childhood Asthma
Management Program
(mean age, 8.9 years).
 250 control subjects
(nonasthmatic and
nonwheezing).
Asthmatics
10.7%
Controls
15 –
10 –
05 –
00
2.7%
Despite good
specificity
(true negative rate),
a cutoff of 12% was
associated with poor
sensitivity
(true positive rate)
=35.6%.
Mean bronchodilator
response: % increase in FEV1

A BDR cutoff of 8% or less performed significantly better
than a cutoff of 12% (P = 0.03, 8% vs 12%) in the CAMP study.
% of sick people who are
correctly identified as
having the condition
% of healthy people who
are correctly identified as
not having the condition
CAMP study: 1041 children with asthma

 The widely accepted BDR cutoff of 12% is based on general
population and asthmatic patient studies consisting of mostly
adults, who might have a higher interindividual variability in
baseline FEV1.
 Studies have shown that the BDR tends to increase with decreasing
baseline lung function, and therefore BDR might be higher in
asthmatic adults.
 In contrast, in asthmatic children baseline lung function tends to
remain normal, even in a subset of patients with severe asthma;
hence a 12% change from baseline with bronchodilator might be
difficult to reach.
 A previous study of the BDR test in a mainly Hispanic pediatric
population, which identified a BDR cutoff of 9% as the optimal
value, with a sensitivity of 42.5% and a specificity of 86.3%.
S.P. Galant, J Pediatr, 2007;151:57–462.e1

Conclusions
 Our findings highlight the poor sensitivity (% of sick people who
are correctly identified as having the condition) associated with
the commonly used 12% cutoff for BDR.
 Although our data show that a threshold of less than 8%
performs better than 12%, given the variability of this test in
children, we conclude that it might be not be appropriate to choose
a specific BDR cutoff as a criterion for the diagnosis of asthma.

Forced expiratory flow between 25% and 75% of vital
capacity and FEV1/forced vital capacity ratio in relation
to clinical and physiological parameters in asthmatic
children with normal FEV1 values.
Simon MR, J Allergy Clin Immunol 2010;126:527–534.
437 children
with asthma
and normal
FEV1 %
predicted
FEF25-75 % pred, and FEV1/FVC % pred were:
(1) positively correlated with log2 methacholine PC20,
(2) positively correlated with morning and evening
peak expiratory flow percent predicted, and
(3) negatively correlated with log10 FENO and
bronchodilator responsiveness.
FEF25-75 % pred.<62% better correlated with
bronchodilator responsiveness and
log2 methacholine PC20
than FEV1 % pred or FEV1/FVC % pred.

437 children
with asthma
and normal
FEV1 %
predicted
Children with a
normal FEV1 both
before and after
a short-acting
β-agonist may
show a
bronchodilator
response in terms
of forced
expiratory flow at
25–75% of FVC
(FEF25–75)

437 children
with asthma
and normal
FEV1 %
predicted
Bronchial
provocation
testing with
exercise or
methacholine
bronchial
challenge may
be indicated
in difficult
cases

•The ROC curve analysis demonstrated that 62 % predicted FEF25-75 had a sensitivity of 90%
and a specificity of 73% in detecting ≥20% increase in FEV1 following inhalation of albuterol.
•The % predicted FEF25-75 has a NNT of 7 relative to the FEV1/FVC % predicted to identify
one child who would benefit from bronchodilator testing. This suggests that the FEF25-75 is
moderately efficacious in identifying otherwise undiagnosed bronchodilator responsiveness.
•What may render the FEF25-75 problematic in a given patient is that the variance is much
higher than that of the FEV1.
•Thus, even though the FEF25-75 is more physiologically sensitive, it lacks specificity due to its
variability; i.e. the lower limit of normal is substantively lower than for FEV1 or FEV1/FVC.
•Therefore, it is of limited diagnostic value in detecting an abnormality per se. However, if a
patient is already known to have asthma, then the sensitivity of the FEF25-75 appears to be
valuable in suggesting the likelihood that reversible bronchoconstriction is present.

•The lower limit of normal for the FEF25-75% can be less than 50% of the mean predicted value,
making it important to use the lower limit of normal defined by the 95% confidence limit of
the mean predicted value rather than a threshold defined by a fixed percentage of the
predicted value.
•The FEF25-75% is also very dependent on expiratory time. If expiratory times of spirometry
efforts vary by more than 10%, comparisons of the FEF25-75% before and after bronchodilator
challenge are difficult to interpret.
• Early termination of expiration shifts the middle 50% of the exhaled volume toward the
start of the exhalation, artifactually raising the FEF25-75%.

FEF25-75 as a marker of airway obstruction in asthmatic
children during reduced mite exposure at high altitude.
Valletta EA, J Asthma. 1997;34:127-31.
14 children with asthma, allergic to house
dust mites, while at high altitude (1756 m).
Forced vital capacity (FVC),
forced expiratory volume in 1 sec (FEV1),
FEF25-75, and peak expiratory flow (PEF)
measured every 2 weeks for 12 weeks
(total, 84 measurements).
Presence or absence of wheezing at the
chest auscultation was ascertained before
each test
PEF
FEV1
FEF25-75

presence or absence of wheezing at the
each test
PEF
FEV1
FEF25-75
During the study period, a
significant improvement of both
FEF25-75 % predicted value,
(p = 0.005) and PEF (p = 0.002)
was observed.
FEV1 changed only marginally
(p = 0.05).

each test
PEF
FEV1
FEF25-75
Wheezing was present on
12/84 occasions.
Wheezing was associated with
abnormal FEF25-75 values on
most occasions but not with
abnormal FEV1 or PEF.

each test
PEF
FEV1
FEF25-75
FEF25-75 may be considered a
good indicator of airflow
obstruction and a sensitive
marker of respiratory
improvement in asthmatic
children during reduced
antigen exposure.

Features of severe asthma in school-age children:
atopy and increased exhaled nitric oxide.
Fitzpatrick AM, J Allergy Clin Immunol 2006;118:1218–1225.
75 children (median age, 10 yrs)
with asthma
(severe n = 39, mild/moderate n = 36)
spirometry and lung volume,
methacholine bronchoprovocation,
allergy evaluation,
exhaled nitric oxide (FENO)
followed longitudinally over
6 months.
% children with atopy, defined as
either a serum IgE ≥ 150 or
≥ 1 positive skin prick reaction,
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
100 -
76%
p=0.012
100%
severe
asthma
mild to
moderate
asthma

with asthma
6 months.
% children with atopy, defined as
either a serum IgE ≥ 150 or
≥ 1 positive skin prick reaction,
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
100 -
76%
p=0.012
100%
severe
asthma
mild to
moderate
asthma
children with severe asthma had
significantly higher serum IgE
(821 ± 1066 vs 301 ± 413 kU/L;
log-transformed P=0.002) and
more positive skin prick reactions
to aeroallergens
(mean 5 ± 3 vs 3 ± 3; P=0.009),
namely
weed mix (34% vs 6%; P=0.023 ),
D. farinae (79% vs 50%; P=0.039),
D. pteryn (86% vs 56%; P=0.024).

20 –
15 –
10 –
05 –
0
P<0.001 16.4
8.2
FENO values (ppb)
at baseline
mild to
moderate
asthma
severe
asthma
with asthma
6 months.

Spirometry and lung volume measurements (means±SD)*
Children with severe versus mild-to-moderate asthma had more symptoms, greater airway
obstruction, more gas trapping, and increased bronchial responsiveness to methacholine.

Children with severe versus mild-to-moderate asthma had more symptoms, greater airway
obstruction, more gas trapping, and increased bronchial responsiveness to methacholine.
“However, some children with severe asthma may have normal
lung function and no acute response to bronchodilators”
Spirometry and lung volume measurements (means±SD)*
96
84
84

Longitudinal FENO and FEV1 data
at baseline and over a period of 6 months.
(severe asthma = black circles). Group
differences depicted with asterisks (P < 0.05).
probability of remaining exacerbation-
free over the 6-month for subjects
grouped according to high (≥0.80) and
low (<0.80) baseline FEV1/FVC.
●severe asthma

Longitudinal FENO and FEV1 data
at baseline and over a period of 6 months.
(severe asthma = black circles). Group
differences depicted with asterisks (P < 0.05).
probability of remaining exacerbation-
free over the 6-month for subjects
grouped according to high (≥0.80) and
low (<0.80) baseline FEV1/FVC.
●severe asthma
•Persisting elevated FENO
suggests that persistent airway
inflammation may be a defining
feature of at least a
subpopulation of children with
severe asthma.
•Allergic sensitization is a unique
defining feature of severe
asthma in children.

Referral to a Specialised Centre
Referred to a specialised centre
Patients with supposed
severe asthma
systematic evaluation
are classed as difficult-to-control
30–50% of patients
previously called severe,
Robinson DS, Eur Respir J 2003; 22: 478–483
Heaney LG, Thorax 2003; 58: 561–566.
Bracken M, Arch Dis Child 2009; 94: 780–784.

Referred to a specialised centre
Patients with supposed
severe asthma
systematic evaluation
are classed as difficult-to-control
30–50% of patients
previously called severe,
Robinson DS, Eur Respir J 2003; 22: 478–483
Heaney LG, Thorax 2003; 58: 561–566.
Bracken M, Arch Dis Child 2009; 94: 780–784.
approximately 50% of children
referred for severe asthma have
persistent symptoms and poor
control because of inadequate
disease management
Bracken M, Arch Dis Child
2009; 94: 780–784.

Referral to a specialised centre where patients can undergo a
systematic evaluation, resulted in 30–50% of patients previously
called severe, being classed as difficult-to-control.
Heaney LG, Thorax 2003; 58: 561–566.
Many children with asthma will also be found not to have severe,
treatment-refractory asthma after a thorough evaluation and
approximately 50% of children referred
for severe asthma have persistent
symptoms and poor control because
of inadequate disease management.
Bracken M, Arch Dis Child 2009;94:780–784.
Bush A, Lancet 2010;376:814–825.

a cohort of 73 sequentially referred
poorly controlled asthmatics
a systematic evaluation protocol
including:
induced sputum analysis,
psychiatric assessment,
ear, nose and throat examination,
pulmonary function testing,
high resolution CT scan of the thorax,
24 hour dual probe ambulatory
ooesophageal pH monitoring.
difficult to
control
asthma
60 –
50 –
40 –
30 –
20 –
10 –
0
53%
% patients who
47%
true
therapy
resistant
asthma
Predictors of therapy resistant asthma: outcome of a
systematic evaluation protocol.Heaney LG, Thorax 2003;58:561.

a cohort of 73 sequentially referred
poorly controlled asthmatics
a systematic evaluation protocol
including:
induced sputum analysis,
psychiatric assessment,
ear, nose and throat examination,
pulmonary function testing,
high resolution CT scan of the thorax,
24 hour dual probe ambulatory
ooesophageal pH monitoring.
60 –
50 –
40 –
30 –
20 –
10 –
0
53%
% patients who
47%
In poorly controlled asthmatics
there is a high prevalence of
co-morbidity, identified by
detailed systematic assessment,
but
no difference in prevalence
between those who respond to
intervention and those with TRA.
co-morbidity
also present
difficult to
control
asthma
true
therapy
resistant
asthma

Subjects
with TRA
had a
greater
period of
instability,
a higher
dose of
inhaled
steroids at
referral,
more rescue
and
maintenance
steroid use,
and a lower
best %FEV1
and
FEV1/FVC.

Diseases which can masquerade as severe asthma
Children
•Dysfunctional breathing/vocal cord dysfunction
•Bronchiolitis, obliterative bronchiolitis
•Recurrent (micro) aspiration, reflux, swallowing dysfunction
•Prematurity and related lung disease
•Cystic fibrosis
•Congenital or acquired immune deficiency
•Primary ciliary dyskinesia
•Central airways obstruction/compression
•Foreign body
•Congenital malformations including vascular ring
•Tracheobronchomalacia
•Carcinoid or other tumour
•Mediastinal mass/enlarged lymph node
•Congenital heart disease
•Interstitial lung disease
•Connective tissue disease
•Allergic bronchopulmonary aspergillosis
ERS/ATS Guidelines,
ERJ 2014;43:343-373

Differential diagnosis of problematic asthma and diseases
that present as recurrent cough and wheeze
Bush A, Eur Respir Mon 2011;51:59-81
1) Upper airway disease: choanal stenosis (in infancy in particular),
adenotonsillar hypertrophy, rhinosinusitis and post-nasal drip
(controversial)
2) Congenital structural bronchial disease:
complete cartilage rings, cysts and webs
3) Bronchial/tracheal compression: vascular rings,
pulmonary and sling, enlarged cardiac chamber
or great vessel, and lymph nodes enlarged by
tuberculosis or lymphoma
4) Endobronchial disease: foreign body and tumour, including carcinoid
5) Oesophageal disease: gastro-oesophageal reflux, H-type fistula or
laryngeal cleft, achalasia, eosinophilic gastroenteritis and familial
dysautonomia

1) Upper airway disease: choanal stenosis (in infancy in particular),
adenotonsillar hypertrophy, rhinosinusitis and post-nasal drip
(controversial)
2) Congenital structural bronchial disease:
complete cartilage rings, cysts and webs
3) Bronchial/tracheal compression: vascular rings,
pulmonary and sling, enlarged cardiac chamber
or great vessel, and lymph nodes enlarged by
tuberculosis or lymphoma
4) Endobronchial disease: foreign body and tumour, including carcinoid
5) Oesophageal disease: gastro-oesophageal reflux, H-type fistula or
laryngeal cleft, achalasia, eosinophilic gastroenteritis and familial
dysautonomia
Is a disorder of the autonomic nervous system which affects the development
and survival of sensory, sympathetic and some parasympathetic neurons in the
autonomic and sensory nervous system resulting in variable symptoms including:
insensitivity to pain, inability to produce tears, poor growth, and
labile blood pressure (episodic hypertension and postural hypotension).
People with FD have frequent vomiting crises, pneumonia, problems with speech
and movement, difficulty swallowing, inappropriate perception of heat, pain, and
taste, as well as unstable blood pressure and gastrointestinal dysmotility.
FD does not affect intelligence.
Familial dysautonomia is seen almost exclusively in Ashkenazi Jews and is inherited
in an autosomal recessive fashion.
Both parents must be carriers in order for a child to be affected.

6) Swallowing problems: incoordinate swallow
due to peripheral or central neurological disease.
7) Fixed airflow obstruction: obliterative bronchiolitis,
usually post-infective in previously well children
(adenovirus and Mycoplasma pneumoniae)
8) Causes of pulmonary suppuration: CF, PCD, persistent
bacterial bronchitis and any systemic immunodeficiency,
(agammaglobulinaemia and severe combined immunodeficiency)
9) Others: bronchopulmonary dysplasia (should be apparent from the
history), congenital or acquired tracheomalacia, pulmonary oedema
secondary to left to right shunting or cardiomyopathy,
idiopathic pulmonary arterial hypertension (presents with syncope,
exercise breathlessness, haemoptysis and hypoxaemia)

BRONCHOMALACIA: LUNG FUNCTION TESTING
Large airway obstruction can generally be differentiated by
the pattern of the flow-volume loops in spirometry
The patient with bronchomalacia demonstrates flattening
of the flow-volume loop.
Tidal loop of an infant with
bronchomalacia
Normal infant PFT
120
60
- 60
- 120
200
100
- 100
- 200
0 60 0 100
Volume (ml)
Flow
(ml/sec)

Primary Bronchomalacia in Infants and Children
Finder J. Pediatr. 1997;130:59-66
6
4
2
0
2
4
0 1 2 3 4
Pre-Rx
Post-Rx
Result of pulmonary function
test in a 17-year-old patient
with left main-stem
bronchomalacia
The dotted line is the
flow-volume loop obtained after
the administration of a 2 agonist.
There is a marked fall in peak
flow rate after use of a
bronchodilator.

BRONCHOMALACIA: BRONCHOSCOPY
Flexible bronchoscopy is
the “gold standard” for
establishing the diagnosis
of bronchomalacia
dynamic collapse of
the affected bronchus
during expiration

% pts with malacia disorders
40 –
30 –
20 –
10 –
0
Series of Laryngomalacia, tracheomalacia, and
bronchomalacia disorders and their associations with
other conditions in children. Masters Ped Pulmonol 2002;34:189
 885 bronchoscopic
procedures in
children with cough,
wheeze and stridor
performed in
10 years
The lesions were
most commonly found
in males (2:1)
34%

Resolution of bronchomalacia presenting as severe
asthma by endoscopic intervention
Andregnette Ann Allergy Asthma Immunol 2011;106:443
 A 42-year-old female with
FEV1, 50% predicted and
persisting dyspnea despite
optimal treatment.
Bronchoscopy revealed a
bronchial collapsibility,
with significant loss of
airway caliber in the left
main bronchus, resulting in
severe bronchomalacia.

Resolution of bronchomalacia presenting as severe
asthma by endoscopic intervention
Andregnette Ann Allergy Asthma Immunol 2011;106:443
Days later, the bronchoscopist
placed a Dumon prosthesis in
the left main bronchus using an
Efer-Dumon rigid bronchoscope.
In subsequent monthly visits, the
patient reported good tolerance to
the prosthesis and demonstrated
clinical improvement. Placement of the prosthesis in
the left bronchus

Diseases which can masquerade as severe asthma
Adults
•Dysfunctional breathlessness/vocal cord dysfunction
•Chronic obstructive pulmonary disease (COPD)
•Hyperventilation with panic attacks
•Bronchiolitis obliterans
•Congestive heart failure
•Adverse drug reaction (e.g. angiotensin-converting enzyme inhibitors)
•Bronchiectasis/cystic fibrosis
•Hypersensitivity pneumonitis
•Hypereosinophilic syndromes
•Pulmonary embolus
•Herpetic tracheobronchitis
•Endobronchial lesion/foreign body (e.g. amyloid, carcinoid, tracheal stricture)
•Allergic bronchopulmonary aspergillosis
•Acquired tracheobronchomalacia
•Churg–Strauss syndrome
•Pulmonary eosinophilic syndromes ERS/ATS Guidelines,
ERJ 2014;43:343-373

Assessing Comorbidities and Contributory Factors
1) Rhinosinusitis/(adults) nasal polyps
2) Psychological factors: personality trait, symptom perception,
anxiety, depression
3) Vocal cord dysfunction, Hyperventilation syndrome
4) Obesity
5) Smoking/smoking related disease
6) Obstructive sleep apnoea
7) Allergen exposure including foods
8) Hormonal influences: premenstrual, menarche, menopause,
thyroid disorders
9) Gastro-oesophageal reflux disease (symptomatic)
10) Drugs: aspirin, non-steroidal anti-inflammatory drugs (NSAIDs),
β-adrenergic blockers, angiotensinconverting enzyme inhibitors

Assessing Comorbidities and Contributory Factors
1) Rhinosinusitis/(adults) nasal polyps
2) Psychological factors: personality trait, symptom perception,
anxiety, depression
3) Vocal cord dysfunction, Hyperventilation syndrome
4) Obesity
5) Smoking/smoking related disease
6) Obstructive sleep apnoea
7) Allergen exposure including foods
8) Hormonal influences: premenstrual, menarche, menopause,
thyroid disorders
9) Gastro-oesophageal reflux disease (symptomatic)
10) Drugs: aspirin, non-steroidal anti-inflammatory drugs (NSAIDs),
β-adrenergic blockers, angiotensinconverting enzyme inhibitors
That other conditions may coexist
with asthma should always be
borne in mind,
since
continuing respiratory symptoms
may be wrongly attributed to
asthma alone.

Comorbidities: rhinitis
Up to 60-80% of patients with asthma have rhinitis,
and up to 15% of patients with allergic rhinitis
have asthma.
de Benedictis FM, Chest 1999;115:550–556.
Nevertheless, allergic rhinitis commonly goes unrecognised
and undertreated in children with asthma
Hamouda S, Clin Exp Allergy 2008;38:761–766
There is evidence that neglecting to treat rhinitis
increases asthma morbidity.
Hellings PW, Immunol Allergy Clin North Am 2009;29:733–740.
Bourdin A, Thorax 2009; 64: 999–1004.
Hedlin G, ERJ 2010;36:196-201

 557 patients
with severe
asthma.
 1 year of
follow-up.
NO
60 –
50 –
40 –
30 –
20 –
10 –
0
% PATIENTS WITH
MILD MODERATE
SEVERE
15%
54%
31%
Lack of Control of Severe Asthma is Associated with
Co-existence of Moderate-to-Severe Rhinitis
Ponte EV, Allergy 2008;63:564
RHINITIS

ED VISIT
IN PRESENCE OF MODERATE SEVERE-RHINITIS OR FOR
UNCONTROLLED
ASTHMA
<10% BRONCHODILATION
AFTER SALBUTAMOL
3.83
12.68
2.94
15 –
10 –
5 –
0

ED VISIT
IN PRESENCE OF MODERATE SEVERE-RHINITIS OR FOR
UNCONTROLLED
ASTHMA
<10% BRONCHODILATION
AFTER SALBUTAMOL
3.83
12.68
2.94
15 –
10 –
5 –
0
In a population with severe asthma,
moderate/severe rhinitis is a strong
predictor for greater severity of
asthma.

Effect of allergic rhinitis on the use and cost of health
services by children with asthma.
Kang HY, Yonsei Med J 2008; 49: 521–529.

Rhinitis therapy and the prevention of hospital care for
asthma: a case-control study.
Corren J, J Allergy Clin Immunol 2004;113:415–419.
a nested, case-control study to
determine whether treatment with
intranasal corticosteroids and/or
second-generation antihistamines
is associated with changes in rates
of asthma exacerbations resulting
in emergency room visits and/or
hospitalizations in patients with
asthma and allergic rhinitis.
In patients who used nasal
corticosteroids OR for
asthma-related
0.75
emergency room
treatment
1.0 –
0.5 –
0.0
hospitalization
0.56

Rhinitis therapy and the prevention of hospital care for
asthma: a case-control study.
Corren J, J Allergy Clin Immunol 2004;113:415–419.
a nested, case-control study to
determine whether treatment with
intranasal corticosteroids and/or
second-generation antihistamines
is associated with changes in rates
of asthma exacerbations resulting
in emergency room visits and/or
hospitalizations in patients with
asthma and allergic rhinitis.
In patients who used nasal
corticosteroids OR for
asthma-related
0.75
emergency room
treatment
1.0 –
0.5 –
0.0
hospitalization
0.56
whereas
there was a trend toward
lower risk of emergency
room treatment and
hospitalization in patients
who used
second-generation
antihistamines
(adjusted OR, 0.88; and
0.68, respectively).

Nasal beclomethasone prevents the seasonal increase in
bronchial responsiveness in patients with allergic rhinitis
and asthma. Corren J, J Allergy Clin Immunol 1992;90:250-256.
18 subjects with seasonal
allergic rhinitis and asthma
with (+) SPTs to ragweed and
BHR to inhaled methacholine
nasal BDP
(336 micrograms/day) or
placebo for the entire
ragweed season.
BR to methacholine
measured at baseline and 6
weeks later into the ragweed
season.
geometric mean PC20 from
baseline to 6 week
placebo
p=0.022
1.0 –
0.9 –
0.8 –
0.7 –
0.6 –
0.5 –
0.4 –
0.3 –
0.2 –
0.1 –
0
0.70
0.29
BDP
0.80
0.93

Nasal beclomethasone prevents the seasonal increase in
bronchial responsiveness in patients with allergic rhinitis
and asthma. Corren J, J Allergy Clin Immunol 1992;90:250-256.
18 subjects with seasonal
allergic rhinitis and asthma
with (+) SPTs to ragweed and
BHR to inhaled methacholine
nasal BDP
(336 micrograms/day) or
placebo for the entire
ragweed season.
BR to methacholine
measured at baseline and 6
weeks later into the ragweed
season.
geometric mean PC20 from
baseline to 6 week
placebo
p=0.022
1.0 –
0.9 –
0.8 –
0.7 –
0.6 –
0.5 –
0.4 –
0.3 –
0.2 –
0.1 –
0
0.70
0.29
BDP
0.80
0.93
nasal corticosteroid
therapy can prevent
the increase in BR
associated with
seasonal pollen exposure
in patients with allergic
rhinitis and asthma.

Upper airway 1: Allergic rhinitis and asthma: united
disease through epithelial cells.Bourdin A, Thorax 2009;64:999.
(a) Nasal and (b)
bronchial biopsies
obtained from the
same patient
with mild asthma
showing CD8 T
lymphocyte
immunoreactivity
of nasal and
bronchial biopsies,
epithelial columnar
cells, epithelial
shedding and
basement membrane
Epithelial cells represent the first barrier of the upper and lower
respiratory tracts and thus are logical targets for a comprehensive
integrated therapeutic approach.

Evidence for rhinosinusitis has been
reported to be as high at 75–80%.
•Moore WC, JACI 2007; 119:405–413.
•ten Brinke A, JACI 2002; 109: 621–626.
Nasal polyps are seen in a small subset of adults.
Nasal polyps are unusual in asthmatic children and
more often associated with cystic fibrosis and
sometimes primary ciliary dyskinesia.
Comorbidities: rhinosinusitis

Allergic rhinitis and sinusitis in asthma: differential
effects on symptoms and pulmonary function.
Dixon AE Chest. 2006;130:429-35.
2,031 asthmatics
presence of
sinusitis
6 -
5 –
4 –
3 –
2 –
1 –
0
5.7
sinusitis
n° exacerbations/patient/year
YES NO
3.7
P<0.01

Chronic sinusitis in severe asthma is related to sputum
eosinophilia. ten Brinke A, J Allergy Clin Immunol 2002;109:621–6.
89 nonsmoking outpatients with
severe asthma
(age range, 18-74 years)
CT scans scored (0-30)
Lung function,
NO in exhaled air,
sputum eosinophils
CT scans
abnormalities
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
% patients with
84%
Extensive
sinus disease
24%

a direct relationship between sinonasal mucosa thickness
and bronchial inflammation in severe asthma,
particularly in patients with adult-onset disease.

nasal irrigation use in the treatment of
pediatric CRS can be part of the
treatment
in severe asthmatics
Pham V, Laryngoscope. 2014;124:1000-7.
Isaacs S, Am J Rhinol Allergy. 2011;25:e27-9.

Evaluation of airway hyperresponsiveness in chronic
rhinosinusitis: values of sinus computed tomography
Chen Ann Allergy 2014;113:609
CT and Sinus Score
In the Lund-Mackay staging system, which is
based on a simple numeric score derived from
the CT, each sinus group is assigned a
numeric grade:
0 = no abnormality;
1 = partial opacification;
2 = total opacification.
The sinus groups include the maxillary sinus, frontal sinus, sphenoid sinus,
anterior ethmoid sinus, and posterior ethmoid sinuses.
The ostiomeatal complex is scored as 0 (not obstructed) or 2 (obstructed).

CT and Sinus Score
The olfactory cleft (OC) score was observed on the
posterior ethmoid sinus and superior turbinate level.
Each OC was awarded 0 to 2 points:
0 = no abnormality;
1 = partial opacification;
2 = total opacification.
The total score was the Lund-Mackay total scores supplemented
with the OC scores, producing a maximum of 28 points.

Olfactory cleft (OC) score
was observed on the
posterior ethmoid sinus
and superior turbinate.
Each OC score was 0. Left OC score was 2,
right OC score was 0,
total OC score was 2.
Each OC score was 1,
Each OC score was 2,
BHR
0 0
02
2 21 1

 125 consecutive patients
with chronic rhinosinusitis
(CRS).
 Patients subdivided into
airway hyperresponsiveness
(AHR) and non-AHR (NAHR)
groups based on histamine
provocation test.
% patients with AHR
60 –
50 –
40 –
30 –
20 –
10 –
00
45.4%

Mean (SD) sinus computed tomography
scores for the AHR and NAHR groups
Abbreviations: AHR, airway hyperresponsiveness; NAHR, non-airway
hyperresponsiveness. aP value of Mann-Whitney test except where
indicated otherwise. bP value of the unpaired t test.
(CRS).
provocation test.

(CRS).
provocation test.
The OC scores and
the eosinophil counts
in the AHR group
were significantly
higher than those in
the NAHR group
(p<0.001).

(CRS).
provocation test.
The OC score had
a higher predictive
value for AHR than
eosinophil counts.

Comorbidities: Gastro-oesophageal reflux
Hedlin G, E. RJ 2010;36:196-201
The relationship between the oesophagus
and the lung is complex.
Lung disease can cause gastro-oesophageal reflux,
reflux can cause lung disease or
reflux may be of no clinical significance.
Depending upon the criteria used for diagnosis, 25–80% of children
with chronic respiratory disease have gastro-oesophageal reflux.
Bechard DE, Gastroenterology 1998; 114: 849–850
A precise mechanistic link between gastro-oesophageal reflux
and decline in asthma control has not been established.
Stordal K, Arch Dis Child 2005; 90:956–960.

Systematic review: the extra-oesophageal symptoms of
gastro-oesophageal reflux disease in children.
Tolia V, Aliment Pharmacol Ther 2009;29:258–272.
prevalence of GERD
in children with asthma
18 relevant articles
pooled weighted average
prevalence of GERD in
healthy
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
4.0%
23.0%
asthmatics
19.3%
65%

Systematic review: the extra-oesophageal symptoms of
gastro-oesophageal reflux disease in children.
Tolia V, Aliment Pharmacol Ther 2009;29:258–272.
prevalence of GERD
in children with asthma
18 relevant articles
pooled weighted average
prevalence of GERD in
healthy
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
4.0%
23.0%
asthmatics
19.3%
65%
respiratory symptoms,
sinusitis and
dental erosion
were significantly
more prevalent in
children with GERD
than in controls.

Extraesophageal associations of gastroesophageal reflux
disease in children without neurologic defects.
El Serag HB, Gastroenterology 2001;121:1294–1299.
1980 children
with GERD
7920 controls
without GERD.
Compared with controls in univariate
analyses, cases with GERD had more:
1) sinusitis (4.2% vs. 1.4%, P < 0.0001),
2) laryngitis (0.7% vs. 0.2%),
3) asthma (13.2% vs. 6.8%, P < 0.0001),
4) pneumonia (6.3% vs. 2.3%, P < 0.0001),
5) bronchiectasis (1.0% vs. 0.1%, P <0.0001).

The relationship between the oesophagus
and the lung is complex.
Lung disease can cause gastro-oesophageal reflux,
reflux can cause lung disease or
reflux may be of no clinical significance.
Depending upon the criteria used for diagnosis, 25–80% of children
with chronic respiratory disease have gastro-oesophageal reflux.
Bechard DE, Gastroenterology 1998; 114: 849–850
A precise mechanistic link between gastro-oesophageal reflux and
decline in asthma control has not been established.
Stordal K, Arch Dis Child 2005; 90:956–960.
The results of trials of anti-reflux
therapy are often disappointing, especially
in older children,
but
an empirical trial is
reasonable
in younger children if
the history is
suggestive
Hedlin G, E. RJ 2010;36:196-201

Acid suppression does not change respiratory symptoms in
children with asthma and gastro-oesophageal reflux
disease. Stordal K, Arch Dis Child 2005;90:956–960.
38 children
(mean age 10.8
years,)
with asthma and
a reflux index ≥ 5.0
assessed by 24 hour
oesophageal pH
monitoring
12 weeks of
treatment with
omeprazole 20 mg
daily or placebo.

38 children
(mean age 10.8
years,)
with asthma and
a reflux index ≥ 5.0
assessed by 24 hour
oesophageal pH
monitoring
12 weeks of
treatment with
omeprazole 20 mg
daily or placebo.
The change in total symptom score and the improvement in quality of
life (PAQLQ) did not differ significantly between the omeprazole and
the placebo group.
Change in lung function and use of short acting bronchodilators were
similar in the groups.
The acid suppression was adequate (reflux index <5.0) under
omeprazole treatment.

Lansoprazole for children with poorly controlled asthma:
a randomized controlled trial.
Holbrook JT, JAMA 2012;307:373–381.
306 children
lansoprazole, 15 mg/d
if weighing <30 kg or
30 mg/d if weighing ≥ 30 kg
(n = 149), or placebo (n = 157).
followed up for 24 weeks.
change in Asthma Control
Questionnaire (ACQ) score
(range, 0-6; a 0.5-unit change
is considered clinically
meaningful).
Change in Asthma Control Questionnaire
(ACQ) Score in Children With Poor Asthma
Control Receiving Lansoprazole vs Placebo
ns

Lansoprazole for children with poorly controlled asthma:
a randomized controlled trial.
Holbrook JT, JAMA 2012;307:373–381.
306 children
lansoprazole, 15 mg/d if
weighing <30 kg or
30 mg/d if weighing ≥ 30 kg
(n = 149), or placebo (n = 157).
followed up for 24 weeks.
change in Asthma Control
Questionnaire (ACQ) score
(range, 0-6; a 0.5-unit change
is considered clinically
meaningful).
Change in Asthma Control Questionnaire
(ACQ) Score in Children With Poor Asthma
Control Receiving Lansoprazole vs Placebo
children with poorly
controlled asthma without
symptoms of GER who were
using inhaled corticosteroids,
the addition of lansoprazole,
compared with placebo,
improved neither symptoms
nor lung function but was
associated with increased
respiratory infections
(relative risk, 1.3)
ns

The role of ‘‘silent’’ GOR disease (GORD)
as a cause of poor asthma control
in general may be over-emphasised,
but
the child with gastrointestinal symptoms and problematic asthma
should be evaluated and treated for GORD.
•Holbrook JT, JAMA 2012; 307: 373–381.

Comorbidities: Obesity
Hedlin G, E. RJ 2010;36:196-201
The relationship between obesity and asthma is complex.
There are a number of
confounding factors:
Obesity
causes
gastro-oesophageal reflux
 obstructive sleep apnoea.
Beuther DA,
AJRCCM
2006;174:112–119.
 reduction in respiratory system compliance,
lung volumes (ERV, FRC, TV), and peripheral airway diameter,
 increase in BHR,
 alteration in pulmonary blood volume, and
ventilation–perfusion mismatch.

Hedlin G, E. RJ 2010;36:196-201
The relationship between obesity and asthma is complex.
There are a number of
confounding factors:
Obesity
causes
gastro-oesophageal reflux
 obstructive sleep apnoea.
Beuther DA,
AJRCCM
2006;174:112–119.
 reduction in respiratory system compliance,
lung volumes (ERV, FRC, TV), and peripheral airway diameter,
 increase in BHR,
 alteration in pulmonary blood volume, and
ventilation–perfusion mismatch.
obese children could have asthma-like symptoms
(shortness of breath) without having asthma.

Lung volumes in obesity
deep inhalation effect

R
E
D
U
C
E
D
1) Mechanical Airway Changes in Obesity
Increased
work of
breathing

Obesity is also a common
comorbidity associated with
difficult asthma, although
the relationship to asthma
may vary by age at onset,
with implications for
treatment.
•Holguin F, Bleecker ER, Busse WW, et al. Obesity and asthma: an association modified by age
of asthma onset. J Allergy Clin Immunol 2011; 127: 1486–1493.
•Dixon AE, Pratley RE, Forgione PM, et al. Effects of obesity and bariatric surgery on airway
hyperresponsiveness, asthma control, and inflammation. J Allergy Clin Immunol 2011; 128:
508–515.

Obesity and Asthma.
Beuther DA. Am J Respir Crit Care Med. 2006;174:112-9.
Obesity leads to alterations of lung
volumes (top), particularly
expiratory reserve volume
(ERV), TV and FRC, leading to a
rapid, shallow breathing pattern
that occurs close to closing volume.
Obesity also causes reduced
peripheral airway diameter
(middle), which can lead to
increased airway
hyperresponsiveness due to
alterations of smooth muscle
structure and function
Remember that obesity per se is
a cause of respiratory symptoms
apart from asthma before
escalation of asthma therapy.

Obesity and Asthma.
the closing volume (CV) is
the point at which
dynamic compression of
the airways begins.

Retractile forces
of the lung
parenchyma on the
airways are
reduced at low lung
volume.
Mechanical Airway Changes in Obesity

Retractile forces
of the lung
parenchyma on the
airways are
reduced at low lung
volume.
Thus, it has been
hypothesized that
in obese patients,
breathing at low TV
does not allow the
normal stretching of
airway smooth muscle
during breathing, which
causes detachment of
actin–myosin
crossbridge of the
airway smooth muscle.

Retractile forces
of the lung
parenchyma on the
airways are
reduced at low lung
volume.
The bigger the TV,
the greater the ensuing
‘deep inhalation effect’
which allows restoration
of the dilation of the
airways in normal
conditions.
This protective effect
is reduced in asthmatics
and also in obese
individuals in comparison
to lean controls.

Additional mechanical factors may involve a mechanism of
uncoupling the airways from the retractile forces of the
lung parenchyma due to the repeated chronic small airway
closure observed in many obese patients breathing at low TV.
Repeated opening and closing of
peripheral airways may determine the
rupture of alveolar attachments to
bronchioles that lead to exacerbation
of the airway narrowing.
Milic-Emili J, J Appl Physiol 2007; 99: 567–583.
X

How changes in FRC and VT in the obese may lead to asthma
Shore SA. JACI 2008;121:1087

1) Reduced lung volume and tidal volume in obesity that promote
narrowing of the airways
2) Low grade of inflammation may act on the lungs to exacerbate
symptoms
3) Obesity-related changes in hormones
4) Dyslipidaemia
5) Gastro-oesophageal reflux
6) Sleep-disordered breathing
7) Type-2 diabetes De Groot EP, Eur Respir J 2010;36:671-78
Obesity and asthma: possible mechanisms.
Shore SA. J Allergy Clin Immunol 2008;121:1087–1093.

Obesity and Asthma.
In obesity, visceral adiposity is
correlated with circulating levels of
proinflammatory cytokines, and adipose
tissue propagates inflammation both
locally and systemically, in part through
recruitment of macrophages via
chemokines such as monocyte
chemoattractant protein-1 (MCP-1) and
in part via elaboration of
proinflammatory cytokines and
chemokines such as:
leptin,
interleukin 6 (IL-6),
tumor necrosis factor α (TNF-α),
transforming growth factor 1 (TGF-1),
eotaxin.

It is not surprisingly
that exercise capacity is
often impaired in obese
children.
This can be due to the
increased work of
breathing with the
resulting increased
perception of breathing
effort and dyspnoea.
1) Mechanical Airway Changes in Obesity

Obesity and asthma: an association modified by age of
asthma onset. Holguin F, JACI 2011;127:1486–1493.
1049 subjects,
age of asthma onset as
early (<12 years of age)
late (≥12 years of age).
BMI categories
Compared with obese subjects with
late-onset asthma,
obese subjects with
early-onset asthma had:
1) more airway obstruction,
2)more BHR,
3)higher odds ratios (OR= 2.4 vs 1.1)
of ever having ≥ 3 previous oral
steroid tapers per year or intensive
care unit admissions (OR= 6.0 vs 1.3)
for asthma per preceding year
(P = 0.055 and P = 0.02, respectively).
*
*
*

Obesity and asthma: an association modified by age of
asthma onset. Holguin F, JACI 2011;127:1486–1493.
Association between age of asthma onset with asthma morbidity outcomes

Do obese inner-city children with asthma have more
symptoms than nonobese children with asthma?
Belamarich PF, Pediatrics 2000;106:1436–1441.
1322 children
(4 to 9 years)
with asthma.
Obesity defined as
BMI (Kg/m2) >95th
percentile.
Follow-up = 9 months
mean number of days of
wheeze per 2-week period
4 –
3 –
2 –
1 –
0-
4
Obese Non obese
3.4

4 –
3 –
2 –
1 –
0-
43.4
mean number of days of
wheeze per 2-week period
1322 children
(4 to 9 years)
with asthma.
BMI (Kg/m2) >95th
percentile.

40 –
30 –
20 –
10 –
0-
39%
Obese Non obese
31%
% children with
unscheduled ED visits
1322 children
(4 to 9 years)
with asthma.
BMI (Kg/m2) >95th
percentile.

40 –
30 –
20 –
10 –
0-
39%31%
% children with
unscheduled ED visits
1322 children
(4 to 9 years)
with asthma.
BMI (Kg/m2) >95th
percentile.

HOSPITAL ICU
27%
4%
% CHILDREN ADMITTED TO
30 –
25 –
20 –
15 –
10 –
5 –
0
 Children classified
as nonoverweight
(≤95% weight-for-
age percentile)
or overweight
(>95% weight for
age).
 884 visits to the
emergency
department for an
asthma exacerbation
by 813 children.
Childhood Overweight Increases Hospital Admission Rates
for Asthma Carroll Pediatrics 2007;120:734

HOSPITAL ICU
27%
4%
% CHILDREN ADMITTED TO
30 –
25 –
20 –
15 –
10 –
5 –
0
as nonoverweight
(≤95% weight-for-
age percentile)
or overweight
(>95% weight for
age).
emergency
department for an
asthma exacerbation
by 813 children.
Presenting clinical asthma
score and therapeutic
interventions in the
emergency department
were similar for
overweight and
nonoverweight children;
however, overweight
children were significantly
more likely to be
admitted to the
hospital (49%).

MODIFIED PULMONARY INDEX SCORE (MPIS)
Carroll Ann All Asthma Imm 2005;94:355
In the MPIS, 6 different categories are evaluated:
Oxygen saturation in room air;
Accessory muscle use;
Inspiratory-to-expiratory ratio;
Degree of wheezing;
Heart rate,
Respiratory rate.
For each of these 6 measurements or observations, a score of
0 to 3 is assigned, resulting in a minimum possible score of 0 and
a maximum possible score of 18. In general, scores of <6 are
associated with mild asthma exacerbations, scores of 6 to 10 with
moderate asthma exacerbations, and scores of >10 with severe
asthma exacerbations.

At the study institution, patients may be treated with continuous
albuterol nebulizer treatments on the ward.
An ICU consultation was required for patients with MPIS >12 after 2
hours of treatment in the ED.
A patient was admitted to the ICU when he or she required
bronchodilator therapy of ≥20 mg/hour of continuous albuterol
aerosol, he or she required supplemental oxygen at ≥ 40%, and the
MPIS was >12.

EXACERBATION CLASSIFICATION
1)
2)

3)
EXACERBATION CLASSIFICATION

% asthatic children admitted to50 –
40 –
30 –
20 –
10 –
0
HOSPITAL ICU
14%
Normal
weight
Over
weight
Over
weight
Normal
weight
49%
11%
46.6%
emergency
department for an
asthma exacerbation
by 813 children.
as nonoverweight
(≤95% weight-for-
age percentile)
or overweight
(>95% weight for
age).

Potential Mechanisms for the Observed Association of
Overweight and Increased Hospitalization for Asthma
Beuter AJRCCM 2006;174:112
Belamarich Pediatrics 2000;106:1436 Akerman J Asthma 2004;41;521
 Overweight children may have previously undiagnosed concomitant
medical problems related to overweight, such as upper airway
obstruction, obesity hypoventilation syndrome, or gastroesophageal
reflux
 Overweight children may have increased ventilation/perfusion
mismatching as a result of atelectasis, possibly from reduced
respiratory excursions from their increased body habitus and
resultant decreased chest wall compliance.
 Overweight per se may contribute to a more severe asthma
phenotype.

Immediate and long term effects of weight reduction in
obese people with asthma: randomised controlled study.
Stenius-Aarniala B, BMJ 2000;320:827–832.
Two groups of 19 obese
patients with asthma (body mass
index (kg/m2) 30 to 42)
8 week very low energy diet.
At the end of the weight
reducing programme, the
participants in the treatment
group had lost a mean of 14.5%
of their pretreatment weight,
the controls 0.3%.
Mean morning
premedication
values for
PEF,
FEV1,
FVC
% pred
at different
stages during
study.
P=0. 009
P<0.0001

Immediate and long term effects of weight reduction in
obese people with asthma: randomised controlled study.
Stenius-Aarniala B, BMJ 2000;320:827–832.
Health status:
mean scores for
symptoms, impact,
and activity,
and mean total
scores, according
to St George's
respiratory
questionnaire.
*Change from
baseline shows
significant
(P<0.05)
Mean values
for cough and
dyspnoea
(mm on visual
analogue
scale) and
mean number
of daily rescue
medication
doses at
different
stages during
study. *Change
from baseline
shows
significant
(P<0.05)

PC20 Methacoline
Pre Post
Bariatric surgery
8 –
7 –
6 –
5 –
4 –
3 –
2 –
1 –
0
3.90
7.28
 Patients
undergoing
bariatric surgery
followed for
12 months.
 23 asthmatic and
21 nonasthmatic
patients.
Effects of obesity and bariatric surgery on airway
hyperresponsiveness, asthma control and inflammation
Dixon JACI 2011;128:508-515
BHR

PC20 Methacoline
Pre Post
Bariatric surgery
8 –
7 –
6 –
5 –
4 –
3 –
2 –
1 –
0
3.90
7.28
 Patients
undergoing
bariatric surgery
followed for
12 months.
21 nonasthmatic
patients.
Dixon JACI 2011;128:508-515
Breathing at low lung
volumes unloads airway
smooth muscle,
allowing it to shorten
excessively when
activated.
BHR

PC20 Methacoline
Pre Post
Bariatric surgery
8 –
7 –
6 –
5 –
4 –
3 –
2 –
1 –
0
3.90
7.28
 Patients
undergoing
bariatric surgery
followed for
12 months.
21 nonasthmatic
patients.
Dixon JACI 2011;128:508-515
In addition, deep
breaths are potent
bronchodilators;
this bronchodilatory
effect might be
compromised
by breathing at low
lung volumes.
BHR

p= 0.001 p= 0.89 Patients
undergoing
bariatric surgery
followed for
12 months.
21 nonasthmatic
patients.
Dixon JACI 2011;128:508-515
Change in AHR in
patients with
normal IgE.
Change in AHR in
patients with
elevated IgE.

Change in AHR in
patients with
normal IgE.
Change in AHR in
patients with
elevated IgE.
p= 0.001 p= 0.89 Patients
undergoing
bariatric surgery
followed for
12 months.
21 nonasthmatic
patients.
There was
a statistically
significant interaction
between
IgE status and change
in airways
responsiveness
(p for interaction
=0.01)
Dixon JACI 2011;128:508-515

FEV1 % predicted
Pre Post
Bariatric surgery
82.4%
90.4%
 Patients
undergoing
bariatric surgery
followed for
12 months.
21 nonasthmatic
patients.
100 –
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
p< 0.01
Dixon JACI 2011;128:508-515

FEV1 % predicted
Pre Post
Bariatric surgery
82.4%
90.4%
 Patients
undergoing
bariatric surgery
followed for
12 months.
21 nonasthmatic
patients.
100 –
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
p< 0.01
Dixon JACI 2011;128:508-515
Weight loss
has dichotomous effects
on airway physiology and
T-cell function typically
involved in the pathogenesis
of asthma, suggesting that
obesity produces a unique
phenotype of asthma
that will require
a distinct therapeutic
approach.

Body mass and glucocorticoid response in asthma.
Sutherland ER, Am J Respir Crit Care Med 2008;178:682–687.
reduced induction
in obese asthmatics
A total of 45 nonsmoking adults,
33 with asthma
(mean FEV1% PRED = 70.7%) and
12 without asthma
Dexamethasone (DEX, 10-6)M)-induced
mitogen-activated protein kinase
phosphatase-1 (MKP-1) a negative
regulator of proinflammatory cytokines
and baseline tumor necrosis factor
(TNF)-alpha expression evaluated by
polymerase chain reaction in peripheral
blood mononuclear cells (PBMCs) and
bronchoalveolar lavage cells

(A) Reduced dexamethasone (DEX)-induced mitogen-activated
protein kinase phosphatase (MKP)-1 expression in PBMCs from
overweight/obese (gray) versus lean (black) subjects with asthma.
(B) PBMCs from patients with asthma demonstrates significantly
reduced DEX-induced MKP-1 expression with increased body mass
index (BMI). Lines represent regression with (solid line) and
without outlying data point (arrow).
33 with asthma
12 without asthma

(A) Peripheral blood mononuclear cells (PBMCs) from
patients with asthma demonstrate significantly increased log (TNF-a)
mRNA expression with increasing body mass index (BMI).
(B) PBMCs from subjects without asthma do not demonstrate significantly
increased log (TNF-a) mRNA expression with increasing BMI.
asthmatics
non-asthmatics
33 with asthma
12 without asthma

Hedlin G, E. RJ 2010;36:196-201
Being overweight per se is also known to induce
respiratory symptoms, such as dyspnoea and wheezing,
which can mimic asthma.
Overweight children with asthma are more likely to be
admitted to hospital when presenting at the emergency
department with exacerbations.
Carroll CL, Pediatrics 2007; 120:734–740.
Obesity may cause steroid resistance, in part at least, by reducing
steroid-induced mitogen-activated protein kinase phosphatase-1,
a negative regulator of the expression of pro-inflammatory genes
Sutherland ER, Am J Respir Crit Care Med 2008; 178: 682–687.
asthmatics

Comorbidities: Dysfunctional Breathing
De Groot EP, Eur Respir J 2010;36:671-78
Dysfunctional breathing is defined as:
Symptoms of dysfunctional
breathing include:
chronic or recurrent
changes in breathing pattern,
causing respiratory and
non-respiratory complaints.
•Morgan MD. Thorax 2002;57:Suppl. 2, 1131–1135.
dyspnoea with normal lung function,
chest tightness,
chest pain,
deep sighing,
exercise-induced breathlessness,
frequent yawning
hyperventilation
•Thomas M, Thorax 2003;58: 10–115

Comorbidities: Dysfunctional Breathing
mimic asthma,
or,
more usually, complicate the
assessment of a known asthmatic
vocal cord dysfunction,
hyperventilation and
other forms of
dysfunctional breathing
1) The disappearance of these symptoms when the child is
asleep is a useful pointer, and
2) asking the family to video an attack may also be useful.
may
Seear M, Arch Dis Child 2005;90:898–902.
Van Dixhoorn DJ, J Psychosom Res 1985;29:199–206.

Prevalence of Dysfunctional Breathing in Patients Treated
for Asthma in Primary Care: Cross Sectional Survey
Thomas BMJ 2001; 322: 1098
 219 adult
asthmatics
 Nijmegen
questionnaire
(+) when score >23
% ASTMATIC PATIENTS
30 –
20 –
10 –
0
Nijmegen SCORE >23
29%

Comorbidities: Dysfunctional Breathing: Hyperventilation
There is no accepted gold
standard of the diagnosis of
dysfunctional breathing
beyond the clinical
description, but the
Nijmegen Questionnaire is a
symptom checklist that can
be used to discriminate
dysfunctional breathers
from normal individuals in
adults.
van Dixhoorn DJ,
J Psychosom Res
1985; 29: 199–206.
>23

40 –
30 –
20 –
10 –
0
35%
20%
p=0.016
 219 adult
asthmatics
 Nijmegen
questionnaire
(+) when score >23
Thomas BMJ 2001; 322: 1098
Nijmegen SCORE >23
% PATIENTS

40 –
30 –
20 –
10 –
0
35%
20%
p=0.016
 219 adult
asthmatics
 Nijmegen
questionnaire
(+) when score >23
Thomas BMJ 2001; 322: 1098
Nijmegen SCORE >23
% PATIENTS
Patients at different
treatment steps of the
British Thoracic Society
Asthma guidelines were
affected equally.
These prevalences
suggest scope for
therapeutic intervention
and may explain the
anecdotal success of
the Butteyko method
of treating asthma



Thomas BMJ 2001; 322: 1098
 219 adult
asthmatics
 Nijmegen
questionnaire
(+) when score >23
% PATIENTS
30 –
20 –
10 –
0
Nijmegen SCORE >23
29%
“Asthma and anxiety with
dysfunctional breathing are
both common conditions
and frequently coexist,
even if this % seems
too big.”
Keeley BMJ 2001;322:1075

 47 pts with HVS
 Bronchodilator
response
80%
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
Hyperventilation syndrome and asthma.
Demeter SL, Am J Med. 1986;81(6):989-94.
% pts with asthma
i.e. with (+) response
to the bronchodilator

 47 pts with HVS
 Bronchodilator
response
80%
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
Hyperventilation syndrome and asthma.
Demeter SL, Am J Med. 1986;81(6):989-94.
% pts with asthma
i.e. with (+) response
to the bronchodilator
Asthma and anxiety with
dysfunctional breathing are
both common conditions and
they often coexist
Keeley BMJ 2001;322: 1075

Exercise-induced Hyperventilation: A Pseudoasthma
Syndrome. Hammo Ann Allergy Asthma Immunol 1999; 82: 574
32 children with a
diagnosis of
exercise induced
asthma but poorly
responsive to
treatment and with
on atypical history
of asthma
Exercise test by
treadmill
End-tidal CO2
All these patients
described chest
tightness during
the exercise with
a greater decreases
in end tidal CO2
(measured by nasal
cannula) greater
than all the other
21 pts
(mean 23.2% vs
9.8% p<0.01)
n° patients
20 -
15 –
10 –
5 –
0
FEV1 FEV1
>15% <10%
(mean 5.6%)
4
11
17 patients
had
neither their
symptoms
neither
abnormal CO2

32 children with a
diagnosis of
exercise induced
asthma but poorly
responsive to
treatment and with
on atypical history
of asthma
Exercise test by
treadmill
End-tidal CO2
All these patients
described chest
tightness during
the exercise with
a greater decreases
in end tidal CO2
(measured by nasal
cannula) greater
than all the other
21 pts
(mean 23.2% vs
9.8% p<0.01)
n° patients
20 -
15 –
10 –
5 –
0
FEV1 FEV1
>15% <10%
(mean 5.6%)
4
11
17 patients
had
neither their
symptoms
neither
abnormal CO2
Chest discomfort
perceived as dyspnea
during vigorous exercise
may be associated with
hypocapnia from
hyperventilation without
bronchospasm in children
and adolescents
previously misdiagnosed
and treated as having
exercise-induced
asthma

Percent
decrease
Wheezing, cough,
chest tightness
n = 4
No symptoms
n = 17
Chest tightness
No wheezing or cough,
n = 11
FEV1
O2 Sat
End-tidal CO2
0
10
20
30
Symptoms and associated mean values for FEV1, pulse oximetry, and
end-tidal CO2 taken at the time of the greatest decrease in FEV1
among 32 patients undergoing treadmill running
-9.8%
-23.2%
Those
have
HVS

Percent
decrease
Wheezing, cough,
chest tightness
n = 4
No symptoms
n = 17
Chest tightness
No wheezing or cough,
n = 11
FEV1
O2 Sat
End-tidal CO2
0
10
20
30
Symptoms and associated mean values for FEV1, pulse oximetry, and
end-tidal CO2 taken at the time of the greatest decrease in FEV1
among 32 patients undergoing treadmill running
-9.8%
-23.2%
Those
have
HVS
End tidal CO2 normally decreases somewhat during heavy exercise
when the anaerobic threshold (the exercise intensity at
which lactic acid starts to accumulate in the blood stream. ) is
exceeded and a degree of respiratory alkalosis begins to
compensate for the metabolic lactic acidosis that occurs at
sustained high exercise levels

EIA UNFIT VCD HABIT NO
% CHILDREN
30 –
25 –
20 –
15 –
10 –
5 –
0
How Accurate is the Diagnosis of Exercise Induced
Asthma among Vancouver Schoolchildren?
Seear Arch. Dis. Child. 2005; 90: 898
 52 children
referred for
investigation
of poorly
controlled EIA.
 Standardised
treadmill
exercise test.
 (+)EIA =
FEV1 >10%
PROBLEMCOUGH
8/52 12/52 14/52 7/52 11/52
15.4%
23.1%
26.9%
13.5%
21.1%

142 pts with
exercise induced
dyspnea (EID)
Exercise test
Exercise-induced Dyspnea in Children and
Adolescents: If Not Asthma Then What?
Abu-Hasan Ann. Allergy AsthmaImmunol. 2005; 94: 366
% PATIENTS WITH A PREVIOUS
DIAGNOSIS OF ASTHMA
69%
(98/142)
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0

% PATIENTS WITH A
CONFIRMED DIAGNOSIS OF
EXERCISE INDUCED ASTHMA
8% (11/142)
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
142 pts with
exercise induced
dyspnea (EID)
Exercise test

% patients with confirmed EID
during the challenge
100 –
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
83.4%
(117/142)
142 pts with
exercise induced
dyspnea (EID)
Exercise test

100 –
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
Of those:
-74 normal physiologic
exercise limitations
- 11 had EIA
- 15 restrictive
abnormalities,
- 13 VCD
- 2 EI laryngomalacia
- 1 hyperventilation S.
- 1 supraventicular
tachycardia.
83.4%
(117/142)

100 –
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
83.4%
(117/142)
Of the 74 with normal
physiologic exercise
limitations:
48 had normal to high
cardiovascular conditioning,
and
26 had poor conditioning

100 –
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
83.4%
(117/142)
Of the 74 with normal
physiologic exercise
limitations:
Lactic acidosis, that
occurs when exercise
exceedes the anaerobic or
ventilatory threshold,
increases the respiratory
drives in an attempt to rise
the pH by reducing the Pco2.

The lactate threshold (LT) (or lactate inflection point (LIP) or anaerobic threshold (AT)) is
the exercise intensity at which lactate (more specifically, lactic acid) starts to accumulate in
theblood stream. The reason for the acidification of the blood at high exercise intensities is
two-fold: the high rates of ATP hydrolysis in the muscle release hydrogen ions, as they are
co-transported out of the muscle into the blood via the MCT— monocarboxylate transporter,
and also bicarbonate stores in the blood begin to be used up. This happens when lactate is
produced faster than it can be removed (metabolized) in the muscle. When exercising at or
below the LT, any lactate produced by the muscles is removed by the body without it building
up.
With a higher exercise intensity the lactate level in the blood reaches the anaerobic
threshold (AT), or the onset of blood lactate accumulation (OBLA).
The lactate threshold is a useful measure for deciding exercise intensity for training and
racing in endurance sports (e.g. long distance running, cycling, rowing, swimming and cross
country skiing), but varies between individuals and can be increased with training. Interval
training takes advantage of the body being able to temporarily exceed the lactate threshold,
and then recover (reduce blood-lactate) while operating below the threshold and while still
doing physical activity.

Making the correct diagnosis by treadmill
exercise with cardiopulmonary monitoring
including gas exchange enables the cessation
of ineffective asthma pharmacotherapy and
appropriate corrective action.
Moreover, by providing an explanation for the
patient’s exercise-induced dyspnea, the anxiety
typically associated with the dyspnea
can generally be relieved.
For those with physiologic dyspnea, counseling regarding
conditioning and appropriate training can be of cosiderable value.

81 Morgan MD. Dysfunctional breathing in asthma: is it common,
identifiable and correctable? Thorax 2002; 57: Suppl. 2, 1131–1135.
82 Thomas M, McKinley RK, Freeman E, et al. Breathing retraining for dysfunctional breathing
in asthma: a randomised controlled trial. Thorax 2003; 58: 110–115
Enzer NB, Walker PA. Hyperventilation syndrome in childhood.
A review of 44 cases. J Pediatr 1967; 70: 521–532.
Herman SP, Stickler GB, Lucas AR. Hyperventilation syndrome
in children and adolescents: long-term follow-up. Pediatrics 1981;67: 183–187.
Abu-Hassan M, Tannous B, Weinberger M. Exercise induced dyspnea in children and
adolescents: if not asthma then what? Ann Allergy Asthma Immunol 2005; 94: 366–371.
90 Thomas M, McKinley RK, Freeman E, et al. The prevalence of dysfunctional breathing in
adults in the community with and without asthma. Prim Care Respir J 2005; 14: 78–82.
91 Thomas M, McKinley RK, Freeman E, et al. Prevalence of dysfunctional breathing in patients
treated for asthma in primary care: cross sectional survey. BMJ 2001; 322: 1098–1100.
92 De Baets F, Bodart E, Dramaix-Wilmet M, et al. Exercise-induced respiratory symptoms
are poor predictors of bronchoconstriction. Pediatr Pulmonol 2005; 39: 301–305.

52. Seear M, Wensley D, West N. How accurate is the diagnosis of exercise-induced
asthma among Vancouver schoolchildren? Arch Dis Child 2005; 90: 898–902.
53. Van Dixhoorn DJ, Duivendorm HJ. Efficacy of Nijmegen Questionnaire in
recognition of the hyperventilation syndrome. J Psychosom Res 1985; 29: 199–206.

Comorbidities: Dysfunctional Breathing:
Vocal Cord Dysfunction
Vocal cord dysfunction (VCD) syndrome is a functional
disorder of the vocal cords, characterised by the
inappropriate adduction of the vocal cords during
inspiration. Weinberger M, Pediatrics 2007;120:855–864.
Two phenotypes of VCD syndrome have been described.
One type occurs spontaneously, with the patient experiencing
dyspnoea and inspiratory stridor (often described as ‘‘wheezing’’) at
various and often unpredictable times, thus mimicking asthma.
The other phenotype only occurs with exercise.
Doshi DR, Ann Allergy Asthma Immunol 2006;96:794–799.
Flexible fiberoptic endoscopy while the patient is
symptomatic is the gold standard for the diagnosis of VCD.

Vocal Cord Dysfunction and Severe Asthma
Ayres AJRCCM 2012;184:3
• When an individual patient with a known pulmonary condition
presents with worsening respiratory symptoms, it is inevitable
that such worsening is attributed to that condition.
• Sometimes another reason for the change in symptoms is
present.
• Vocal cord dysfunction (VCD) occurring in someone with asthma
is a case in point, and in this circumstance assuming worsening
symptoms to be due to asthma rather than VCD often results
in inappropriately high treatment with anti-asthma medication.

• VCD is characterized by episodes of paradoxical inspiratory
/expiratory adduction of the true and/or false vocal cords.
• The true prevalence of VCD is unknown, largely due to
difficulties in diagnosis, although around 4 to 10% of patients
referred to difficult asthma clinics were diagnosed as having
VCD.
• VCD is more common in females; athletes; army recruits with
exercise-induced asthma, asthma, and chronic cough; and has
been reported following upper respiratory tract infection,
thyroid surgery, and with gastroesophageal reflux.

• VCD is most often regarded as a conversion disorder*, and
the complex innervation of the larynx and the association
between VCD and stress and comorbid psychology strengthens
this view.
• More specifically, it has been suggested that altered
autonomic balance maintained by central brain activity may
underlie VCD.
*The term "conversion" has its origins in Freud's doctrine that
anxiety is "converted" into physical symptoms.

• Symptoms are similar to those of asthma
(wheezy breathlessness and cough), but the pattern may be
different, breathlessness often being inspiratory in VCD, in
which attacks are often associated with voice change.
• Objective evidence to date has focused on flow–volume loop
deformation and direct visualization of the vocal cords.

• Flow–volume loops may show inspiratory loop
truncation representing variable extrathoracic
airflow obstruction, which may result in reduced
maximal inspiratory flow at 50% vital
capacity/maximal expiratory flow at 50% vital
capacity ratio due to predominant inspiratory flow
limitation.
• An abnormally high forced inspiratory flow at 25%
vital capacity/forced inspiratory flow at 75% vital
capacity ratio would indicate an initial normal flow
followed by rapid flow decline, reflecting paradoxical
vocal cord movement during inspiration.

• The gold standard for VCD diagnosis is laryngoscopic
demonstration of paradoxical vocal cord movement during
spontaneous or induced symptoms, but normal laryngeal function
when the patient is asymptomatic does not exclude VCD.
• Specific maneuvers such as repeating low- and high-pitched
sounds, forceful inspiration and expiration, and exposure to
substances known by the individual patient to induce symptoms
can be helpful in inducing an attack during laryngoscopy.
• Classically in VCD, the vocal cords adduct anteriorly
leaving an open posterior glottic chink, the adduction
occurring either during inspiration or throughout
the respiratory cycle.

High and low pitch
According to the American National Standards Institute, pitch is
the auditory attribute of sound according to which sounds can be
ordered on a scale from low to high.
Since pitch is such a close proxy for frequency, it is almost
entirely determined by how quickly the sound wave is making the
air vibrate and has almost nothing to do with the intensity,
or amplitude, of the wave.
That is, "high" pitch means very rapid oscillation, and "low" pitch
corresponds to slower oscillation. Despite that, the idiom relating
vertical height to sound pitch is shared by most languages.[12]

1) Vocal fold motion disorder, also known as
vocal cord dysfunction (VCD), is a disorder
caused by episodic unintentional paradoxical
adduction of the vocal cords.
2) The symptoms are similar to those of asthma and patients with
VCD are often misdiagnosed.
3) Although VCD dyspnea typically occurs as a hyperacute attack
during inspiration, patients with asthma develop problems
predominantly with expiration, and the 2 diseases are not
mutually exclusive.
Asthma and vocal cord dysfunction related symptoms
in the general populationda pilot study
Bisdorff Ann Allergy 2014;113:576

Format 2015: asthma severe or difficult

Format 2015: asthma severe or difficult

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