Format 2016: how to get asthma control: from PubMed to the tricks of the trade.

How to get Asthma Control:
from PubMed to the Tricks of the Trade
Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it
 Introduction
 Establishment of a partnership
 The problem of adherence
 Effective use of devices
 Written action plans
 Effective use of controller medications
 Effective use of quick-relief medications
 Environment control
 Oxidative stress reduction and diet
 Addressing co-morbidities
 Monitoring the child asthma
 Summary and Conclusions

Asthma Control General Considerations
Guidelines for asthma management have evolved
considerably during the last decade, from
treatment recommendations based on the level
of asthma severity to the current emphasis
on achieving full asthma control.
•National Asthma Education and Prevention Program Coordinating Committee. Expert Panel Report 3
(EPR3): Guidelines for the Diagnosis and Management of Asthma. 2008.
http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm Date last accessed: December 18, 2012.
Date last updated: 2008.
•British Thoracic Society Scottish Intercollegiate Guidelines Network. British Guideline on the
Management of Asthma: a national clinical guideline. Thorax 2009;63(Suppl. 4):i1–21.
Asthma control is defined as the extent to which the various
manifestations of asthma are reduced or removed by treatment.
•Reddel HK, Taylor DR, Bateman ED, et al. An official American Thoracic Society/ European Respiratory
Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials
and clinical practice. Am J Respir Crit Care Med 2009;180:59–99.

An official American Thoracic Society/ European
Respiratory Society statement: asthma control and
exacerbations: standardizing endpoints for clinical asthma
trials and clinical practice.
Reddel HK, Am J Respir Crit Care Med 2009;180:59–99.
Asthma control
includes
2 components:
1. The level of clinical asthma control, which
is gauged from features such as
symptoms and the extent to which the
patient can carry out activities of daily
living and achieve optimum
quality of life, and
2. The risk of future adverse events
including loss of control, exacerbations,
accelerated decline in lung function,
and side-effects of treatment.

refers to the difficulty in controlling asthma
with treatment (i.e. the activity of
the underlying disease state)
Asthma Severity and Control
Asthma severity and control are
related but
not interchangeable
concepts
Asthma control
refers to the extent to which asthma symptoms or
associated features are alleviated by treatment
asthma severity
Reddel HK, Am J Respir Crit Care Med 2009;180:59–99.
Taylor DR, Eur Respir J 2008;32:545–554.

Bronchial biopsy specimens before and after
repeated inhaled methacoline challenge.
Panels A and C
respiratory
epithelium
before
the challenges.
Biopsy specimens
immunostained
with an antibody
to collegen type
III
(in Panels A
and B).
Panels B and D
respiratory
epithelium
4 days after
the challenges.
Biopsy specimens
stained with
peridic
acid-Shiff to
detect goblet
cells (in Panels
C and D).
Effect of bronchoconstriction on airway remodeling
in asthma. Grainge CL. N Engl J Med. 2011;364(21):2006-15

Progression of Irreversible Airflow Limitation in Asthma:
Correlation with Severe Exacerbations.
Matsunaga K, J Allergy Clin Immunol Pract. 2015;3(5):759-764.
annual rate of decline in post-bronchodilator FEV1 (mL/year)
-10 –
-10 –
-20 –
-30 –
-40 –
-50 –
-60 -
exacerbation numbers
0 1 ≥2
-13.6 mL/year
-41.3 mL/year
-58.3 mL/year
P < 0.01
P < 0.0001
128 patients with asthma
3-year follow-up

Trajectories of lung function during childhood.
Belgrave DC, Custovic A. Am J Respir Crit Care Med. 2014;189:1101-9.
birth cohort,
specific airway resistance
(sRaw) at age
3 (n = 560),
5 (n = 829),
8 (n = 786), and
11 years (n = 644).
wheeze phenotypes
(no wheezing, transient,
late-onset, and persistent)
atopy phenotypes
(no atopy, dust mite, non-dust
mite, multiple early, and multiple
late).
wheezers who experienced exacerbation
had significantly poorer lung function
(higher sRaw)
than children who never wheezed.

Lung-Function Trajectories Leading to
Chronic Obstructive Pulmonary Disease.
Lange P, N Engl J Med. 2015;373(2):111-22.
BACKGROUND:
Chronic obstructive pulmonary
disease (COPD) is thought to
result from an accelerated decline
FEV1 over time.
Yet it is possible that a normal
decline in FEV1 could also lead to
COPD in persons whose maximally
attained FEV1 is less than
population norms.

Of the 332 persons with COPD at
the end of the observation period
60 –
50 –
40 –
30 –
20 –
10 –
0
48%
52%
FEV1 before 40 years of age
≥80%
and had a
rapid decline
in FEV1
thereafter,
of 53±21 ml
per year*
<80%
low FEV1
in early
adulthood and
a subsequent
mean decline
in FEV1 of
27±18 ml
per year*
*P<0.001 for the decline
participants in 3 independent cohorts
stratified according to lung function
[FEV1 ≥80% (n=2207) or <80% (n=657) of
the predicted value) at cohort inception
(mean age of patients, approximately
40 years] and the presence or absence of
COPD at the last study visit.
we then determined the rate of decline
in FEV1 over time among the participants
according to their FEV1 at cohort
inception and COPD status at study end.
Follow-up: 22 years.
Lung-Function Trajectories Leading to
Chronic Obstructive Pulmonary Disease.
Lange P, N Engl J Med. 2015;373(2):111-22.

 82 children
(6-11 years) and
725 adolescent/adult
patients ≥12 years
(TENOR study).
 Follow-up: 24 months.
in Children with
Consistently Very Poorly
Controlled Asthma OR for
6.4
HOSPITALIZATION,
ED VISIT, or
CORTICOSTEROID BURST
7 –
6 –
5 –
4 –
3 –
2 –
1 –
0
Consistently very poorly controlled asthma increases risk
for future severe asthma exacerbations.
Haselkorn T, J Allergy Clin Immunol. 2009;124(5):895-902.

The Poorly Explored Impact of Uncontrolled Asthma
O’Byrne, CHEST 2013;143:511
 Poorly controlled asthma adversely affects
children’s cardiovascular fitness,
while children with well-controlled asthma perform at the same level
as their peers.
 Children with uncontrolled asthma also have a
higher frequency of obesity
than children with controlled asthma.
 Children with poorly controlled asthma
are more likely to have learning disabilities
compared with those with good control.

The Poorly Explored Impact of Uncontrolled Asthma
O’Byrne, CHEST 2013;143:511
 Adults patients with asthma are at
greater risk for depression.
 Poorly controlled asthma increases the risks of
severe asthma exacerbations following upper respiratory and
pneumococcal pulmonary infections.
 Lastly, the risks of uncontrolled asthma during
pregnancy are substantially greater than the risks
of recommended asthma medications.
 Treatments to maintain asthma control are the best approach to
optimize maternal and fetal health in the pregnancies of women
with asthma.

The aim of treatment of asthma is:
1) to control symptoms,
2) to restore full physical and psychosocial functioning,
3) to eliminate interference with social relationships and
quality of life.
The goals of asthma treatment
To reach these goals, people with asthma
(including children and their parents) must at least:
1) be able to use prescribed drugs in the proper manner
to prevent or control symptoms,
2) identify and avoid the triggers that cause symptoms,
3) develop or maintain family and other necessary social support,
4) communicate effectively with healthcare providers.

The aim of treatment of asthma is:
1) to control symptoms,
2) to restore full physical and psychosocial functioning,
3) to eliminate interference with social relationships and
quality of life.
The goals of asthma treatment
To reach these goals, people with asthma
(including children and their parents) must at least:
1) be able to use prescribed drugs in the proper manner
to prevent or control symptoms,
2) identify and avoid the triggers that cause symptoms,
3) develop or maintain family and other necessary social support,
4) communicate effectively with healthcare providers.
The failure to see management by
patients as a behavioural process
based largely on an individual's
ability to self regulate may lead to
inefective asthma control despite
optimal therapy prescription

Attilio Boner
University of
Verona, Italy
 Introduction
 Environment control

Management of chronic disease by practitioners and
patients: are we teaching the wrong things?
Clark NM, BMJ 2000;320:572-5.
The patient should be the primary manager of
chronic disease, guided and coached by a doctor or
other practitioner to devise the best therapeutic
regimen.
The practitioner and patient should work as
partners, developing strategies that give the patient the best chance:
1) to control his or her own disease and
2) to reduce the physical, psychological, social, and
economic consequences of chronic illness.
patient

Bandura’s Social Cognitive Theory:
Determinants of Improved Self Regulation
Mastery experiences (practice opportunities)
Social modeling (watching others succeed)
Social persuasion (from a trusted source)
Psychological response (decreased stress)

Self Regulation
Self regulation is
the process of:
It is a means by which
patients determine what
they will do, given:
1) observing,
2) making judgments (evaluations), and
3) reacting realistically and appropriately to one's own
efforts to manage a task.
1) their specific goals,
2) social context, and
3) their perceptions of their own capability.
Clark NM, BMJ. 2000;320:572-5
the patient

Self Regulation
Self regulation is
the process of:
It is a means by which
patients determine what
they will do, given:
For example, a child
with asthma who wants
to play football
1) their specific goals,
2) social context, and
3) their perceptions of their own capability.
i. thinks drugs will help and so uses them
preventively,
ii. takes a reliever drug when exercising strenuously,
iii. seeks moral support from his friends and coaches,
iv. uses other strategies that enable him to reach his
personal goal.
v. he learns which strategies are effective through
self regulation. Clark NM, BMJ. 2000;320:572-5
1) observing,
2) making judgments (evaluations), and
3) reacting realistically and appropriately to one's own
efforts to manage a task.

Motivational interviewing derives from Prochaska and DiClemente’s
transtheoretical model of change.
This model explains behavioral change as a process in which
individuals pass through 5 stages:
1) precontemplation,
2) contemplation,
3) preparation,
4) action,
5) maintenance.
Transtheoretical therapy: toward a more integrative
model of change.
Prochaska, JO. Psychotherapy: Theory, Research & Practice, 1982;19:276

Motivational interviewing offers an alternative response
to ambivalence.
 struggles with ambivalence as a normal part
of the process of change and that
 patient motivation and readiness to change are not
static traits, but rather dynamic states that
can be greatly influenced by interactions
between provider and patient.
N
O
R
M
A
L
OVERCOMING AMBIVALENCE

PRINCIPLES OF MOTIVATIONAL INTERVIEWING:
creating the conditions for change
• Express empathy.
• Avoid argument.
• Develop a discrepancy.
• Roll with resistance.
• Support self-efficacy.
Non-smoking
twin
Twin who smokes 3
cigarettes per
day

“the change
only depends
on me”).
“I have absolutely
no influence on
asthma change,”
Higher risk of poor control
Asthma patients' perception of their ability
to influence disease control and management
Laforest L, Ann Allergy Asthma Immunol 2009;102:378
Internal locus of control
OR = 2.68

There are 2 types of patient needs to be addressed
during the medical interview:
Physicians’ communication and parents’ evaluation of
pediatric consultations. Street RL. Med Care. 1991;29:1146
cognitive (serving the need to know and understand)
and
affective
(serving the emotional need to feel known and understood).
“understand” “be understood”

Active listening is a specific communication skill which involves:
- giving free and undivided attention to the speaker,
- placing all of one’s attention and awareness at the
disposal of another person,
- listening with interest and appreciating without interrupting
- concentrating on everything the person is conveying,
both verbally and nonverbally (body language).
Active listening More than just paying attention
Robertson, Aust Fam Physicians 2005;34:1053
in
out

Active listening is a specific communication skill which involves:
- giving free and undivided attention to the speaker,
- placing all of one’s attention and awareness at the
disposal of another person,
- listening with interest and appreciating without interrupting
- concentrating on everything the person is conveying,
both verbally and nonverbally (body language).
This is a rare and valuable commitment,
as most discussions involve
competition for a space to speak.
Active listening More than just paying attention
Robertson, Aust Fam Physicians 2005;34:1053
in
out

emotions play a part in the process of medical care
in 3 interrelated ways:
EMOTIONS AND THE MEDICAL CARE PROCESS
First, both physicians and patients have emotions.
Second, both physicians and patients show emotions,
Third, both physicians and patients judge each other’s emotions.

Nonverbal Sensitivity of Physicians
element nonverbal index:
-facial expressivity
-frequency of smiling;
-eye contact and nodding,
-body lean
-body posture
-tone of voice
It seems likely that
physicians’ nonverbal
behavior
significantly influences
patients’ likelihood of
deciding for or against
recommended
treatment options.

Three elements of communication –
and the "7%-38%-55% Rule“
Mehrabian (1971) Silent messages. Wadsworth, Belmont, California.
•there are basically three elements in any
face-to-face communication:
1) words,
2) tone of voice and
3) body language.
These three elements account
differently for the meaning of the message:
- Words account for 7%
- Tone of voice accounts for 38% and
- Body language accounts for 55% of the message.
2

Enabling Effective Child Participation
Parents and children
themselves are
more satisfied and
adherence to the
treatment regimen
is enhanced.
when the child is addressed
in information gathering and
in the creation of the
treatment plan.

Children 7 years and older are:
1) more accurate than their parents in providing
health data that predicts future health outcomes,
although
2) they are worse at providing
past medical histories.
Enabling Effective Child Participation

Children's contributions to pediatric outpatient
encounters. van Dulmen AM. Pediatrics. 1998;102:563-8
21 consulting
pediatricians
videotaped a total of
302 consecutive
outpatient encounters.
Children's contributions to
the outpatient encounters
5 –
4 –
3 –
2 –
1 –
0
4%
only

Children's contributions to pediatric outpatient
encounters. van Dulmen AM. Pediatrics. 1998;102:563-8
21 consulting
pediatricians
videotaped a total of
302 consecutive
outpatient encounters.
Children's contributions to
the outpatient encounters
5 –
4 –
3 –
2 –
1 –
0
4%
only
Always
talk
with
the child !

Adolescents’ Roles in Health Care Communication and
Decisional Authority Leveton Pediatrics 2008;121:e1441
Adolescents must receive
understandable information:
1) to enable an understanding of the
condition,
2) what to expect with various tests and
treatments,
3) the range of acceptable and practical
alternative care plans,
4) likely outcomes of each option.

The tolerant model of decision making
1) addresses potentially harmful decisions by giving
weight to the adolescent’s decision,
2) with the proxy taking the role of:
- educator,
- discussant,
- challenger, and
- shared decision maker.

The tolerant model of decision making
1) addresses potentially harmful decisions by giving
weight to the adolescent’s decision,
2) with the proxy taking the role of:
- educator,
- discussant,
- challenger, and
- shared decision maker.
the
adolescent’s
decision should
not be
overrided
but discussed.
X
X

Oral communication strategies for health care providers
Table II
Health literacy and asthma
Rosas-Salazar C, JACI 2012;129:935-42
10 out of 100 instead of 10%

Learning from tragedies: clinical lessons from the
Climbié report.
Marcovitch H. Qual Saf Health Care 2003 ;12:82–3.
“doctors [should be taught] how to
write [so] that readers will
understand”
Trick of the Trade from
Lord Laming
“UK Secretary of State
for Health”
who has carried out child
protection review

•The term adherence is often used interchangeably with compliance
and is preferred by some as it acknowledges the patient’s role
as a partner in the decision-making process.
Tilson HH. Adherence or compliance? Changes in terminology.
Ann Pharmacother 2004; 38: 161-2
•Adherence is defined as “the extent to which a person’s behaviour –
taking medication, following a diet, and/or executing lifestyle
changes –corresponds with agreed recommendations from a
healthcare provider.
World Health Organization. Adherence to long-term therapies: evidence for
action [online]. Available from URL:
http://www.emro.who.int/ncd/Publications/adherence_report.pdf
Haynes R, Taylor D, Sackett D. Compliance in health care. Baltimore:
The Johns Hopkins University Press, 1979.
Definition

non-adherence can be
as high as 32–56%
Robinson DS, Eur Respir J 2003; 22: 478–483.
Heaney LG, Thorax 2003; 58: 561–566.
Gamble J, Respir Med 2011; 105: 1308–1315.
Poor inhaler technique is
also common and should
be addressed
Bracken M, Arch Dis
Child 2009; 94: 780–784.
.
If non-adherence is present, clinicians should empower patients
to make informed choices about their medicines and develop
individualised interventions to manage non-adherence.
Gamble J, Respir Med 2011; 105: 1308–1315.
Non-adherence to treatment
should be considered in all
difficult-to-control patients
Non-Adherence to Treatment

Adherence to therapy
Bush A, Eur Respir Mon 2011;51:59-81
Doctors are notoriously poor at predicting which
patients take treatment, and parents frequently
overestimate adherence.
Useful tools include:
1) measurement of serum medication levels
(prednisolone and theophylline);
2) obtaining a list of prescriptions supplied (collecting a prescription
does not guarantee adherence, but failure to collect guarantees
non-adherence); Warner JO. BMJ 1995;311:663–666.
3) assessment of whether there is a supply of easily accessible in-date
medication in the home.

Other adherence issues to be addressed include:
4) whether the child is supervised (often quite young
children are left unsupervised by the carers);
Orrell-Valente JK, Pediatrics 2008;122:e1186–e1192.
5) whether the child and family have an age-appropriate
drug delivery device that is being used properly.
Repeated education in the use of medication
devices is frequently required.
Kamps AW, Pediatr Pulmonol 2000;29:39–42.
“It is, of course, one thing to identify poor
adherence and quite another to address it.”

Other adherence issues to be addressed include:
4) whether the child is supervised (often quite young
children are left unsupervised by the carers);
Orrell-Valente JK, Pediatrics 2008;122:e1186–e1192.
5) whether the child and family have an age-appropriate
drug delivery device that is being used properly.
Repeated education in the use of medication
devices is frequently required.
Kamps AW, Pediatr Pulmonol 2000;29:39–42.
“It is, of course, one thing to identify poor
adherence and quite another to address it.”
!

 Adherence estimated
from electronic
prescription and
pharmacy fill records.
 Patients were considered
to be adherent if ICS
use was ≥ 80% of
prescribed.
 Health Locus of Control
scale was used to assess
five sources (God,
doctors, other people,
chance, and internal).
OR for medication adherence
in patients’ who had a stronger belief
that God determined asthma control
1.0 –
0.5 –
0.0
0.68
0.89
African
American
White
Asthma medication adherence: the role of God
and other health locus of control factors.
Ahmedani BK, Ann Allergy Asthma Immunol. 2013;110(2):75-9.

Parents
accompanying
150 children
aged 3–9 years
with asthma
attending
asthma clinics.
OR FOR SOUTH ASIAN PARENTS
COMPARED TO WHITE
0.30
3.19
TO GIVE
PREVENTERS
DRUG
TO CONSIDERES
DRUG MORE HARM
THAN GOOD
3.50 –
3.00 –
2.50 –
2.00 –
1.50 –
1.00 –
0.50 –
0
Parental attitudes towards the management of asthma in
ethnic minorities.Smeeton NC, Arch Dis Child. 2007;92:1082-7.

 351 children with
asthma.
 Parents of study
participants
completed the
Asthma Numeracy
Questionnaire.
Low parental numeracy
(1 cp 25 mg = 5 cp 5 mg)
OR for visits to the ED
or urgent care for asthma
1.77
2.0 –
1.5 –
1.0 –
0.5 –
0.0
p=0.04
Parental Numeracy and Asthma Exacerbations
in Puerto Rican Children Rosas-Salazar C. Chest 2013;144:92-8

asthma.
 Parents of study
participants
completed the
Asthma Numeracy
Questionnaire.
OR for visits to the ED
or urgent care for asthma
1.77
2.0 –
1.5 –
1.0 –
0.5 –
0.0
p=0.04
Parental Numeracy and Asthma Exacerbations
in Puerto Rican Children Rosas-Salazar C. Chest 2013;144:92-8
Trick of the trade:
“speak as you eat”
Low parental numeracy
(1 cp 25 mg = 5 cp 5 mg)

ADHERENCE TO ALLERGEN AVOIDANCE ADVICE
%
P
A
T
I
E
N
T
S
U
S
I
N
G
C
O
V
E
R
M
A
T
T
R
E
S
S
40 -
30 -
20 -
10 -
0
17 %
39 %
0 %
Without formal
education program
Eggleston
ARRD 1992;145:213
With usual clinic
based education
effort
Korsgaard
ARRD 1982;125:80
With a computer
education program
Huss
JACI 1992;89:836

Adherence with Inhaled Corticosteroids
typically ranging
from 30% to 70%,
but
on average lower than 50%
1) Rand CS. Adherence to asthma therapy in the
preschool child. Allergy. 2002;57 Suppl 74:48–57.
2) Jentzsch NS, Camargos PA, Colosimo EA, Bousquet J.
Monitoring adherence to beclomethasone in asthmatic
children and adolescents through four different
methods. Allergy. 2009 Oct;64(10):1458–62
3) Bender BG, Bender SE. Patient-identified barriers to
asthma treatment adherence: responses to interviews,
focus groups, and questionnaires. Immunol Allergy Clin
North Am. 2005;25(1):107–30.
4) Milgrom H, Bender B, Ackerson L, Bowry P, Smith B,
Rand C. Noncompliance and treatment failure in
children with asthma. J Allergy Clin Immunol.
1996;98(6 Pt 1):1051–7.
These rates may even be an
overestimate of true adherence in the
general population, as study
participants are likely to increase
their medication use as a
manifestation of
knowing they are being observed
(the Hawthorne effect)
Desai M, Curr Allergy Asthma Rep 2011;11:454
Studies assessing adherence to
ICS in children and adolescents
consistently demonstrate poor
rates of adherence.

typically ranging
from 30% to 70%,
but
North Am. 2005;25(1):107–30.
1996;98(6 Pt 1):1051–7.
manifestation of
rates of adherence.
compliance is
significantly
less of an issue for
‘as required therapy’
with β-agonists,
compared with
regular therapy with
corticosteroids.

typically ranging
from 30% to 70%,
but
North Am. 2005;25(1):107–30.
1996;98(6 Pt 1):1051–7.
manifestation of
rates of adherence.
If β2-agonists
frequently very likely
the child is not taking
ICS or he has a poor
technique !

Background: A validated tool to assess
adherence with inhaled corticosteroids
(ICS) could help physicians and
researchers determine whether poor
asthma control is due to poor
adherence or severe intrinsic asthma.
Objective: To assess the performance
of the Medication Adherence Report
Scale for Asthma (MARS-A),
a 10-item, self-reported measure of
adherence with ICS.
Permission to use it should be obtained by
requests to Rob.horne@pharmacy.ac.uk.
Score: Alaways =1, Often=2, Sometimes=3, Rarely=4, Never=5
Assessing the validity of self-reported medication
adherence among inner-city asthmatic adults:
the Medication Adherence Report Scale for Asthma
CohenJL. Ann Allergy Asthma Immunol 2009;103:325-31
ICS

Self-reported Medication Adherence
How often do you do the following:
1) Alaways
2) Often
3) Sometimes
4) Rarely
5) Never
High self-reported
adherence was defined
as a mean MARS
score of ≥4.5

Self-reported Medication Adherence
How often do you do the following:
1) Alaways
2) Often
3) Sometimes
4) Rarely
5) Never
High self-reported
adherence was defined
as a mean MARS
score of ≥4.5
Ask the patients to tell you the name
of the drugs.
Ask the patients to bring their drugs
and the spacer at each visit.

Poor or non-adherence to treatment
Adolescents
are at risk
reduced adherence to treatment
smoking,
illicit drug use
a higher risk
of fatal episodes
of childhood asthma.
are
common
risk taking behaviours
ERS/ATS Guidelines, ERJ 2014;43:343-373
X
X

Hedlin G, E. RJ 2010;36:196-201
Psychological risk factors are prominent in children
and young adults who subsequently die of asthma.
Strunk RC, JAMA 1985;254:1193–1198.
Bergström SE, Respir Med 2008;102:1335–1341.
Similarly, in near-fatal asthma episodes in children, the
children also showed significant denial, psychosocial
pathology and delay in seeking treatment.
Martin AJ, Pediatr Pulmonol 1995;20:1–8.
lack of concordance with prescribed
medication due to psychosocial
factors in chaotic families,
influence asthma control.
Non-Adherence: Psychosocial Issues

Most well trained professionals adopt
a practical tactic that processes
through an ongoing assessment
and negotiation of the various
components of the treatment.
A contractual approach to improving adherence
Michaud Arch Dis Child 2004;89:943
There are clues for improving
adherence in general and the
adherence of adolescents with a
chronic disorder such as asthma,

Most well trained professionals adopt
a practical tactic that processes
through an ongoing assessment
and negotiation of the various
components of the treatment.
A contractual approach to improving adherence
Michaud Arch Dis Child 2004;89:943
There are clues for improving
adherence in general and the
adherence of adolescents with a
chronic disorder such as asthma,
tricks of the trade:
1) “I have done the same
thing when I was young
so I do understand you
…and I like you but
I cannot agree”.
2) “If you have questions
or doubts this is
my phone
number”.

OR for uncontrolled asthma
Low maternal
education
Parental concerns
about potential
adverse consequences
of medication
2.0 –
1.5 –
1.0 –
0.5 –
0
1.6 1.6
Uncontrolled asthma at age 8: The importance of
parental perception towards medication
Koster ES. Pediatr Allergy Immunol 2011;22:462-8
 Uncontrolled asthma at age 8
in children participating in
the PIAMA birth cohort study.
 Uncontrolled asthma defined as:
≥3 items present in the past month:
 1) day-time asthma symptoms,
 2) night-time asthma symptoms,
 3) limitations in activities,
 4) rescue medication use,
 5) FEV1 < 80% predicted and
 6) unscheduled physician visits
because of asthma.

OR for uncontrolled asthma
Low maternal
education
Parental concerns
about potential
adverse consequences
of medication
2.0 –
1.5 –
1.0 –
0.5 –
0
1.6 1.6
Uncontrolled asthma at age 8: The importance of
parental perception towards medication
Koster ES. Pediatr Allergy Immunol 2011;22:462-8
 Uncontrolled asthma at age 8
in children participating in
the PIAMA birth cohort study.
 Uncontrolled asthma defined as:
≥3 items present in the past month:
 1) day-time asthma symptoms,
 2) night-time asthma symptoms,
 3) limitations in activities,
 4) rescue medication use,
 5) FEV1 < 80% predicted and
 6) unscheduled physician visits
because of asthma.
Talk also
about
treatment
side-efffects

The Madison Avenue effect: How drug presentation style
influences adherence and outcome in patients
with asthma Clerisme-Beaty EM. JACI 2011;127:406-11
 99 participants.
 Randomized to placebo or
montelukast in conjunction
with a presentation mode
that was either neutral or
designed to increase
outcome expectancy.
 Adherence monitored
electronically over 4 weeks.
4.0
OR for good adherence
(≥80% prescribed doses)
4.0 -
3.0 –
2.0 –
1.0 –
0.00
Presentation mode designed to
increase outcome expectancy

 99 participants.
 Randomized to placebo or
montelukast in conjunction
with a presentation mode
that was either neutral or
designed to increase
outcome expectancy.
 Adherence monitored
electronically over 4 weeks.
4.0
OR for good adherence
(≥80% prescribed doses)
4.0 -
3.0 –
2.0 –
1.0 –
0.00
Presentation mode designed to
increase outcome expectancy
The use of an enhanced
presentation aimed
at increasing outcome
expectancy may lead to
improved medication
adherence.
The Madison Avenue effect: How drug presentation style
influences adherence and outcome in patients
with asthma Clerisme-Beaty EM. JACI 2011;127:406-11

Attilio Boner
University of
Verona, Italy
 Introduction
 Effective control of inflammation

Role of inhaler competence and contrivance in
‘‘difficult asthma’’
Mark L. Everard, Paediatric Respiratory Reviews 2003;4:135–142
Failure to deliver drug effectively to the lungs is the most
common cause of referrals with ‘‘uncontrolled asthma’’.
This may be due to:
1) poor regime Compliance
or
2) poor device Compliance
lack of Competence
(the inability to use a device effectively)
and/or Contrivance
(knowing how to use a device effectively
but choosing to use it in a non-effective way ).
the healthcare professional must
be aware of the:
1) principles underlying aerosol
delivery
2) aspects of patient behaviour.
more
difficult
to
address.

Role of inhaler competence and contrivance in
‘‘difficult asthma’’
Mark L. Everard, Paediatric Respiratory Reviews 2003;4:135–142
Failure to deliver drug effectively to the lungs is the most
common cause of referrals with ‘‘uncontrolled asthma’’.
This may be due to:
1) poor regime Compliance
or
2) poor device Compliance
lack of Competence
(the inability to use a device effectively)
and/or Contrivance
(knowing how to use a device effectively
but choosing to use it in a non-effective way ).
the healthcare professional must
be aware of the:
1) principles underlying aerosol
delivery
2) aspects of patient behaviour.
more
difficult
to
address.
‘‘spacer disuse’’, omitting
to use the spacer
because it is
inconvenient, is
one of the most
common forms of
contrivance.
X

Contrivance with holding chamber-Spacer
100
prescribed 65–73%
will use
Studies in children and adults suggest that 65–73% of patients
prescribed an HC for use when administering regularly use their
pMDI alone.
Everard ML. Thorax 2000;55:811–814.
Shim C. Am J Respir Crit Care Med 2000;161:A320

Contrivance with holding chamber-Spacer
100
prescribed >85%
will use
Studies in children and adults suggest that 65–73% of patients
prescribed an HC for use when administering regularly use their
pMDI alone.
Everard ML. Thorax 2000;55:811–814.
Shim C. Am J Respir Crit Care Med 2000;161:A320
‘‘spacer disuse’’ had fallen to
<15% suggesting that
addressing the issue in clinic
can have a major impact on this
potential reason for therapeutic
failure.
Everard ML,
Ped Respir Rev 2003;4:135

Physician knowledge in the use of canister nebulizers.
Kelling JS,. Chest . 1983;83:612-614 .
55 house officers
and non-pulmonary
attending staff from
the Department of
Medicine were
interviewed
individually.
Each physician was
handed a placebo
canister and asked a
series of standard
questions regarding
the recognition,
assembly, and correct
inhalation technique of
the device.
% participants correctly performing
more than 4 of the 7 steps felt to
constitute a correct inhalation
maneuver.
50 –
40 –
30 –
20 –
10 –
0
40%
only!

% patient with difficulty in
Problems patients have using pressurized aerosol inhalers
Crompton GK. Eur J Respir Dis Suppl 1982;119:101 -6
51%
Co-ordinating
aerosol release
with inspiration
Release of aerosol
into the mouth
caused a halt of
inspiration
60 –
50 –
40 –
30 –
20 –
10 –
0
12%
24%
Inspiration was
achieved through
the nose with no
air being drawn in
through the mouth
 Use of pressurized
aerosol inhalers
 1173 out-patients
X
Freon
effect

Nasal inhalation as a cause of inefficient pulmonal
aerosol inhalation technique in children
Pedersen S, Allergy 1983;38:191-194
 71 children were given careful
instruction in aerosol inhalation
technique.
 Inhalation technique was
assessed as being efficient
when a child achieved an
increase of more than 19% in
FEV1 10 min after taking 2 puffs
of terbutaline
(each puff= 0.25 mg).
11.3
% children efficient in inhalation
technique after instruction
5-7 >7
Age (years)
100 –
80 –
60 –
40 –
20 –
0
37%
80%
Inhalation through the
nose after actuation
into the mouth
accounted for about
50% of treatment
failures, with the
problem being more
frequent in the
younger age group.

Nasal inhalation as a cause of inefficient pulmonal
aerosol inhalation technique in children
Pedersen S, Allergy 1983;38:191-194
 71 children were given careful
instruction in aerosol inhalation
technique.
 Inhalation technique was
assessed as being efficient
when a child achieved an
increase of more than 19% in
FEV1 10 min after taking 2 puffs
of terbutaline
(each puff= 0.25 mg).
11.3
% children efficient in inhalation
technique after instruction
5-7 >7
Age (years)
100 –
80 –
60 –
40 –
20 –
0
37%
80%
When this error
was corrected about
83% of the children
were efficient in
the technique.
Trick of the trade

The adequacy of inhalation of aerosol from canister
nebulizers. Shim C. Am J Med 1980;69:891-4
 30 patients hospitalized
with asthma.
 Taught the correct
technique.
% patients that,
when retested,
had reverted to the
old incorrect technique
50%
50 –
40 –
30 –
20 –
10 –
00 -

The adequacy of inhalation of aerosol from canister
nebulizers. Shim C. Am J Med 1980;69:891-4
 30 patients hospitalized
with asthma.
 Taught the correct
technique.
% patients that,
when retested,
had reverted to the
old incorrect technique
50%
50 –
40 –
30 –
20 –
10 –
00 -
Patients
should be taught
repeatedly until
they learn the
correct technique
and retain it !

Contributory Factors: Non-Adherence to Treatment
Hedlin G, E. RJ 2010;36:196-201
Very young children are frequently and inappropriately left to
take their asthma medication unsupervised.
Orrell-Valente JK, Pediatrics 2008; 122: e1186–e1192.
Finally, repeated checking
of inhaler technique is important.
we learn:
10% of what we read
20% of what we hear
30% of what we see
50% of what we see and hear
70% of what we say
90% of what we say and do

Contributory Factors: Non-Adherence to Treatment
Hedlin G, E. RJ 2010;36:196-201
Very young children are frequently and inappropriately left to
take their asthma medication unsupervised.
Orrell-Valente JK, Pediatrics 2008; 122: e1186–e1192.
Finally, repeated checking
of inhaler technique is important.
1) Please read
2)Please do
Trick of the trade

% increase 30 minutes
post salbutamol inhalation
70 -
60 -
50 –
40 –
30 –
20 –
10 –
0
18
asthmatic
children
FEV1
FVC
Mouthpiece (MP) versus Facemask (FM) For Delivery of
Salbutamol in Children With Asthma Exacerbation.
Kishida M. J Asthma 2002;39:337-9
MP FM MP FM
56.4%
28.9%
34.4%
7.5%
* p<0.05
*
*

% increase 30 minutes
post salbutamol inhalation
70 -
60 -
50 –
40 –
30 –
20 –
10 –
0
18
asthmatic
children
FEV1
FVC
Mouthpiece (MP) versus Facemask (FM) For Delivery of
Salbutamol in Children With Asthma Exacerbation.
Kishida M. J Asthma 2002;39:337-9
MP FM MP FM
56.4%
28.9%
34.4%
7.5%
* p<0.05
*
*
Trick of the trade:
train the child to use
the mouthpiece
as soon as possible

How to use an MDI with a spacer

…………spray
1+1 (2) spruzzi al mattino
…………spray
1+1 (2) spruzzi alla sera

Tira su, tira su, tira su
………………………………………………
… tira su.

Inhaled corticosteroids for asthma: impact of
practice level device switching on asthma control.
Thomas M, BMC Pulm Med 2009; 9: 1.
2 –
1 –
0
1.92
in the switched cohort
OR for
unsuccessful treatment
p < 0.001
2-year retrospective matched
cohort study used the UK General
Practice Research Database to
identify practices where ICS devices
were changed without a consultation
individually matched with patients
using the same ICS device who were
not switched.
Asthma control over 12 months
after the switch
compared with controls

Instruct the patient to recognize the effect by the
color of the device

WAPs should include not only instructions in case of deterioration
but importantly recommendations for daily management, which remains
the most effective means to prevent exacerbations in children.
Use of WAPs should be tested for their efficacy, not only
in improving patient compliance and asthma control,
but
also for improving healthcare professionals’ adherence
to recommendations and dispensing of the WAP.
Ducharme FM, Curr Opin Allergy Clin Immunol. 2008;8(2):177-88
Definition of written action plan (WAP)

Written action plans for asthma: an evidence-based
review of the key components.
Gibson GP. Thorax 2004;59:94-9.
Individualised complete written action plans must contain
each of the following four components of an action plan:
– when to increase treatment (action point);
– how to increase treatment;
– for how long;
– when to seek medical help.
a level of symptoms
or lung function
70–85% of
the
personal
best
or pred. PEF
value

Written action plan
symptom-based vs
PEFR
4 studies (355 ch)
Written action plan
use significantly:
1) Reduced acute care visits,
2) Reduced missed school days,
3) Reduced nocturnal awakening,
4) Improved symptom scores.
Systematic review of randomized controlled trials
examining written action plans in children: what is the plan?
Zemek RL, Arch Pediatr Adolesc Med 2008; 162:157–163.
1) Charlton I,
BMJ.1990;301:1355.
2) Wensley D,
AJRCCM. 2004;170:606.
3) Letz KL, Ped Asth All
Immunol. 2004;17:177.
4) Yoos HL, Ann All Asth
Immunol. 2002;88:283

A Low-Literacy
Asthma Action
Plan to Improve
Provider Asthma
Counseling: A
Randomized Study
Yin H S, Pediatrics.
2016;137:e20150468

A Low-Literacy Asthma Action Plan to Improve Provider
Asthma Counseling: A Randomized Study
Yin H S, Pediatrics. 2016;137(1):e20150468
 119 providers were randomly assigned
(61 low literacy, 58 standard)
 Physicians at 2 academic centers
randomized to use a low-literacy or
standard action plan to counsel the
hypothetical parent of child with
moderate persistent asthma
(regimen:
-Flovent 110 μg 2 puffs twice daily,
-Singulair 5 mg daily,
-Albuterol 2 puffs every 4 hours as needed)
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
% providers more likely to use times of day
(eg, Flovent morning and night)
100 -
96.7%
p<0.001
51.7%
The low-literacy
plan
Standard plan

(regimen:
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
% providers recommend spacer use
(eg Albuterol)
83.6%
p<0.001
43.1%
The low-literacy
plan
Standard plan

(regimen:
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
% providers using explicit symptoms
(eg, "ribs show when breathing," )
100 -
54.1%
p<0.001
3.4%
The low-literacy
plan
Standard plan
OR=33.0

Empowering the child and caregiver: yellow zone Asthma
Action Plan. Dinakar C, Curr Allergy Asthma Rep. 2014;14(11):475.
100% lung function
Symptoms’ perception

100% lung function
Symptoms’ perception
The yellow zone
2 weeks

Yellow Zone Strategies:
Repetitive use of inhaled SABA
(from 2 to 4 puffs to 6 to 10 puffs based on the severity of the episode)
Scheduled dosing step-up: increasing total ICS dose per 24 h
(e.g., quadrupling or higher doses of ICS)
Dynamic dosing step-up: ICS along with reliever SABA use
ICS-LABA-adjustable maintenance dosing (AMD)
ICS ≥ 4 X

Attilio Boner
University of
Verona, Italy
 Introduction
 Evironment control

Quantifying the proportion of severe asthma exacerbations
attributable to inhaled corticosteroid nonadherence.
Williams LK, J Allergy Clin Immunol 2011;128:1185–91.
298 asthmatics
ICS adherence estimated from
electronic prescription and
fill information
changes in ICS adherence over
time and effect of this changing
pattern of use on asthma
exacerbations (need for oral
corticosteroids, an asthma-
related emergency department
visit, or an asthma-related
hospitalization)
% asthma exacerbations
30 –
20 –
10 –
00 -
attributable to ICS
medication
non-adherence.
24%

Quantifying the proportion of severe asthma exacerbations
attributable to inhaled corticosteroid nonadherence.
Williams LK, J Allergy Clin Immunol 2011;128:1185–91.
298 asthmatics
ICS adherence estimated from
electronic prescription and
fill information
changes in ICS adherence over
time and effect of this changing
pattern of use on asthma
exacerbations (need for oral
corticosteroids, an asthma-
related emergency department
visit, or an asthma-related
hospitalization)
0.61
patients with adherence > 75%
of the prescribed dose vs
patients with adherence ≤25%
HR for asthma
exacerbations
1.0 –
0.5 –
0.0

Trends in preventive asthma medication use among
children and adolescents,1988-2008.
Kit BK, Pediatrics. 2012;129:62e69.
a cross-sectional analysis of
preventive asthma medication (PAM) use
2499 children aged 1 to 19 years with
current asthma
data from the National Health and
Nutrition Examination Survey (NHANES)
during 3 time periods:
1988-1994, 1999-2002, and 2005-2008.
PAMs included inhaled corticosteroids,
leukotriene receptor antagonists, long-
acting β-agonists, mast-cell stabilizers,
and methylxanthines
compared to
white children
aOR of PAM use in
0.5
1.0 –
0.5 –
0.0
non-Hispanic
black
Mexican
American
0.6

Trends in preventive asthma medication use among
children and adolescents,1988-2008.
Kit BK, Pediatrics. 2012;129:62e69.
a cross-sectional analysis of
preventive asthma medication (PAM) use
2499 children aged 1 to 19 years with
current asthma
data from the National Health and
Nutrition Examination Survey (NHANES)
during 3 time periods:
1988-1994, 1999-2002, and 2005-2008.
PAMs included inhaled corticosteroids,
leukotriene receptor antagonists, long-
acting β-agonists, mast-cell stabilizers,
and methylxanthines
aOR of PAM use
in 12 to 19 year olds
0.5
1.0 –
0.5 –
0.0
compared to
1-11 years old children

Low Rates of Controller Medication Initiation and
Outpatient Follow-Up after Emergency Department Visits
for Asthma. Andrews AL, J Pediatr 2012;160:325
 Retrospective
cohort study.
 ED visit for asthma.
 3435 patients
aged 2-18 yrs.
40 –
30 –
20 –
10 –
0
% children who had a prescription for
ICS after the ED visit & attended a
follow-up appointment.
5.2%

 Retrospective
cohort study.
 3435 patients
aged 2-18 yrs.
40 –
30 –
20 –
10 –
0
5.2%
Children
with asthma
seen in the ED have
low rates of ICS use
& outpatient follow-up.
Prescribe ICS
in the ED and
organize
a follow-up
visit.

 Retrospective
cohort study.
 3435 patients
aged 2-18 yrs.
40 –
30 –
20 –
10 –
0
5.2%
Children
with asthma
seen in the ED have
low rates of ICS use
& outpatient follow-up.
And call the patient if
he is not presenting
to the follow-up
visit.

Dose Response of Inhaled Corticosteroids in Children
With Persistent Asthma: A Systematic Review
Zhang L. Pediatrics 2011;127:129-38
 Systematic review
and meta-analysis
 Randomized controlled
trials comparing
≥2 doses of ICSs
 children 3-18 years
with persistent
asthma.
 To compare moderate
(300–400 μg/day)
with low
(≤200 μg/day
BDP-equivalent)
doses of ICSs.
There was no significant difference between moderate
and low doses of ICSs in terms of efficacy

Dose Response of Inhaled Corticosteroids in Children
With Persistent Asthma: A Systematic Review
Zhang L. Pediatrics 2011;127:129-38
 Systematic review
and meta-analysis
 Randomized controlled
trials comparing
≥2 doses of ICSs
 children 3-18 years
with persistent
asthma.
 To compare moderate
(300–400 μg/day)
with low
(≤200 μg/day
BDP-equivalent)
doses of ICSs.
There was no significant difference between moderate
and low doses of ICSs in terms of efficacy
Reduce the ICS dose
after 3 months of well
controlled asthma.
Use the lowest
ICS dose that
maintains asthma
under control.

Daily vs. intermittent inhaled corticosteroids for
recurrent wheezing and mild persistent asthma:
a systematic review with meta-analysis.
Rodrigo GJ. Respir Med. 2013;107(8):1133-40.
7 trials with a minimum of
8 weeks of daily ICS
(daily ICS with rescue SABA
during exacerbations)
vs.
intermittent ICS
(ICS plus SABA at the onset of
symptoms)
1367 participants
RR for asthma exacerbations
0.96
daily vs.
intermittent ICS
1.0 –
0.5 –
0.0

Daily vs. intermittent inhaled corticosteroids for
recurrent wheezing and mild persistent asthma:
a systematic review with meta-analysis.
Rodrigo GJ. Respir Med. 2013;107(8):1133-40.
Pooled relative risk for percent asthma free days
Pooled relative risk for percent recue medications
If the child/parents have good
perception of symptoms you
can use intermittent strategy.
If not, use the
daily strategy.

The risk of asthma exacerbation after stopping low-dose
inhaled corticosteroids: A systematic review and
meta-analysis of randomized controlled trials
Rank MA. J Allergy Clin Immunol. 2013;131(3):724-9.
 7 trials with a
mean follow-up
of 27 weeks
RR for an asthma exacerbation
in patients who stopped ICSs
2.35
P <0.001
3 –
2 –
1 –
0 compared with
those who continued

The risk of asthma exacerbation after stopping low-dose
inhaled corticosteroids: A systematic review and
meta-analysis of randomized controlled trials
Rank MA. J Allergy Clin Immunol. 2013;131(3):724-9.
 7 trials with a
mean follow-up
of 27 weeks
RR for an asthma exacerbation
in patients who stopped ICSs
2.35
P <0.001
3 –
2 –
1 –
0 compared with
those who continued
Provide the
parents with a
symptom diary
and organize
a follow-up
spirometry within
a month if you
stop treatment

 182 children (6 to 17 yrs of age),
who had uncontrolled asthma while
receiving 100 µg of fluticasone
twice daily;
 16 weeks:
250 µg of fluticasone twice daily
(ICS step-up),
100 µg of fluticasone plus 50 µg of
a long-acting beta-agonist twice
daily (LABA step-up), or
plus 5 or 10 mg of a leukotriene-
receptor antagonist daily
(LTRA step-up).
Step-up Therapy for Children with Uncontrolled Asthma
Receiving Inhaled Corticosteroids Lemanske NEJM 2010;362:975
Relative probability of best
response vs LTRA step-up
1.6
P=0.004
2 –
1 –
0
LABA step-up

Relative probability of best
response vs ICS step-up
1.7
P=0.002
2 –
1 –
0
LABA step-up
 182 children (6 to 17 yrs of age),
who had uncontrolled asthma while
receiving 100 µg of fluticasone
twice daily;
 16 weeks:
(ICS step-up),
100 µg of fluticasone plus 50 µg of
a long-acting beta-agonist twice
daily (LABA step-up), or
plus 5 or 10 mg of a leukotriene-
receptor antagonist daily
(LTRA step-up).
2X

Pairwise comparisons of the three step-up therapies

Pairwise comparisons of the three step-up therapies
Receiving Inhaled Corticosteroids Lemanske NEJM 2010;362:975Always maintain a certain degree of
uncertainty and evaluate objectively
the effects of your choices
Oxford University

OR for receiving ≥6 prescription
for SABA every year
2 -
1 –
0
1.8
A retrospective observational study comparing rescue
medication use in children on combined versus separate
long-acting β-agonists and corticosteroids
Elkout H. Arch Dis Child. 2010;95:817-21
In children reiving
LABA+ICS vs LABA & ICS
 40 primary care
practices for the
years 2002–6
 10 454 children with
received at least
one prescription for
asthma medication
+

OR for receiving ≥6 prescription
for SABA every year
2 -
1 –
0
1.8
A retrospective observational study comparing rescue
medication use in children on combined versus separate
long-acting β-agonists and corticosteroids
Elkout H. Arch Dis Child. 2010;95:817-21
In children reiving
LABA+ICS vs LABA & ICS
 40 primary care
practices for the
years 2002–6
 10 454 children with
received at least
one prescription for
asthma medication
+
Only prescribe
fixed-dose
LABA-&-ICS
combination
deevices!

Loss of asthma control in pediatric patients after
discontinuation of long-acting Beta-agonists.
R O'Hagan A, Pulm Med. 2012;2012:894063.
54 children with
moderate-to-severe persistent
asthma after switching
from combination (ICS/LABA)
to monotherapy with ICS.
mean followup of 10.7 weeks
% children with loss of asthma control
leading to addition of
leukotriene receptor antagonists,
increased ICS,
or restarting LABA.
40 –
30 –
20 –
10 –
0
37%

Loss of asthma control in pediatric patients after
discontinuation of long-acting Beta-agonists.
R O'Hagan A, Pulm Med. 2012;2012:894063.
54 children with
moderate-to-severe persistent
asthma after switching
from combination (ICS/LABA)
to monotherapy with ICS.
mean followup of 10.7 weeks
% children with loss of asthma control
leading to addition of
leukotriene receptor antagonists,
increased ICS,
or restarting LABA.
40 –
30 –
20 –
10 –
0
37%
Provide the
parents with a
symptom diary
and organize
a follow-up
spirometry within
a month if you
stop treatment

Pre-treatment by omalizumab allows allergen
immunotherapy in children and young adults
with severe allergic asthma
Lambert N, Pediatr Allergy Immunol. 2014;25:829-832
Asthma control and therapeutic
level for the four periods.
SCIT, Subcutaneous allergen-specific
immunotherapy;
BDP, Equivalent of beclomethasone
dipropionate;
LAT, Long-acting theophylline.

Pre-treatment by omalizumab allows allergen
immunotherapy in children and young adults
with severe allergic asthma
Lambert N, Pediatr Allergy Immunol. 2014;25:829-832
Asthma control and therapeutic
level for the four periods.
SCIT, Subcutaneous allergen-specific
immunotherapy;
BDP, Equivalent of beclomethasone
dipropionate;
LAT, Long-acting theophylline.
Consider
the opportunity
to start
immunotherapy
in a child
on omalizumab
treatment.

Asthma Guidelines recommend early treatment
of asthma exacerbation as ‘‘key in management’
Reddel HK, Am J Respir Crit Care Med. 2009;180:59-99
Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma.
1) earlier recognition of an impending exacerbation
2) coupled with earlier augmentation of treatment
at home to avoid therapy delays
A strategy to reduce exacerbations
might be:
Parents report a vast number of symptoms observed
in their children before an exacerbation.
•Beer S, Arch Dis Child. 1987;62:345-8.
•Rivera-Spoljaric K, J Pediatr 2009;154:877-81, e4.
•Yoos HL, J Pediatr Health Care 2005;19:197-205.
•Garbutt J, Ann Allergy Asthma Immunol 2009;103:469-73.

134 children with
bronchial asthma
Mean age 7.0 years
(range 1-5-14 years).
A standardised
questionnaire recording
the symptoms that
preceded the attack of
asthma completed
by the parents.
Prodromal features of asthma
Beer S, Arch Dis Child 1987;62:345
% children with prodromal
symptoms and/or signs
70.4%
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
(95/134)

bronchial asthma
Mean age 7.0 years
(range 1-5-14 years).
A standardised
questionnaire recording
the symptoms that
preceded the attack of
asthma completed
by the parents.
Prodromal features of asthma
Beer S, Arch Dis Child 1987;62:345
% children with prodromal
symptoms and/or signs
70.4%
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
(95/134)
Respiratory symptoms
(cough, rhinorrhoea, and
wheezing).
Behavioural changes
(irritability, apathy,
anxiety, and sleep
disorders).
Gastrointestinal symptoms
(abdominal pain and
anorexia).
Others: fever, itching,
skin eruptions, and
toothache.

 Parents of children
(n=101) 2 to 12 years old
with asthma
exacerbations that
required urgent care
in the past 12 mo.
 Telephone questionnaires
to describe antecedent
symptoms and signs of
asthma exacerbations
noticed by parents and
to learn when and how
parents intensify asthma
treatment.
Respiratory
symptoms
24%
% Signs and Symptoms Preceding
Exacerbations
Cold Behaviour
change
Other
nonspecific
symptoms
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
29%
43%
79%
Detection and home management of worsening asthma
symptoms. Garbutt J. Ann Allergy Asthma Immunol 2009;103:469

Cough
Treatment was Most Often
Intensified When the Parent Noticed
Shortness
of breath
Wheeze
60 –
50 –
40 –
30 –
20 –
10 –
0
55% 54%
25%
with asthma
exacerbations that
in the past 12 mo.
treatment.

Cough
Treatment was Most Often
Intensified When the Parent Noticed
Shortness
of breath
Wheeze
60 –
50 –
40 –
30 –
20 –
10 –
0
55% 54%
25%
with asthma
exacerbations that
in the past 12 mo.
treatment.
Cold is not
considered
an allarming
sign by
parents !

Nonrespiratory symptoms before loss of asthma control
in children. Newton L, JACI Pract 2013;1:304
 Caregivers of children aged
2 to 11 years with asthma.
 Diary cards daily for 16 weeks
during cold and flu season.
 Likert scale from 1 to 5
(3 represented baseline or usual;
1 or 2, less than usual; and
4 or 5, more than usual).
 Multiple nonrespiratory (NR)
 Upper respiratory (UR) signs and
symptoms.
 Mood changes (MC)
 Lower respiratory tract (LR).
 Loss of asthma control (LOC)
Percentage of days with
a nonusual symptom before and
during a LOC episode
(≥2 consecutive days with LR symptoms)

Nonrespiratory symptoms before loss of asthma control
in children. Newton L, JACI Pract 2013;1:304
 Caregivers of children aged
2 to 11 years with asthma.
 Diary cards daily for 16 weeks
during cold and flu season.
 Likert scale from 1 to 5
(3 represented baseline or usual;
1 or 2, less than usual; and
4 or 5, more than usual).
 Multiple nonrespiratory (NR)
 Upper respiratory (UR) signs and
symptoms.
 Mood changes (MC)
 Lower respiratory tract (LR).
 Loss of asthma control (LOC)
Percentage of days with
a nonusual symptom before and
during a LOC episode
(≥2 consecutive days with LR symptoms)
changes in behavior
(moody, irritability,
tension)
and appearance
(dry skin, eye swelling,
sunken eyes)
can be present 3 days
before an
exacerbations

Difficulty in obtaining peak expiratory flow measurements
in children with acute asthma.
Gorelick MH, Pediatr Emerg Care 2004;20:22-6.
65%
70 –
60 -
50 -
40 -
30 –
20 –
10 –
0
% of children aged 5 to 18
years able to complete
PEF or FEV1 during an
exacerbation456 children
(age 6-18 years old)
treated in a pediatric
ED for an acute
exacerbation of
asthma
PEFR in all children
age ≥ 6 years
among children
< 5 years,
these maneuvers
were almost
impossible

Brown Asthma Visual Analogue Scale
Pictorial visual analogue scale for rating severity of childhood asthma episodes.
Fritz J. Asthma 1994;31:473
None A tiny A little Some Quite Alot Very much
at all bit a bit terrible
ALB
Trick of the trade for extimating the child of perception
an asthma exacerbation at home of the child

Criteria for categorizing the severity of asthma exacerbations
Camargo CA, J Allergy Clin Immunol. 2009;124(2 Suppl):S5-14

Criteria for categorizing the severity of asthma exacerbations
1,2,3,4,5,6,7,8,9,10,….

Mechanism of reduced blood pressure during inspiration
During inspiration the increased
negative intrathoracic pressure causes
increased right sided venous return to
the right atrium and, subsequently, to
the right ventricle during diastole.
This causes an increase in right
ventricular filling pressures because of
increased volume and stretch, leading
to a bulging of the intraventricular
septum towards the left ventricle, thus
decreasing the left ventricular size and
filling volume due to this protrusion.
Thus, there is a subsequently
decreased left sided stroke volume and
therefore a lower systolic blood
pressure.
+
> 20 mm Hg+

•Severe pulsus paradoxus can easily be palpated in the radial,
brachial, or femoral pulses as a weakening or disappearance
of the pulse during inspiration (which is usually best observed
by watching the rise and fall of the abdomen).
•With a sphygmomanometer, the blood pressure is
measured in the standard fashion except that
the cuff is deflated more slowly than usual.
•During deflation, the first Korotkoff sound is audible only during
expiration, but with further deflation additional Korotkoff sounds are
clearly heard throughout the respiratory cycle. The difference
between the systolic pressure at which the first beats are heard and
the pressure at which all beats are heard is the size of the pulsus.
Trick of the trade measurement of pulsus paradoxus

ED MANAGEMENT OF ASTHMA EXACERBATIONS
Dosages of drugs for asthma exacerbations
≤ 12 years of age

Caregivers of 82 children
with asthma aged 4 to 14
yrs, presenting to the ED
with an asthma
exacerbation;
Home albuterol use
was measured using a
structured interview guide.
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
Inappropriate Appropriate
Home albuterol use for the
current asthma exacerbation was
68%
56/82
32%
26/82
Inappropriate home albuterol use during an acute asthma
exacerabtion Clayton K, Ann Allergy Asthma Immunol 2012;109:416
69% (39/56)
Undertreating
Only 5%
overtreating

with an asthma
exacerbation;
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
68%
56/82
32%
26/82
Reasons for
incorrect home
albuterol use included:
 no spacer (17 pts),
 overtreating (3 pts),
 overreacting (5 pts),
 using a controller
medicine for quick
relief (6 pts).
69% (39/56)
Undertreating
Only 5%
overtreating

with an asthma
exacerbation;
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
68%
56/82
32%
26/82
In addition, most
children in the entire
study population used an
albuterol MDI (52%)
but were giving only
2 puffs (63%)
instead of 4-6-8 puffs
suggested by Guidelines
69% (39/56)
Undertreating
Only 5%
overtreating
This finding suggests
some concern about
the use of albuterol
at home!!!!!!!

Nota informativa importante concordata con l’Agenzia
Italiana del Farmaco (AIFA) ottobre 2014
Paragrafo 4.1 Indicazioni terapeutiche
Broncovaleas soluzione da nebulizzare 5mg/mL è indicato nel
trattamento del broncospasmo nei pazienti di età superiore ai 2 anni…
Paragrafo 4.2 Posologia e modo di somministrazione
Bambini da 2 a 12 anni: il dosaggio iniziale deve basarsi sul peso
corporeo (da 0.1 a 0.15 mg/Kg per dose), con successiva titolazione fino
al raggiungimento della risposta clinica desiderata.
La dose non deve mai eccedere i 2.5 mg 3 o 4 volte al giorno per
nebulizzazione:
Peso corporeo (KG) Dose (mg) Volume di soluzione (mL) N° gocce
10-15 1.25 0.25 5 gtt
> 15 2.5 0.5 10 gtt
Cordiali saluti Valeas SPA

Nota informativa importante concordata con l’Agenzia
Italiana del Farmaco (AIFA) ottobre 2014
Paragrafo 4.1 Indicazioni terapeutiche
Broncovaleas soluzione da nebulizzare 5mg/mL è indicato nel
trattamento del broncospasmo nei pazienti di età superiore ai 2 anni…
Paragrafo 4.2 Posologia e modo di somministrazione
Bambini da 2 a 12 anni: il dosaggio iniziale deve basarsi sul peso
corporeo (da 0.1 a 0.15 mg/Kg per dose), con successiva titolazione fino
al raggiungimento della risposta clinica desiderata.
La dose non deve mai eccedere i 2.5 mg 3 o 4 volte al giorno per
nebulizzazione:
Peso corporeo (KG) Dose (mg) Volume di soluzione (mL) N° gocce
10-15 1.25 0.25 5 gtt
> 15 2.5 0.5 10 gtt
Cordiali saluti Valeas SPA
?

Safety of Continuous Nebulized Albuterol for
Bronchospasm in Infants and Children
Katz RW, Pediatrics 1993;92:666-9
incidence of
cardiotoxicity
19 infants (mean age
20.7 ± 3.8 months) who
receive continuous
nebulized albuterol
(CNA) for bronchospasm.
ADM=admission
Dose of albuterol during
continuous nebulization.

The Dilemma of Albuterol Dosing for Acute Asthma
Exacerbations in Pediatric Patients
Arnold Chest 2011;139:472
For moderate-
severity
exacerbations,
six (60%) of 10
completing the
question reported
using CNA doses
that exceed
current expert
guidelines.
 Nebulized albuterol doses recommended
by expert consensus guidelines for
exacerbations in children ≤ 12 yrs of age
are “ 0.15-0.3 mg/kg up to 10 mg
every 1-4 hours as needed, or
0.5 mg/kg/hour by continuous
nebulization.”
 Continuous nebulized albuterol (CNA) dose
(10 mg/h = 2 mL Broncovaleas sol 0.5%).
 We administered an Internet-based
questionnaire to respiratory care
directors of the Child Health Corporation
of America.

Trick of the trade with MDI use in acute asthma
Only half of patients regularly used a holding chamber
with their MDI.
Scarfone R, Pediatrics. 2001;108:1332e1338.
Multiple studies have demonstrated the effectiveness of
albuterol delivery using a holding chamber with an MDI when
compared with using an MDI alone.
Brown PH, Thorax. 1990;45:736e739.
Lipworth BJ. Thorax. 1995;50:105e110.
Newman SP, Thorax. 1984;39:935e941.
Selroos O, Thorax. 1991;46:891e894.
Camargo CA, JACI.
2009;124(2 Suppl):S5-14

Beta-agonists through metered-dose inhaler with valved
holding chamber versus nebulizer for acute exacerbation of
wheezing or asthma in children under 5 year of age:
a systematic review with meta-analysis
Castro-Rodriguez JA. J Pediatr 2004;145:172-7
6 trials (n=491)
OR for hospital admission in
MDI+spacer vs nebulizers
0.42
ALL PATIENTS
0.27
PATIENTS WITH
MODERATE-SEVERE
EXACERBATIONS
1.00 –
0.75 –
0.50 –
0.25 –
0

Holding chambers (spacers) versus nebulisers for beta-
agonist treatment of acute asthma.
Cates CJ, Cochrane Database Syst Rev. 2013 Sep 13;9:CD000052
1897 children
and 729 adults
39 trials: 33 from
emergency room and
community settings,
6 trials on inpatients
with acute asthma
Relative Risk of hospital admission
for spacer versus nebuliser
1.0 –
0.5 –
0
0.94
0.61 to 1.43
Adults Children
0.71
0.47 to 1.08

Holding chambers (spacers) versus nebulisers for beta-
agonist treatment of acute asthma.
Cates CJ, Cochrane Database Syst Rev. 2013 Sep 13;9:CD000052
1897 children
and 729 adults
39 trials: 33 from
emergency room and
community settings,
6 trials on inpatients
with acute asthma
Relative Risk of hospital admission
for spacer versus nebuliser
1.0 –
0.5 –
0
0.94
0.61 to 1.43
Adults Children
0.71
0.47 to 1.08
The mean duration in
the ED for children
given nebulised
treatment was
103 minutes,
and
for children given
treatment via spacers
≤33 minutes

How do patients determine that their metered-dose
inhaler is empty? Rubin BK. Chest 2004;126:1134-7
 50 consecutive
patients attending
the Children’s Hospital
Asthma Center
% patients or parents who
did not know how many actuations
were in their canisters
74%
75 -
60 –
45 –
30 –
15 –
0
?

Checking How Much Medicine Is Left in the Canister
A full canister will sink to the bottom.
An empty canister will float on the water surface.

50 consecutive
patients attending
the Children’s
Hospital Asthma
Center
% patients or parents who
did not know how many actuations
were in their canisters
74%
75 -
60 –
45 –
30 –
15 –
0
?
Canister flotation
was ineffective in
identifying when a
pMDI was
depleted, and
water obstructed
the valve opening
27% of the time
How do patients determine that their metered-dose
inhaler is empty? Rubin BK. Chest 2004;126:1134-7

Dose counting and the use of pressurized metered-dose
inhalers: running on empty.
Sander N, Ann Allergy Asthma Immunol. 2006;97(1):34-8.
how patients
evaluate the
contents of their
pMDI
a 6.5-minute
telephone interview
with a random
sample of 500
families with
asthma
% of bronchodilator users
reporting having
been told to keep
track of pMDI
doses used.
40 –
30 –
20 –
10 –
0
20%
36%
reporting having
found their pMDI
empty during an
asthma
exacerbation.

Dose counting and the use of pressurized metered-dose
inhalers: running on empty.
Sander N, Ann Allergy Asthma Immunol. 2006;97(1):34-8.
how patients
evaluate the
contents of their
pMDI
a 6.5-minute
telephone interview
with a random
sample of 500
families with
asthma
% of bronchodilator users
reporting having
been told to keep
track of pMDI
doses used.
40 –
30 –
20 –
10 –
0
20%
36%
reporting having
found their pMDI
empty during an
asthma
exacerbation.
82% of the
patients
considered their
pMDI empty
when absolutely
nothing came
out !!!!!!!!!!
instruct
the patient

Corticosteroids for hospitalised children with acute
asthma. Smith M Cochrane Database Syst Rev. 2003;(2):CD002886.
To determine the benefit
of systemic corticosteroids
(oral, intravenous, or
intramuscular) compared to
placebo and inhaled steroids
in acute paediatric asthma.
426 children aged 1-18 yrs
7 trials
7 –
6 –
5 –
4 –
3 –
2 –
1 –
0
7.0
OR for discharge early
(< 4 hrs) after admission
NNT of 3
systemic corticosteroids

Mean Asthma Control Questionnaire symptom score and mean FEV1 % pred
in participants with and without subsequent acute asthma.
AT DISCHARGE AT DISCHARGE AT FOLLOW-UPAT FOLLOW-UP
ns
ns
ns
Symptom score FEV1 % pred
No
asthma
No
asthma
No
asthma
No
asthma
YES
asthma
YES
asthma
YES
asthma
YES
asthma
Perception of airflow obstruction in patients hospitalized
for acute asthma
Davis SQ. Ann Allergy Asthma Immunol 2009;102:455-61

Mean Asthma Control Questionnaire symptom score and mean FEV1 % pred
in participants with and without subsequent acute asthma.
AT DISCHARGE AT DISCHARGE AT FOLLOW-UPAT FOLLOW-UP
ns
ns
ns
Symptom score FEV1 % pred
No
asthma
No
asthma
No
asthma
No
asthma
YES
asthma
YES
asthma
YES
asthma
YES
asthma
Perception of airflow obstruction in patients hospitalized
for acute asthma
Davis SQ. Ann Allergy Asthma Immunol 2009;102:455-61
An asthmatic patient
admited to hospital
should have a
spirometry
two weeks
after discharge!

Home environment as a Contributory Factor
Hedlin G, E. RJ 2010;36:196-201
It is difficult to evaluate the home environment without visiting.
Families rarely give accurate descriptions of:
1) the degree of social deprivation and stress,
2) passive smoking,
3) house dust and pet allergen exposure, and
4) damp and mould in their homes.
Fireplaces, wood-stoves, kerosene heaters and gas for cooking have
been associated with increased asthma morbidity.
Belanger K, ImmunolAllergy Clin North Am 2008; 28: 507–519.
Installation of more effective nonpolluting heating in the homes of
children with asthma may significantly reduce symptoms.
Howden-Chapman P, BMJ 2008; 337: a1411.

The importance of nurse-led home visits in the
assessment of children with problematic asthma.
Bracken M, Bush A, Arch Dis Child 2009;94:780–784.
% asthmatic children with
potentially modifiable factors
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
79%
Many children had
multiple causes for
poor control
71 children, aged
4.5-17.5 years, with
problematic asthma
currently under follow-up
at a tertiary respiratory
centre.
A nurse-led hospital visit
followed by a home visit.

% asthmatic children with potentially modifiable factors
60 –
50 –
40 –
30 –
20 –
10 –
0
59%
psychosocial
factors
allergen
exposure
31%
passive or
active smoking
25%
medication issues
including adherence
48%

% asthmatic children that
with the home visit
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
84%
23%
house dust mite
avoidance
measures inadequate
in those sensitised
medications not easily
available for
inspection
or out of date
71 children, aged
4.5-17.5 years, with
problematic asthma
currently under follow-up
at a tertiary respiratory
centre.
A nurse-led hospital visit
followed by a home visit.

Home environment: smoking
Hedlin G, E. RJ 2010;36:196-201
There is ample evidence from adult studies that
active smoking causes steroid resistance,
Chalmers GW, Thorax 2002;57:226–230.
Chaudhuri R, Am J Respir Crit Care Med 2003;168:1308–1311.
Livingston E, Eur Respir J 2007;29:64–71.
Lazarus SC, Am J Respir Crit Care Med 2007;175:783–790.
Tomlinson JE, Thorax 2005;60:282–287.
and
It is likely that passive smoke exposure has the same effects.

Physicians' Counseling of Adolescents Regarding
E-Cigarette Use.Pepper JK, J Adolesc Health. 2015;57:580-6
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
p<0.001
% physicians reporting routinely
screening adolescent patients for
cigarette
smoking
86%
e-cigarette
use
14%
776 pediatricians and
family medicine physicians
who provide primary care
to adolescent patients
completed an online survey
in Spring 2014.

90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
p<0.001
couseling for avoiding
cigarette
smoking
79%
e-cigarette
use
18%
in Spring 2014.

90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
p<0.001
couseling for avoiding
cigarette
smoking
79%
e-cigarette
use
18%
in Spring 2014.
Ask the
adolescent
about
e-cigarette use
X

Asymmetrical Peer Influence
Nonsmokers must learn
how and where to obtain cigarettes,
where they can smoke without being
discovered by authorities,
how to conceal evidence of their
smoking behavior, and
most importantly, how to smoke.
By contrast,
the types of
information and other
resources required
for successful
smoking cessation
knowledge of effective methods,
access to smoking cessation programs
access to nicotine replacement products
With a Little Help from My Friends? Asymmetrical Social
Influence on Adolescent Smoking Initiation and Cessation.
Haas SA, J Health Soc Behav. 2014;55(2):126-143.

Asymmetrical Peer Influence
Nonsmokers must learn
how and where to obtain cigarettes,
where they can smoke without being
discovered by authorities,
how to conceal evidence of their
smoking behavior, and
most importantly, how to smoke.
By contrast,
the types of
information and other
resources required
for successful
smoking cessation
knowledge of effective methods,
access to smoking cessation programs
access to nicotine replacement products
With a Little Help from My Friends? Asymmetrical Social
Influence on Adolescent Smoking Initiation and Cessation.
Haas SA, J Health Soc Behav. 2014;55(2):126-143.
Adolescents rarely initiate smoking without
peer influence but will cease smoking while
their friends continue smoking.
Uncle Mario may be of help!

Home environment: Allergens
1) low-dose allergen exposure, even in school, can lead
to deterioration of asthma control;
Almqvist C, Am J Respir Crit Care Med 2001;163:694–698.
Sulakvelidze I, Eur Respir J 1998;11:821–827.
2) allergen exposure and sensitisation are associated with
increased severity of viral-induced exacerbations in school-age
children; Murray CS, Thorax 2006;61:376–382.
3) ongoing allergen exposure in sensitised adults leads to an IL-2- and
IL-4 mediated steroid resistance;
Kam JC, J Immunol 1993;151:3460–3466.
Nimmagadda SR, Am Rev Respir Crit Care Med 1997; 155: 87–93.
4) allergens may have non-IgE-mediated adverse effects.
Langley SJ, Thorax 2005;60:17–21.
Chinn S, Am J Respir Crit Care Med 2007;176:20–26.

Reduction of bronchial hyperreactivity during prolonged
allergen avoidance. Platts-Mills TA, Lancet 1982; ii:675-678.
9 patients with severe
aaasthma
allergic to dust mites
lived in hospital rooms
fofor ≥ 2 months
Time course of changes in BHR to histamine
in five patients showing ≥ 8 fold increase in PD30

Days with symptoms/2 weeks 1°yr
5–
4–
3–
2–
1–
0
Results of a Home-Based Environmental Intervention
among Urban Children with Asthma Morgan NEJM 2004;351:1068
• 937 ch (5-11 yrs)
• Controls or
Intervention groups:
-covers
-high efficiency
vacuum cleaner
-HEPA air purifier
(to address multiple
allergens)
• Education
• Follow-up 1-2 yrs
INTERVENTION CONTROL
3.39
4.2
P<0.001

% REDUCTION PER YEAR IN INTERVENTION GROUP
0 –
-10 –
-20 –
-30 -
Unscheduled
visits
(-2.1/yr)
-13.6%
-19.5% -20.7%
Days with
symptoms
(-21.3/yr)
Missed days
of school
(-4.4/yr)
Results of a home-based environmental intervention
among urban children with asthma
Morgan WJ, N Egl J Med 2004;351:1068

Allergen avoidance to reduce asthma-related morbidity
Sheffer AL, N Egl J Med 2004;351:1134 Editorial
“Environmental control of multiple allergens, coupled
with repeated educational endeavors, can significantly
reduce asthma-related complications among inner-city
children with atopic asthma.
The results are similar to those of studies evaluating
the effects of corticosteroid therapy on asthma.”
≈

Effect of mattress and pillow encasings on children with
asthma and house dust mite allergy.
Halken S, J Allergy Clin Immunol. 2003;111(1):169-76.
60 children (age range, 6-15 yrs)
with asthma and HDM allergy
randomized to active (allergy
control) or placebo
mattress and pillow encasings.
After a 2-week baseline period,
follow-up was performed every
3 months for 1 year.
During the entire study period,
the dose of inhaled steroids was
tapered off to the lowest effective
dose
% children who could
reduce the dose of ICS
≥ 50% after 1 year
active placebo
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
p<0.01
24%
73%

Combination of IL-2 and IL-4 Reduces Glucocorticoid
Receptor-Binding Affinity and T Cell Response to
Glucocorticoids Kam JC, J Immunology, 1993;151:3460
PBMC from normal
donors and patients
with Steroid
Resistant asthma,
cultured in the
absence and presence
of IL-2 andIL-4
glucocorticoid
receptors (GR)
dissociation
constant (Kd)
50 –
40 –
30 –
20 –
10 –
0
6.74
medium
alone
p=0.0001
medium (+)
IL-2 & IL-4
36.1
Glucocorticoids
dissociation costant

In vivo exposure to
ragweed reduces the
glucocorticoid receptor
binding affinity
(increases the
dissociation kostant) of
peripheral blood
mononuclear cells (PBMC)
from 12 atopic
asthmatics.
Allergen exposure decrease glucocorticoid receptor
binding affinity and steroid responsiveness in atopic
asthmatics. Nimmagadda SR, AJRCCM 1997;155:87
Before During 8 Weeks after
GCRKd(nM)
80
50
40
30
20
10
Relation to ragweed season
p < 0.001
(75)
21.0
27.0
37.5

Passive Sensitization of Human Airways Increases
Responsiveness to Leukotriene C4
Schmidt Eur Respir J. 1999;14:315
Contraction (change in tension) mg1000
800
600
0
400
200
10-12 10-11 10-10 10-9 10-8 10-7 10-6
Leukotriene C4 concentration M
 Bronchial rings
passively sensitized
with IgE for mites
 LC4 induced
contraction







   
    


   
Passively
sensitized
Non sensitized
alb

 Passive sensitization of
bronchial rings with serum
containing high IgE levels for
mites
 Challenged with mites
 Precontraction with
carbachol (CCh)
 Addition of salbutamol
Allergen Challenge of Passively Sensitized Human Bronchi
Alter M2 and 2 Receptor Function
Song P, AJRCCM 1997;155:1230
120
100
60
0
40
20
9 8 7 6 5 4
Salbutamol concentration (-10g M)
80
% of CCh-induced contraction








 











  




 
Control ()
Sensitized ()
p<0.05
Sensitized and
mite challenged ()
alb

Corticosteroids and antigen avoidance decrease airway
smooth muscle mass in an equine asthma model.
Leclere M, Am J Respir Cell Mol Biol. 2012;47(5):589-96
 Heaves-affected (a naturally
occurring asthma-like disease ) adult
horses with ongoing airway
inflammation and bronchoconstriction
Treated with fluticasone
propionate (with and without
concurrent antigen avoidance) (n = 6)
or
with antigen (hay) avoidance alone
(n = 5).
Lung function and bronchoalveolar
lavage at multiple time points, and
peripheral lung biopsies before and
after 6 and 12 months of treatment.
Heaves is a naturally occurring disease of adult
horses that shares numerous similarities with
asthma, including reversible bronchoconstriction
and airway inflammation when susceptible horses
inhale antigens of their environment.
Coughing, wheezing, and exercise intolerance are
present during clinical exacerbations, and can be
controlled by antigen avoidance or corticosteroids
and bronchodilators
Heaves line

Corticosteroids and antigen avoidance decrease airway
smooth muscle mass in an equine asthma model.
Leclere M, Am J Respir Cell Mol Biol. 2012;47(5):589-96
Lung function improved more
quickly with inhaled
corticosteroids, but eventually
normalized in both groups.
Inflammation was better
controlled with antigen
avoidance.
Airway smooth muscle
remodeling decreased by
approximately 30% in both
groups
 Heaves-affected (a naturally
occurring asthma-like disease ) adult
horses with ongoing airway
inflammation and bronchoconstriction
Treated with fluticasone
propionate (with and without
concurrent antigen avoidance) (n = 6)
or
with antigen (hay) avoidance alone
(n = 5).
Lung function and bronchoalveolar
lavage at multiple time points, and
peripheral lung biopsies before and
after 6 and 12 months of treatment.

Allergen Avoidance
Lødrup Carlsen, Eur Respir J. 2011;37:432-40.
The value of house dust mite avoidance for asthmatic patients
has been questioned, (Gotzsche PC, Allergy 2008; 63: 646–659.) but
several lines of evidence suggest it may be useful in severe asthma:
First, low-dose allergen exposure, insufficient to cause acute
deterioration, may lead to steroid resistance by an interleukin
(IL)-2 and IL-4 dependent mechanism.
McKinley L, J Immunol 2008; 181: 4089–4097.
Adcock IM, Curr Allergy Asthma Rep 2008;8: 171–178.
Secondly, the combination of viral infection, allergen sensitisation and
high levels of exposure to that allergen in the home are predictive of
severe exacerbations, and of these factors only allergen exposure is
amenable to intervention. Murray CS, Thorax 2006; 61: 376–382.

Smoke & Pollution Exposure and Epigenetics
Rahman I , Eur Respir J . 2006;28:219-242 .
1) by altering nuclear factor kB
(NF- kB) activation or
2) by histone modification and
3) chromatin remodeling
•allergic reactions
•infections
•cigarette smoke
•air pollution
overexpression of
proinflammatory genes
Oxidative
stress
epigenetic
effects

Moreno-Macias H, JACI 2014;133:1237
Oxidative stress in allergies and asthma prevalence
Some researchers have proposed that the increased
prevalence of allergic diseases is a consequence of
decreasing intake of antioxidants as people adopt
Western diets characterized by a reduced amount
of fresh fruits and vegetables.
Allan K, Clin Exp Allergy 2009;40:370-80.
Others have suggested that it is linked to the increased
consumption of processed and oxidants enriched foods.
Feary J, Thorax 2007;62:466-8.
(-)
(+)

Increased exhaled 8-isoprostane in childhood asthma.
Baraldi E, Chest. 2003;124(1):25-31.
12 healthy children,
12 steroid-naïve
asthmatic children,
30 children in stable
condition with mild-to-
moderate persistent
asthma treated with inhaled
corticosteroids (ICSs)
[average dose, 300 micro g
per day]
exhaled breath
condensate (EBC),
8-isoprostane levels in EBC
(marker of lipid peroxidation)
ns

Urinary Bromotyrosine Measures Asthma Control and
Predicts Asthma Exacerbations in Children
Wedes, J Ped 2011;159:248
 Urinary bromotyrosine,
a non invasive marker
of eosinophil-catalyzed
protein oxidation.
asthma.
 Follow-up 6 weeks.
ORs and 95% CI for the associations between high levels of
bromotyrosine and nitric oxide and uncontrolled asthma at baseline

in asthmatic
airways
Oxidative
Stress
Asthma and the REDOX System
1) peroxidation of lipids, proteins,
and DNA
2) production of chemoattractants,
3) BHR,
4) airway secretion,
5) vascular permeability,
increases
Barnes Free Rad Biol Med 1990;9:235.
Rahman I. J Biochem Mol Biol 2003;36:95.
Henderson WR J Immunol 2002;169:5294.
ROS also
promote the
activities of
6) proinflammatory redox-sensitive
nuclear factors, (NF-kB).
thus increasing the allergic inflammation

Histone deacetylase-2 and airway disease.
Barnes PJ. Ther Adv Respir Dis. 2009;3:235-43.
whereas
histone deacetylase-2
(HDAC2) suppresses
inflammatory gene
expression.
increased expression of
inflammatory genes
suppresses inflammatory
gene expression

whereas
(HDAC2) suppresses
inflammatory gene
expression.
inflammatory genes
gene expression
The reduction in HDAC2
appears to be secondary
to increased oxidative
stress in the lungs.

whereas
(HDAC2) suppresses
inflammatory gene
expression.
inflammatory genes
gene expression
The reduction in HDAC2
appears to be secondary
to increased oxidative
stress in the lungs.
Antioxidants such
as curcumin may
therefore restore
corticosteroid
sensitivity

Serum heavy metal and antioxidant element levels of
children with recurrent wheezing.
Razi CH, Allergol Immunopathol (Madr). 2011;39:85-9.
Correlation between serum zinc levels and
n° of Acute Respiratory Tract Infections.
r:−0.332, p = 0.001
recurrent wheezing
from 1 to 6 years
116 age- and sex-
matched healthy
children.
serum mercury, lead,
aluminium, zinc, selenium,
and copper levels in
blood

Serum heavy metal and antioxidant element levels of
children with recurrent wheezing.
Razi CH, Allergol Immunopathol (Madr). 2011;39:85-9.
Correlation between serum zinc levels and
n° of wheezy attacks during the previous year
r:−0.776, p < 0.001
recurrent wheezing
from 1 to 6 years
116 age- and sex-
matched healthy
children.
serum mercury, lead,
aluminium, zinc, selenium,
and copper levels in
blood

Zinc status in infantile wheezing.
Tahan F, Pediatr Pulmonol. 2006;41:630-4.
Wheezy infants (n = 34)
Healthy children (n = 14)
Levels of zinc in hair
34
140 –
120 –
100 -
800 -
600 –
400 –
200 –
0
Wheezing Controls
CHILDREN WITH
136.5
Hair zinc level (μg/g hair)
p<0.001
A normal hair zinc range is around
150 - 240µg/gram.
Levels of < 70µg/gram would be
indicative of zinc deficiency.

 Erythrocyte zinc levels.
 67 asthmatic and
45 healthy children.
Mean concentrations (μg/dl)
of erythrocyte zinc
in children hospitalized for an asthma
attack in the previous 12 mo.
NO YES
1248
1300 –
1200 –
1100 –
1000
1095
p<0.0001
Erythrocyte zinc levels in children with bronchial asthma.
Arik Yilmaz E, Pediatr Pulmonol. 2011;46(12):1189-93.

 Erythrocyte zinc levels.
 67 asthmatic and
45 healthy children.
Mean concentrations (μg/dl)
of erythrocyte zinc
in children hospitalized for an asthma
attack in the previous 12 mo.
NO YES
1248
1300 –
1200 –
1100 –
1000
1095
p<0.0001
Erythrocyte zinc levels in children with bronchial asthma.
Arik Yilmaz E, Pediatr Pulmonol. 2011;46(12):1189-93.
Zalewski PD. J Nutr Immun 1996;4:39–101.
Arm JP, Am Rev Respir Dis 1989;139:1395–1400.
Kadrabova J, J Trace Elem Med Biol 1996;10:50–53.
Richter M, Chest 2003;123:446.
It is possible that zinc supplementation
may decrease the risk for persistent
wheezing in children

% children with acute
lower respiratory infections
during 180 days follow-up
The efficacy of zinc supplementation in young children
with acute lower respiratory infections: a randomized
double-blind controlled trial. Shah UH, Clin Nutr. 2013;32:193
60 –
50 –
40 –
30 –
20 –
10 –
0
20.8%
P=0.009
45.8%
Zinc Placebo
96 children living
in India
10 mg zinc
gluconate or placebo
for 60 days.
Follow-up:
180 days.
supplementation

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