What lung function ultrasound physiology bronchoscopy

WHAT 2018
LUNG FUNCTION
Attilio Boner
University of Verona, Italy
attilio.boner@univr.it

Lung-function
in newborn
Effect of
gestational age

Lung-function
non-collaborante
Oscillometria
Rint

Small airway oscillometry indices: Repeatability
and bronchodilator responsiveness in young children
H Knihtilä, Pediatr Pulmonol 2017;52:1260-1267
Introduction
• The impulse oscillometry (IOS) indices
absolute and relative difference between
respiratory resistance at 5 and 20 Hz
(R5-20 and R5-20%, respectively) and
the area under the reactance curve (AX)
are postulated to reflect small airway function.
• Data on their cutoff values to evaluate bronchodilator responsiveness
(BDR) or between-visit changes after interventions are limited in young
children.

 Bronchodilator responsiveness
(BDR) of 103 healthy children
aged 2-7 years, who received
either salbutamol (n = 84) or
placebo (n = 19).
 Cutoff values for BDR of
R5-20, R5-20%, and AX.
The investigated IOS
parameters showed:
• marked BDR
(5°percentile cutoff of 75-110%
of the baseline value) in healthy
children, whereas
• no significant changes were
seen after inhalation of placebo.

Changes in lung function after inhalation of salbutamol among healthy children (n = 84)

Asthma Diagnosis
lung function

Assessing bronchodilator response in preschool children
using spirometry. Busi LE, Thorax 2017;72:367-372
 431 healthy children and
289 children with asthma,
aged 3–5 years.
 Spirometry repeated
after 15 min, with children
randomised to placebo
or salbutamol (400 µg).
 Spirometry was again
performed within 8 wks
at visit 2.
 Children with asthma had:
• lower lung function
(FVC 1.11±0.12 L vs 1.01±0.15 L;
FEV0.75 1.01±0.10 L vs 0.91±0.15 L)
and a
• greater Bronchodilator Response
(FEV0.75 group difference 8.6%)
than healthy children.

• Bronchodilator Response was
best defined by change in FEV0.75;
• an increase of 11% showed the
best balance between sensitivity
(51%), specificity (88%), positive
predictive value (47%) and
negative predictive value (89%)
for discriminating healthy from
preschool-aged children with
asthma.
aged 3–5 years.
at visit 2.

• Bronchodilator Response was
best defined by change in FEV0.75;
• an increase of 11% showed the
best balance between sensitivity
(51%), specificity (88%), positive
predictive value (47%) and
negative predictive value (89%)
for discriminating healthy from
preschool-aged children with
asthma.
aged 3–5 years.
at visit 2.
A negative BDR in a
child suspected of
having asthma makes
a diagnosis of asthma
less likely.

Change in lung function after salbutamol inhalation in healthy children
and those with asthma measured on the first visit
Children with
asthma (n=124)
Healthy
children
(n=181)
Difference
(mean (95% CI))
p Value
FVC (%) 7.2 (9.7%) 3.2 (5.2%) 4.0% (0.2 to 8.1) 0.032
FEV1 (%) 10.3 (8.7%) 4.3 (6.3%) 6.0 % (−2.7 to 10.8) 0.008
FEV0.75 (%) 13.2 (11.4%) 4.6 (4.9%) 8.6% (−5.0 to 14.3) <0.001
FEV0.5 (%) 14.1 (12.6%) 5.1 (6.0%) 9.0% (−2.3 to 11.4) 0.002
Data are shown as group mean change (mean (SD)%) within the asthmatic and healthy groups and
the difference (mean (95% CIs)) between groups.

Effect of extending the time after bronchodilator
administration on identifying bronchodilator
responsiveness in a pediatric pulmonary clinic
JD Cogen, Pediatr Pulmonol 2017;52:984-989
Objectives
• American Thoracic Society/European Respiratory Society
(ATS/ERS) spirometry interpretation guidelines
recommend ≥15 min between pre-and post-bronchodilator
testing to evaluate for a bronchodilator response.
• We aimed to lengthen the time between albuterol administration and
post-bronchodilator testing to adhere to ATS/ERS guidelines and
evaluated if lengthening this wait time would increase the percentage
of patients classified as bronchodilator responsive.

 2 groups of children with
asthma, one group in which
post-bronchodilator
administration wait times
were not standardized
(pre-intervention) to another
in which the wait time was
extended to 15 min to adhere
to ATS/ERS standards
(post-intervention).
 271 patients
(145 pre-intervention and
126 post-intervention).
Average wait time in minutes
Pre-intervention
group
Post intervention
6.5
16.2
20 –
15 –
10 –
05 –
00 –
P<0.001

post-bronchodilator
 271 patients
Pre-intervention
group
Post intervention
6.5
16.2
20 –
15 –
10 –
05 –
00 –
P<0.001
Clinic times increased
from 83.0 ± 29.6 min
to 91.7 ±22.5 min
(P < 0.007) from
the pre- to post-
intervention group,
respectively.

post-bronchodilator
 271 patients
Pre-intervention
group
Post intervention
6.5
16.2
20 –
15 –
10 –
05 –
00 –
P<0.001
There was no
significant change
in FEV1% predicted
between the
two groups.

Change in FEV1% predicted in the
pre- and post-intervention cohorts
Change in FEF25-75% predicted in the
pre- and post-intervention cohorts

• In a busy pediatric pulmonary clinic, while we successfully lengthened time
between albuterol administration and post-bronchodilator testing in the
vast majority of patients, no difference was seen in the percentage of
patients classified as bronchodilator responsive.
• Results from this study appear to question
the ATS/ERS recommended 15 min post-bronchodilator
administration wait time for children.

•Lung function
evaluation
in children

 Children without any
respiratory disorders
with a mean age of
9.7 years.
 Neck circumference (NC)
was above the 90th
percentile in 65 children.
Association of neck circumference
and pulmonary function in children
O Akın, Ann Allergy Asthma Immunol 2017;119:27-30
Respiratory Function Test Results of
Groups According to Neck Circumference

 Children without any
respiratory disorders
with a mean age of
9.7 years.
 Neck circumference (NC)
was above the 90th
percentile in 65 children.
Association of neck circumference
and pulmonary function in children
O Akın, Ann Allergy Asthma Immunol 2017;119:27-30
Respiratory Function Test Results of
Groups According to Neck Circumference
FEV1 and
FEV1 /FVC,
were lower in
subjects with
a large NC.

Risk factors
for reduced lung function

A population-based prospective cohort study examining
the influence of early-life respiratory tract infections
on school-age lung function and asthma.
van Meel ER, Thorax. 2018 Feb;73(2):167-173.
a population-based prospective
cohort study of 5197 children
born between April 2002 and
January 2006
Information on physician-
attended upper and lower
respiratory tract infections at
age ≤ 3 and >3–6 years obtained
by annual questionnaires.
Spirometry and physician-
diagnosed asthma assessed
at age 10 years.
Prevalence of upper respiratory tract
infections.
Values represent % of specific upper respiratory
tract infections per age and were not imputed.

January 2006
at age 10 years.
Prevalence of lower respiratory tract
infections.
Values represent % of specific upper respiratory
tract infections per age and were not imputed.

January 2006
at age 10 years.
Compared with children without lower
respiratory tract infections ≤3 years,
children with lower respiratory tract
infections ≤3 years had a lower:
•FEV1,
•FVC,
•FEV1/FVC and
•FEF75 (forced expiratory flow at 75% of FVC)

January 2006
at age 10 years.
OR of asthma at age 10 years
2.0 –
1.0 –
0.0
1.79
In children with lower respiratory
tract infections ≤3 years vs
without infections

January 2006
at age 10 years.
4.0 –
3.0 –
2.0 –
1.0 –
0.0
3.53
Children with lower respiratory
tract infections >3–6 years

January 2006
at age 10 years.
4.0 –
3.0 –
2.0 –
1.0 –
0.0
3.53
but no reduction
in lung function

January 2006
at age 10 years.
4.0 –
3.0 –
2.0 –
1.0 –
0.0
3.53
but no reduction
in lung function
Early-life lower
respiratory tract
infections
≤3 years are most
consistently associated
with lower
lung function and
increased risk of
asthma in schoolaged
children.

Potential mechanisms
•Lung development starts in utero and continues during childhood, similar to
the development of the immune system.
•In early life, the developing respiratory and immune system could be
affected by lower respiratory tract infections, leading to persistent adverse
adaptations and subsequently lower lung function and an increased risk of
asthma.
•Because of the immaturity of the respiratory and immune systems at a
young age, these processes with potential persistent consequences are more
likely to occur when lower respiratory tract infections occur early in life.

asthma.
Our findings are in line with this hypothesis because we observed that
mainly lower respiratory tract infections ≤3 years were associated
with lower lung function and increased risk of asthma.

asthma.
The immune response to infections and the risk of
developing lower lung function and asthma could both be
dependent on common factors,
such as the microbiome
or (epi)genetic factors.

Lower respiratory infections in early life are linked
to later asthma. Editorial
Moraes TJ, Thorax. 2018 Feb;73(2):105-106.
•A popular paradigm postulates that recurrent respiratory viral infections at
critical time periods of immune and lung development in childhood and infancy
coupled with allergic sensitisation are associated with the development of
asthma.
•What is often questioned is the direction of this association;
is a child with an underlying asthma phenotype more likely to experience
viral infections and develop allergy?
•Or is an otherwise healthy child who happens to get viral infections
subsequently pushed into an asthma phenotype?

•In Thorax, van Meel et al provide more evidence to link respiratory tract
infections in early life with a diagnosis of asthma and reduced lung function
in later life.
•The authors found, in a population- based cohort, that lower respiratory
tract infections before the age of 3 years were strongly and consistently
associated with lower lung function (FEV1) and with a diagnosis of current
asthma at age 10.
•Lower respiratory tract infections between the ages of 3 and 6 years were
also associated with a diagnosis of asthma, but there was no significant
effect of these infections on lung function.

in later life.
asthma at age 10.
The authors hypothesise
that early life respiratory tract infections might have
a direct effect on lung development
and the risk of asthma

in later life.
asthma at age 10.
Thus, respiratory tract infections in early life
were associated with subsequent reduced
lung function and a diagnosis of asthma,
but not vice versa.

•van Meel et al also report that gastroenteritis in early life was associated
with asthma (but not lung function changes) at age 10.
•The authors suggest that gastrointestinal infections may alter the intestinal
microbiome in early life and hence the development of asthma.
•However, antibiotic use was examined in this study and no associations were
noted.
•Thus, while the association of gastrointestinal infections with asthma is
interesting, it remains of uncertain significance.

Combined Impact of Smoking and Early-Life Exposures
on Adult Lung Function Trajectories.
Allinson JP. Am J Respir Crit Care Med. 2017;196(8):1021-1030.
overlapping prevalence (%) of infant lower
respiratory infection, father’s occupational class,
home overcrowding, and high pollution exposure
during early life.
Numbers shown indicate percentages of the included population
a nationally representative cohort,
initially of 5,362 individuals,
followed since enrollment
at birth in March 1946.
how the relationships between
early-life exposures (infant lower
respiratory infection, manual social
class, home overcrowding, and
pollution exposure)
and FEV1 and FVC trajectories
between ages 43 and 60-64 years
were influenced by smoking behavior.

pollution exposure)
OR of having an infant lower respiratory
infection according to the presence
of early life exposures

pollution exposure)
there were synergistic
interactions of smoking with:
i) infant respiratory infection
(P = 0.04)
and
ii) early-life home overcrowding
(P = 0.009),
for FEV1 at 43 years.

pollution exposure)
there were FEV1 deficits among
ever-smokers associated with:
i) infant lower respiratory infection
(-108.2 ml; P = 0.001)
and
ii) home overcrowding
(-89.2 ml; P = 0.002),
which were not evident among
never-smokers
(-15.9 ml; P = 0.69
and -13.7 ml; P = 0.70, respectively).

Nondisadvantaged early life = no lower respiratory infection, father in nonmanual social class, nonovercrowded home, and
low pollution exposure during early life.
Maximally disadvantaged early life = lower respiratory infection present, father in manual social class, overcrowded
home, and high pollution exposure during early life.

FEV1 decline in relation to FVC decline between ages 43 and 60–64 years for males

The relationship between the deficit in adult FEV1 associated with early-life
respiratory infection and the prevalence of ever-smoking among study members.
The data shown are taken from the National Survey of Health and Development and five other major prospective studies.

pollution exposure)
CONCLUSIONS:
Besides accelerating adult FEV1
decline, cigarette smoking also
modifies how early-life exposures
impact on both midlife FEV1 and FVC.
These findings are consistent with
smoking impairing pulmonary
development during adolescence or
early adulthood, thereby
preventing catch-up from earlier
acquired deficits.

Neonatal Caffeine Treatment and Respiratory Function
at 11 Years in Children under 1,251 g at Birth.
Doyle LW, Am J Respir Crit Care Med. 2017;196(10):1318-1324.
RATIONALE:
Caffeine in the newborn period
shortens the duration of
assisted ventilation and
reduces the incidence of
bronchopulmonary dysplasia,
but its effects on respiratory
function in later childhood are unknown.
OBJECTIVES:
To determine if children born with birth weight less than 1,251 g who were
treated with neonatal caffeine had improved respiratory function at 11 years
of age compared with children treated with placebo.

•Infants born very preterm (<32 wk gestational age) or
very low birth weight (<1,500 g) have worse expiratory airflow
in childhood and adulthood than those born at term or
with normal birth weight (1).
•Among preterm infants, those who develop bronchopulmonary dysplasia
(BPD) in the newborn period have even worse lung function in later life than
those who did not have BPD (1–5).
1. Bolton CE, Thorax 2015;70:574–580.
2. Vollsæter M, Thorax 2013;68:767–776.
3. Gough A, Eur Respir J 2014;43:808–816.
4. Gibson AM, Pediatr Pulmonol 2015;50:987–994.
5. Saarenpaa HK, Pediatrics 2015;136:642–650.

•There are few treatments in the newborn period
that can reduce the rates of BPD, and caffeine is one of them.
•In the CAP (Caffeine for Apnea of Prematurity) randomized controlled trial,
2,006 infants with birth weight less than 1,251 g and who were less than 10
days after birth were randomly allocated to either caffeine citrate or
placebo if their treating doctor considered that they were likely to have
apnea of prematurity (6).
•Infants in the CAP trial who were treated with caffeine had assisted
ventilation ceased approximately 1 week earlier than those treated with
placebo, and they had a reduction in the rate of BPD
(i.e., supplemental oxygen at 36 wk postmenstrual age)
from 47 to 36% (6).
6. Schmidt B, N Engl J Med 2006;354:2112–2121.
47%
36%

Children enrolled in the CAP
(Caffeine for Apnea of Prematurity)
randomized controlled trial
of caffene vs placebo
at the Royal Women's Hospital
in Melbourne
A total of 142 children had
expiratory flows measured
at 11 years of age
% children with values for
FVC below the fifth centile
30 –
25 –
20 –
15 –
10 –
15 –
10 -
11%
28%
caffeine
group
placebo
P = 0.012
OR=0.31

Children enrolled in the CAP
(Caffeine for Apnea of Prematurity)
randomized controlled trial
of caffene vs placebo
at the Royal Women's Hospital
in Melbourne
A total of 142 children had
expiratory flows measured
at 11 years of age
z-scores for expiratory flow variables
comparing caffeine (C) and placebo (P)
% below the fifth centile are shown for each subgroup
Expected mean value of zero is shown as a solid line;
Mean value for each subgroup is shown as a short solid line.
Fifth centile is shown as dashed line;

Expiratory Flow Variables Contrasted between Caffeine and Control Groups

Expiratory flows were better in the caffeine group,
by approximately 0.5 SD for most variables
(e.g., FEV1; mean z-score, -1.00 vs. -1.53; mean difference, 0.54;
95% confidence interval, 0.14-0.94; P = 0.008).

When the respiratory outcomes were adjusted for the
higher incidence of bronchopulmonary dysplasia in the
no-caffeine group, the independent effect of caffeine
was lost.

•The major finding of this study is that expiratory flow rates were better at
11 years of age among children born weighing less than 1,251 g who had been
treat ed withcaffeine in the newborn period thanamong those who had been
treated with placebo.
•Caffeine substantially reduced the rate of BPD in the newborn period, and
the effects of caffeine on expiratory flows were reduced when BPD was
added as a covariate.
•There was little evidence of an additional effect
of caffeine on expiratory flows independent
of its effects via reducing BPD. 47%
36%

•The major finding of this study is that expiratory flow rates were better at
11 years of age among children born weighing less than 1,251 g who had been
treat ed withcaffeine in the newborn period thanamong those who had been
treated with placebo.
•Caffeine substantially reduced the rate of BPD in the newborn period, and
the effects of caffeine on expiratory flows were reduced when BPD was
added as a covariate.
•There was little evidence of an additional effect
of caffeine on expiratory flows independent
of its effects via reducing BPD. 47%
36%
Because caffeine had clear short-term and
long-term benefits, with no evidence of any
harmful effects, there is little likelihood that
there will be any future placebo-controlled
randomized trials of caffeine.

Caffeine: A Lung Drug for All Very Low Birth Weight
Preterm Infants? Editorial
Jobe AH. Am J Respir Crit Care Med. 2017;196(10):1241-1243
•In this issue of the Journal, Doyle and colleagues (pp. 1318–1324)
report the better pulmonary outcomes at 11 years of age of a cohort
of infants with birth weight ,1,250 g randomly assigned to the CAP
(Caffeine for Apnea of Prematurity) trial.
•This landmark trial of 2,006 infants reported in 2006 and 2007 that infants
treated with caffeine had less bronchopulmonary dysplasia, fewer cases of
patent ductus arteriosus, and increased survival without neurodevelopmental
disability at 18–21 months.
•Subsequent reports demonstrated subtle motor deficits
in infants not treated with caffeine at 5 and 11 years of age.

•In this issue of the Journal, Doyle and colleagues (pp. 1318–1324)
report the better pulmonary outcomes at 11 years of age of a cohort
of infants with birth weight ,1,250 g randomly assigned to the CAP
(Caffeine for Apnea of Prematurity) trial.
•This landmark trial of 2,006 infants reported in 2006 and 2007 that infants
treated with caffeine had less bronchopulmonary dysplasia, fewer cases of
patent ductus arteriosus, and increased survival without neurodevelopmental
disability at 18–21 months.
•Subsequent reports demonstrated subtle motor deficits
in infants not treated with caffeine at 5 and 11 years of age.
the clinical take-home message was that relative to no
caffeine, caffeine treatment decreased
bronchopulmonary dysplasia, and the end result was
better pulmonary outcomes at 11 years of age.

•Caffeine is a drug with pleiotropic organ effects.
Caffeine inhibits adenosine receptors and increases respiratory drive, metabolic
rate, diaphragm function, and diuresis, among other effects .
•The major clinical concern for infants was adverse effects of caffeine on brain
development. For perspective on dosing, the average cup of brewed coffee contains
about 100 mg caffeine.
•The standard loading dose of caffeine for infants and the dose used in the CAP
trial is 20 mg/kg with a maintenance dose of 10 mg/kg for about 8 weeks.
•Thus, the infant receives the caffeine content of 10–14 cups of coffee for an adult
as a loading dose, and then is chronically exposed to a high dose of caffeine.
•There is surprisingly little apparent toxicity in clinical practice.

•In the CAP (Caffeine for Apnea of Prematurity) trial caffeine-treated infants
received significantly less mechanical ventilation, oxygen therapy, and treatment
with postnatal steroids, consistent with the decreased incidence of
bronchopulmonary dysplasia.
•Apnea events are frequently associated with bradycardias and desaturations, which
result in short-term interventions such as increased ventilatory support, increased
oxygen exposure, increased stimulation, and interventions such as evaluation for
infection.
•Thus, the benefits of caffeine result from prevention of interventions generally
suspected of adverse long-term neurodevelopmental effects.
•Caffeine likely is not a direct brain or a lung drug but, rather, a drug that decreases
adverse effects of interventions to treat apnea.

•In the CAP (Caffeine for Apnea of Prematurity) trial caffeine-treated infants
received significantly less mechanical ventilation, oxygen therapy, and treatment
with postnatal steroids, consistent with the decreased incidence of
bronchopulmonary dysplasia.
•Apnea events are frequently associated with bradycardias and desaturations, which
result in short-term interventions such as increased ventilatory support, increased
oxygen exposure, increased stimulation, and interventions such as evaluation for
infection.
•Thus, the benefits of caffeine result from prevention of interventions generally
suspected of adverse long-term neurodevelopmental effects.
•Caffeine likely is not a direct brain or a lung drug but, rather, a drug that decreases
adverse effects of interventions to treat apnea.
The net effect is a great benefit
to infants with apnea of prematurity.

Fetal and Infant Growth Patterns and Risk of Lower Lung
Function and Asthma. The Generation R Study.
den Dekker HT, Am J Respir Crit Care Med. 2018 Jan 15;197:183-192
cohort study of 5,635 children.
Growth estimated by repeated
ultrasounds in the second and third
trimesters, and measured at birth
and at 3, 6, and 12 months.
At age 10 years, spirometry
and asthma assessed by
parental questionnaire.
•Overall greater weight in the
second and third trimesters, at
birth, and at 12 months was
associated with
higher FEV1 and FVC at age 10 yrs.
•Greater weight at 3 months was
associated with lower FEV1/FVC
and forced expiratory flow at 75%
of the pulmonary volume (FEF75%)

•Restricted fetal weight growth
was associated with lower
childhood lung-function measures,
partly depending on infant weight
growth patterns.
•Accelerated fetal weight growth
was associated with higher FVC
and lower FEV1/FVC t age 10 yrs
only if followed by accelerated
infant weight growth.

•Restricted fetal weight growth
was associated with lower
childhood lung-function measures,
partly depending on infant weight
growth patterns.
•Accelerated fetal weight growth
was associated with higher FVC
and lower FEV1/FVC t age 10 yrs
only if followed by accelerated
infant weight growth.
Both restricted fetal weight
growth, partly depending on
infant weight growth, and
accelerated fetal and infant
weight growth predispose
children to lower lung
function and a potential risk
for respiratory diseases
later in life.

This study suggests that fetal and infant length patterns
are not associated with childhood lung function and asthma.
Children with fetal restricted weight growth partly
depending on infant weight growth (“catch up”)
and
those with persistently large fetal and infant weight growth
(“fat happy wheezer”) are most likely at risk
for lower lung function.
These two distinct growth patterns might increase the risk of chronic
obstructive respiratory diseases in later life.

Associations of weight growth patterns combined from fetal life
and infancy with lung function

Interpretation of Results
Fetal growth restriction might affect airway compliance.
Restricted fetal growth might lead to impaired growth of bronchial walls,
alterations in mucus-producing tissues, a decrease in the number of alveoli,
thicker interalveolar septa, and a greater volume density of lung tissue.
Catch-up growth is associated with lower pulmonary
function and an increased risk of childhood asthma.

Accelerated fetal weight growth followed by accelerated weight growth
between birth and 3 months was associated with a higher FVC, but not with
FEV1, resulting in a lower FEV1/FVC.
This could suggest dysanapsis, a determinant of expiratory flow limitation,
in which disproportionate growth of the airways relative to the lung volume
occurs.

Several potential mechanisms may underlie the link between early growth
and respiratory diseases in children.
Increased weight could lead to increased intrathoracic and abdominal fat
deposition, which would reduce the pulmonary vital capacity and increase
obstruction-related respiratory resistance and the risk of asthma symptoms.
Also, adiposity-related inflammation and an effect of energy-regulating
hormones such as leptin and adiponectin might cause tissue-specific
immunological and inflammatory effects with lung and airway remodeling.

The Fetus or the Infant:
Which Is the Father of the Man? (Both).Editorial
Turner S, Am J Respir Crit Care Med. 2018;197(2):147-148.
•A 35-mm slide showing the
Fletcher-Peto graph was a key
element in the carousel used for
teaching medical students life
course epidemiology
in respiratory medicine.
The natural history of chronic airflow
obstruction.
Fletcher C, Peto R. Br Med
J. 1977;1(6077):1645-8.
•The slide tracked various
downward trajectories in lung
function from a peak of 100% at
approximately age 25 years.
Risks for various men if they smoke

•Life does not begin at age 25 years,
but it has taken several decades for
birth cohorts to map lung function
trajectories from early life to
adulthood.
•These cohorts have led to
the “modern” Fletcher-Peto curve,
which has a number of upward
trajectories from 0 to 25 years of
age, some of which attain a “normal”
100%, but some of which fall short
of this peak through more than one
trajectory.
The two solid lines indicate fixed
trajectories throughout the life course
from conception to 25 years of age.
The dashed line corresponds to those
individuals whose lung function
changes from “reduced” to “normal.”
The dotted line tracks those whose
lung function is initially “normal” but
becomes “abnormal.”

•Life does not begin at age 25 years,
but it has taken several decades for
birth cohorts to map lung function
trajectories from early life to
adulthood.
•These cohorts have led to
the “modern” Fletcher-Peto curve,
which has a number of upward
trajectories from 0 to 25 years of
age, some of which attain a “normal”
100%, but some of which fall short
of this peak through more than one
trajectory.
The two solid lines indicate fixed
trajectories throughout the life course
from conception to 25 years of age.
The dashed line corresponds to those
individuals whose lung function
changes from “reduced” to “normal.”
The dotted line tracks those whose
lung function is initially “normal” but
becomes “abnormal.”
The height of the peak
in lung function achieved
is a measure of
respiratory “reserve”
against fixed
airways disease
in later life.

•A paper in this edition by den Dekker HT et al. has shed light on the very early
origins of lung function (2) . den Dekker HT AJRCCM 2018;197:183–192.
•What was previously understood was that, at a population level, low lung function
in the first 2 months was weakly predictive of lung function in early adulthood (3,
4), and that low lung function in some infants may apparently resolve but
persists in those with a family history of asthma or early-onset atopy (5).
3. Stern DA, Lancet 2007;370:758–764.
4. Mullane D, JAMA Pediatr 2013;167:368–373.
5. Turner S, Thorax 2014;69:1015–1020.
•Work from other cohorts indicates that the development of asthma may lead to
“deterioration” in lung function between early infancy and 7 years of age (6),
whereas improved air quality may lead to improved growth of lung function
between ages 11 and 15 years (7).
6. Bisgaard H, Am J Respir Crit Care Med 2012;185:1183–1189.
7. Gauderman WJ, N Engl J Med 2015;372:905–913.

An additional factor associated with changing trajectory of lung function in
early life is postnatal weight gain (8).
8. Turner S, Thorax 2008;63:234–239.
Accelerated postnatal growth may occur de novo or may represent “catch up”
growth after suppressed antenatal growth, and any intervention aimed at
influencing lung function outcome needs to understand whether to target the
antenatal or postnatal period.

•The novelty of the study published in this issue of the Journal by
den Dekker and colleagues (pp. 183–192) is that it demonstrates two
pathways to airway obstruction at 10 years of age
(i.e., reduced FEV1/FVC ratio).
•The first of restricted antenatal growth followed by normal or accelerated
(“catch up”) postnatal growth is associated with reduced FEV1/FVC ratio
because of a reduction in FEV1 relative to FVC; interestingly, ongoing
postnatal growth restriction is not associated with airways obstruction.
•The second “pathway to airway obstruction” is one in which accelerated
antenatal growth is maintained during infancy, and here the mechanism
is a result of a greater increase in FVC relative to FEV1.
FEV1/FVC
FEV1/FVC

Occupational exposure to pesticides are associated
with fixed airflow obstruction in middle-age
Alif SM, Thorax 2017;72:990-997
RR for postbronchodilator
FEV1/FVC <0.7
Biological
dust
Pesticides Herbicides
1.58 1.74
2.09
2.5 –
2.0 –
1.5 –
1.0 –
0.5 –
0.0
1335 participants from
2002 to 2008 follow-up
of the Tasmanian
Longitudinal Health Study.
Fixed airflow obstruction
defined by
post-bronchodilator
FEV1/FVC <0.7
Exposure to

Alif SM, Thorax 2017;72:990-997
RR for postbronchodilator
FEV1/FVC <0.7
Biological
dust
Pesticides Herbicides
1.58 1.74
2.09
2.5 –
2.0 –
1.5 –
1.0 –
0.5 –
0.0
1335 participants from
2002 to 2008 follow-up
of the Tasmanian
Longitudinal Health Study.
Fixed airflow obstruction
defined by
post-bronchodilator
FEV1/FVC <0.7
Exposure to
In addition, all
pesticides exposure
was consistently
associated with
chronic bronchitis
and symptoms that
are consistent with
airflow obstruction.

Alif SM, Thorax 2017;72:990-997
• Pesticides can be classified according to their targets into 3 main areas:
insecticides, herbicides and fungicides.
1. Insecticides include organochlorines, organophosphates and carbamates.
2. Herbicides include phenoxy herbicides.
3. Fungicides include dithiocarbamates.

Alif SM, Thorax 2017;72:990-997
• Pesticides can enter the body through inhalation into the respiratory tract
and absorption through the skin during use for fumigation, preparation and
spraying or during manufacture, storage or transport.
• Long-term exposure to organophosphate and carbamate pesticides has
been shown to lead to inhibition of acetylcholinesterase (an enzyme that
catalyzes the breakdown of acetylcholine) synthesis from M2 muscarinic receptors
that results in mucus hypersecretion and airway smooth muscle
contraction causing breathlessness, cough and wheeze.
• The inactive acetylcholinesterase is also responsible for thickening
of alveolar-capillary membrane leading to reduced level of lung function.

Decrease in an anti-ageing factor, growth differentiation
factor 11, in chronic obstructive pulmonary disease
Onodera K, Thorax 2017;72:893-904
• A protease–antiprotease imbalance and oxidative stress have been
reported to be involved in the pathogenesis of COPD.
• The age-dependent increase in the prevalence of COPD suggests an
intimate relationship between the pathogenesis of COPD and ageing.
• Many reports have shown that cellular senescence in COPD is accelerated
in many types of cells, including bronchial epithelial cells, lung fibroblasts,
and circulating leukocytes, and that oxidative stress accelerates cellular
senescence

Rationale
• Cellular senescence is observed in the lungs of patients with COPD
and may contribute to the disease pathogenesis.
• Growth differentiation factor 11 (GDF11) belongs to the transforming
growth factor β superfamily and was recently reported to be a circulating
protein that may have rejuvenating effects in mice.
• We aimed to investigate the amounts of GDF11 in the plasma and the lungs
of patients with COPD and elucidate the possible roles of GDF11 in cellular
senescence.

Plasma levels of GDF11.
Two separate cohorts.
Effects of GDF11 on both
cigarette smoke extract
(CSE)-induced cellular
senescence in vitro and
on elastase-induced
cellular senescence in
vivo were investigated.
The levels of plasma growth differentiation factor 11
(GDF11) and the correlations between the levels
of GDF11 and clinical parameters in cohort
Control never-smokers (CNS, n=20), the control
ex-smokers (CES, n=23), and the ex-smokers with
COPD (COPD, n=69) in cohort 1
P<0.001

Open circles: CNS; closed circles (grey):
CES; closed circles (black): COPD
Correlations between the
levels of GDF11 and the
values of FEV1% predicted
DLCO/VA% predicted
on elastase-induced

Open circles: CNS; closed circles (grey):
CES; closed circles (black): COPD
Smoking Age
on elastase-induced

The levels of plasma growth differentiation factor 11 (GDF11) and
the correlations between the levels of GDF11 and clinical parameters in cohort 2
Control never-smokers (CNS, n=15), the control ex-smokers (CES, n=16),
and the ex-smokers with COPD (COPD, n=56) in cohort 2
Open circles: CNS; closed circles (grey) CES; closed circles (black)
P<0.001

• The mRNA expression of
GDF11 in mesenchymal cells
from the COPD group was
decreased.
• Chronic exposure to CSE
decreased the production
of GDF11.
on elastase-induced

• The mRNA expression of
GDF11 in mesenchymal cells
from the COPD group was
decreased.
• Chronic exposure to CSE
decreased the production
of GDF11.
on elastase-induced
Treatment with GDF11
significantly inhibited
CSE-induced cellular
senescence and
upregulation of
inflammatory
mediators.

• In the present study, we demonstrated that the levels of plasma GDF11,
an anti-ageing factor, were significantly decreased in patients with COPD
and that the GDF11 levels were significantly correlated with the values of
FEV1% predicted, lung diffusing capacity and smoking, but not age.
• The expression of GDF11 in parenchymal cells from the patients with COPD
was decreased.
• In the in vitro culture study, we observed that CSE attenuated the
expression of GDF11 and that N-acetyl-cysteine (NAC) inhibited the CSE-
mediated attenuation of GDF11 expression, suggesting that oxidative
stress could be involved in the CSE-induced attenuation.

• Administration of GDF11 ameliorated the stress-induced cellular
senescence and production of ROS and inflammatory mediators
in the lung cells.
• Although the precise mechanisms of cellular senescence in COPD have not
been elucidated yet, oxidative stress and chronic inflammation are
believed to play a key role in the observed senescence.
Ito K, Chest 2009;135:173–80
• Excessive oxidative stress reportedly occurs in patients with COPD, and it
induces DNA damage and premature senescence.
Kostikas K, Chest 2003;124:1373–80 ; Rahman I, Am J Respir Crit Care Med 2002;166:490–5
Caramori G, Thorax 2011;66:521–7 ; Ahmad T, FASEB J 2015;29:2912–29

Riduzione di funzionalità
nel tempo
Loss of lung function with age

AHRR hypomethylation, lung function,
lung function decline and respiratory symptoms.
Kodal JB, Eur Respir J 2018;51:1701512
Background
Epigenome-wide association studies have shown a
consistent association between smoking
exposure and hypomethylation in the
aryl hydrocarbon receptor repressor (AHRR) gene
(cg05575921).
Wetested the hypothesis that AHRR hypomethylation
is associated with low lung function, steeper lung
function decline, and respiratory symptoms in the
general population.

AHRR methylation extent in 9113
individuals from the 1991–1994
examination of the
Copenhagen City Heart Study, using
bisulfite-treated leukocyte DNA.
Spirometry at the time of blood
Sampling for all individuals.
Lung function measured again
for 4532 of these individuals
in 2001–2003.
Cross-sectionally,
a 10% lower methylation extent
was associated with lower:
FEV1
FVC
FEV1/FVC
after multivariable
adjustment including
smoking.

Associations of aryl hydrocarbon receptor repressor (AHRR) methylation extent
with lung function parameters.
FEV1
FVC FEV1/FVC

examination of the
in 2001–2003.
In prospective analyses, individuals
in the lowest versus highest tertile
of methylation extent had
a steeper decline in:
FEV1/height3 (p =0.003) and
FVC/height3 (p=0.01)

per 10% lower methylation
extent OR of
2.0 –
1.0 –
0.0
1.45
chronic
bronchitis
any respiratory
symptoms
1.45
examination of the
in 2001–2003.

Hypomethylation was associated with a larger difference between
measured FEV1 and predicted FEV1 both cross-sectionally and prospectively
10 years later.
AHRR hypomethylation is a potential biomarker of smoking history and
captures former smoking even after >35 years of smoking cessation.
The concept of AHRR methylation extent as a biomarker of long-term
smoking history is supported by our findings that AHRR methylation extent
in former smokers is associated with duration of abstinence as well as with
respiratory symptoms.
The association between AHRR hypomethylation and low lung function and
chronic bronchitis in never-smokers may be due to residual confounding, or
reflect other non-measured environmental exposures, such as air pollution.

Dietary antioxidants and 10-year lung function decline
in adults from the ECRHS survey.
Garcia-Larsen V, Eur Respir J. 2017 Dec 21;50(6). pii: 1602286.
In 2002, 680 adults
(baseline mean age 43.8±6.6 years)
from 3 participating countries
of the European Community
Respiratory Health Survey
(ECRHS) answered a questionnaire
and underwent spirometry which
were repeated 10 years later.
A per-tertile increase in apple and
banana intake was associated with
a 3.59 mL·year−1
and
3.69 mL·year−1
slower decline in FEV1 and FVC,
respectively.
Tomato intake was also associated
with a slower decline in FVC
(4.5 mL·year−1).

•Our findings suggest that a higher total intake of fruits, and of apples in
middle-aged adults in Europe, was associated with a slower FEV1 decline;
whilst the intake of apples, bananas, tomatoes, herbal tea and vitamin C was
associated with a slower FVC decline.
•These associations remained robust even after adjustment for relevant
potential confounders, and our results suggest that these protective effects
are likely of greater impact in those who have quit smoking.
•Observational evidence suggests that the intake of foods that are rich in
antioxidants (e.g. fruits and vegetables), as well as specific antioxidants, is
associated with a slower decline in lung function in adults.
Carey IM, Strachan DP, Cook DG. Effects of changes in fresh fruit consumption on ventilatory
function in healthy British adults. Am J Respir Crit Care Med 1998;158:728–733.

Predictors of accelerated decline
in lung function in adult-onset asthma.
Coumou H, Eur Respir J 2018;51:1701785
•Adult-onset asthma covers more than 50% of new diagnoses of asthma.
•Adult-onset asthma is associated with more (persistent) eosinophilic airway
inflammation and more chronic sinus disease.
•It has also been suggested both in cross-sectional and longitudinal studies
that these patients have a more rapid decline in FEV1.
•Potential factors that have been shown to contribute to accelerated lung
function decline in the general asthma population are smoking, recurrent
exacerbations and low baseline FEV1.
•However, severity of inflammation could also be an important contributor
by inducing airway remodelling.

a prospective 5-year
follow-up study in 200
adults with newly
diagnosed asthma
clinical, functional
and inflammatory
parameters assessed
annually for 5 years..
•Median (interquartile range) change in
postbronchodilator FEV1 was
−17.5 (−54.2 to +22.4) mL per year.
•Accelerated decline
in FEV1 was defined
by the lower quartile
of decline
(>54.2 mL per year).

adults with newly
diagnosed asthma
and inflammatory
parameters assessed
•Nasal polyps, number of blood and sputum
eosinophils, body mass index, and level of
exhaled nitric oxide were univariably associated
with decline in lung function.
•Only the latter two
were independently
associated.

adults with newly
diagnosed asthma
and inflammatory
parameters assessed
•accelerated decline in FEV1 in all patients
were observed with combined exhaled nitric
oxide fraction
(FeNO) ⩾57 ppb
and
body mass index
(BMI) ⩽23 kg·m−2.

Univariable models for FEV1 decline with different biomarkers
b) body mass index
(BMI) (p=0.011)
a) FeNO (p<0.001);

Univariable models for FEV1 decline with different biomarkers
c) sputum eosinophils (p=0.022) d) blood eosinophils (p=0.044)

•How can we explain the association between high FeNO and accelerated decline in lung
function? An obvious explanation would be that patients with high levels of FeNO were not
using adequate amounts of anti-inflammatory medications, owing to poor adherence or under-
treatment. Inhaled corticosteroids have been shown to decrease FeNO values [29] and
prevent deterioration in lung function over time in patients with newly diagnosed asthma.
•The effect of lower BMI can be explained by the fact that patients with a very low BMI have
low muscle mass due to lack of exercise or have a mild wasting syndrome related to ongoing
inflammation.

The "Complex Restrictive" Pulmonary Function Pattern:
Clinical and Radiologic Analysis of a Common but
Previously Undescribed Restrictive Pattern.
Clay RD, Chest. 2017 Dec;152(6):1258-1265.
BACKGROUND:
Most patients with restriction have
a pulmonary function test (PFT) pattern
in which total lung capacity (TLC),
FVC, and FEV1 are reduced to
a similar degree.
This pattern is called
"simple restriction" (SR).
In contrast, we commonly observe a pattern in which FVC percent predicted (pp)
is disproportionately reduced relative to TLCpp.
This pattern is termed "complex restriction" (CR), and we attempted to characterize its
clinical, radiologic, and physiologic features

Clay RD, Chest. 2017 Dec;152(6):1258-1265.
 Restriction (TLC < lower limit of normal).
 Simple Restriction defined as
TLCpp-FVCpp ≤ 10%,
 Complex Restriction stratified into 4 classes
based on TLCpp-FVCpp discrepancy:
Class 1 CR, TLCpp-FVCpp > 10% and ≤ 15%;
Class 2 CR, TLCpp-FVCpp > 15% and ≤20%;
Class 4 CR, TLCpp-FVCpp > 25%
 39,277 PFTs
20 –
15 –
10 –
05 –
0
11.5%
% patients with restriction
•6.1% with SR,
•4.1% with CR,
•1.3% with a
mixed pattern.

Clay RD, Chest. 2017 Dec;152(6):1258-1265.
 Restriction (TLC < lower limit of normal).
 Simple Restriction defined as
TLCpp-FVCpp ≤ 10%,
 Complex Restriction stratified into 4 classes
based on TLCpp-FVCpp discrepancy:
Class 2 CR, TLCpp-FVCpp > 15% and ≤20%;
Class 4 CR, TLCpp-FVCpp > 25%
 39,277 PFTs

Patients with Complex Restriction were:
• younger, P < 0.0001
• more often women, P< 0.0001
• had a higher prevalence of neuromuscular disease, P< 0.001
• BMI > 40 kg/m2 or < 18.5 kg/m2, P=0.004
• diaphragmatic dysfunction, P=0.0008
• bronchiectasis, P=0.002
• CT mosaic attenuation, P=0.008
• pulmonary hypertension P=0.009
• lower prevalence of interstitial lung disease P < 0.0001
Clay RD, Chest. 2017 Dec;152(6):1258-1265.

Clay RD, Chest. 2017 Dec;152(6):1258-1265.
Diagnoses Associated With a Complex Restrictive Pattern
BOOP =
bronchiolitis
obliterans with
organizing
pneumonia;
CHF = congestive
heart failure;
HP =
hypersensitivity
pneumonitis;
ILD = interstitial
lung disease;
NSIP =
nonspecific
interstitial
pneumonitis;
UIP = usual
interstitial
pneumonia.

Clay RD, Chest. 2017 Dec;152(6):1258-1265.
Median FVC vs median TLC by
differing disease processes and
radiologic findings.
ILD = interstitial lung disease;
HRCT = high-resolution CT;
UIP = usual interstitial pneumonia;
WHO = World Health Organization.

Clay RD, Chest. 2017 Dec;152(6):1258-1265.
Lung volume profiles for normal, simple
restriction, and CR contrast the
proportionate reduction in TLC, VC, and
RV in simple restriction to the
disproportionate reduction in VC
compared with TLC in CR and relative
increase in RV suggestive of incomplete
lung emptying.
RV = residual volume;
VC = vital capacity.

Clay RD, Chest. 2017 Dec;152(6):1258-1265.
Pulmonary function tests and flow volume
curve for a representative example of complex
restriction in a 73-year-old man with
the following interpretation:
“Abnormal. Complex restriction indicated
by the mild reduction in TLC.
The disproportionate severe reductions in
VC and FEV1 relative to TLC suggest an
additional process such as muscle weakness,
poor performance, pulmonary hypertension, a
chest wall limitation or occult obstruction.
DLCO is severely reduced consistent
with a pulmonary parenchymal or vascular
process.”
Solid line = prebronchodilator;
dashed line = postbronchodilator;
dotted line = predicted flow/volume.
DLCO = diffusing capacity for carbon monoxide.

Restrictive Spirometry Pattern Is Associated With
Increased Arterial Stiffness in Men and Women.
Wu IH, Chest. 2017 Aug;152(2):394-401.
BACKGROUND:
There is growing evidence that pulmonary function impairment is related to
cardiovascular events and death.
Some studies have shown that the level of FVC is negatively related to
arterial stiffness, but most studies were confined to men, and none of them
examined the association of the presence of restrictive spirometry pattern
with arterial stiffness.
Therefore, this study aimed to investigate the association of restrictive
spirometry pattern with arterial stiffness by sex.

Wu IH, Chest. 2017 Aug;152(2):394-401.
2,961 healthy subjects
Restrictive spirometry pattern
defined as an FVC < 80% of the
predicted value and an
FEV1/FVC ratio ≥ 70%.
Increased arterial stiffness
defined as right brachial ankle
pulse wave velocity (baPWV)
≥ 1,400 cm/s.
2.16
3.0 –
2.0 –
1.0 –
0.0
1.95
men women
OR of increased arterial stiffness

Wu IH, Chest. 2017 Aug;152(2):394-401.
Relationship between FVC and brachial ankle pulse wave velocity in men and women.
baPWV = brachial-ankle pulse wave velocity.

Wu IH, Chest. 2017 Aug;152(2):394-401.
2,961 healthy subjects
Restrictive spirometry pattern
defined as an FVC < 80% of the
predicted value and an
FEV1/FVC ratio ≥ 70%.
Increased arterial stiffness
defined as right brachial ankle
pulse wave velocity (baPWV)
≥ 1,400 cm/s.
2.16
3.0 –
2.0 –
1.0 –
0.0
1.95
men women
OR of increased arterial stiffness
Clinically, assessment
of arterial stiffness
might be considered
in individuals with
restrictive
spirometry pattern.

• The mechanism of reduced lung function and arterial stiffness is not fully
understood, but their relationship may be linked by a cardiovascular risk
factor and systemic inflammation.
• the Coronary Artery Risk Development in Young Adults study
demonstrated that a decline in FVC predicted incident hypertension after
10 years follow-up in a young adult population with a mean age of 34.9
years.
• Declined FVC with preserved FEV1/FVC ratio has been found to be
associated with left ventricular hypertrophy and diastolic dysfunction.
• Restrictive ventilator dysfunction is associated with the development of
prediabetes and type 2 diabetes.
Wu IH, Chest. 2017 Aug;152(2):394-401.

• The mechanism of reduced lung function and arterial stiffness is not fully
understood, but their relationship may be linked by a cardiovascular risk
factor and systemic inflammation.
• the Coronary Artery Risk Development in Young Adults study
demonstrated that a decline in FVC predicted incident hypertension after
10 years follow-up in a young adult population with a mean age of 34.9
years.
• Declined FVC with preserved FEV1/FVC ratio has been found to be
associated with left ventricular hypertrophy and diastolic dysfunction.
• Restrictive ventilator dysfunction is associated with the development of
prediabetes and type 2 diabetes.
Wu IH, Chest. 2017 Aug;152(2):394-401.
The most plausible explanation for an inverse relationship
between FVC and arterial stiffness is that reduced lung
function is related to increased levels of systemic
inflammation markers, which has been reported to
be associated with arterial elasticity.

Lung function
e trapianto di midollo

Fruit and vegetable consumption and risk of COPD:
a prospective cohort study of men
Kaluza J, Thorax 2017;72:500-509
• During a mean follow-up of
13.2 years, 1918 incident
cases (4.3%) of COPD
were ascertained.
 Population-based prospective
Cohort of Swedish Men.
 44 335 men, aged 45–79 years.
 No history of COPD at baseline.
 Fruit and vegetable consumption
assessed with a self-administered
questionnaire.

Multivariable-adjusted HR (solid line) of COPD incidence as a function
of total fruit and vegetable consumption among current smokers and ex-smokers.
The long dashed lines represent 95% CIs.

of fruit consumption among current smokers and ex-smokers.

of vegetable consumption among current smokers and ex-smokers.

HRs (95% CIs) of COPD by quintiles of total fruit and vegetable consumption and smoking status

HRs (95% CIs) of COPD by quintiles of total fruit and vegetable consumption and smoking statusThe risk of COPD in smokers with total fruit and vegetable consumption <2
servings/day was 13.5-fold increased in current and 6 fold in
ex-smokers compared with never-smokers with high consumption.

HRs (95% CIs) of COPD by quintiles of total fruit and vegetable consumption and smoking statusIn those with ≥5.3 servings/day, it was increased by 7.5-fold
(current smokers) and by 3.6-fold (ex-smokers).

In current
smokers
In ex-smokers
0.60
During a mean follow-up of 13.2 years
HR of developing COPD in in the highest
quintile (≥ 5.3 servings/day)
vs the lowest quintile (<2 servings/day)
of total fruit and vegetable
1.0 –
0.5 –
00
0.66
P for trend
<0.0001
P for trend
=0.001
 Population-based prospective Cohort
of Swedish Men (4.3%).
 44 335 men, aged 45–79 years.
questionnaire.

In current
smokers
In ex-smokers
-8%
% reduction in the risk of developing
COPD with each one serving per day
increment in total fruit and vegetable
-4%
--0 –
--1 –
--2 –
--3 –
--4 –
--5 –
--6 –
--7 –
--8 –
 44 335 men, aged 45–79 years.
questionnaire.

 44 335 men, aged 45–79 years.
questionnaire.
Consumption of
1) apples or pears,
2) green leafy vegetables
3) peppers
was inversely associated with COPD;
for each daily serving increment in
the intake of these foods,
the risk of COPD decreased by:
1) 23% (95% CI 9% to 34%),
2) 32% (95% CI 13% to 47%) and
3) 39%(95% CI 13% to 57%),
respectively.

It is known that the pathogenesis of COPD may involve oxidative stress
and inflammation.
Potent proinflammatory compounds trigger local tissue remodelling
that can impair lung function over long periods of time.
Impaired antioxidant status correlates with increased severity of COPD.
Ahmad A, Int J Tuberc Lung Dis 2013;17:1104–9; Arja C, Respirology 2013;18:1069–75

Some studies, have found significant associations of high fruit and
vegetable consumption with reduced levels of oxidative stress and
inflammation parameters as well as with increased levels of antioxidant
defence.
Rink SM, J Acad Nutr Diet 2013;113:776–85; Holt EM, J Am Diet Assoc 2009;109:414–21
It has been observed that vitamin C, β-carotene and vitamin E intake
correlate positively with lung function.
Schwartz J, Am J Epidemiol.1990;132:67–76; Hu G, Am J Epidemiol 2000;151:975–81

Could a healthy diet attenuate COPD risk in smokers?
Varraso R, Thorax 2017;72:491-492. Editorial
• The predominant risk factor for COPD in high-income
countries is cigarette smoking, but not all smokers develop COPD.
• It has been hypothesised that a diet rich in antioxidants may counteract
the deleterious oxidant effects of smoking and hence prevent COPD.
• Cohort studies have also reported associations between higher intake and
a slower decline of lung function or a lower incidence of COPD.
Walda IC, Eur J Clin Nutr 2002;56:638–43; Miedema I, Am J Epidemiol 1993;138:37–45;
Butler LM, Am J Respir Crit Care Med 2004;170:279–87; Butland BK, Thorax 2000;55:102–8
• In Thorax Kaluza et al. reported a negative and significant association
between fruit and vegetable intake and the risk of COPD.

• The beneficial dietary associations were restricted
to ex-smokers and current smokers.
• These results are in agreement with the hypothesis that smokers, who
have a higher exposure to oxidants, are more likely than never smokers
to benefit from dietary antioxidants.
• The authors also investigated the association between individual food
items and the risk of COPD, and reported strong negative associations
between intakes of apples and pears (quercitin) and green leafy
vegetables (sulphoraphane) and COPD risk.

• Researchers from the Harvard Chan School
of Public Health have proposed
‘The Healthy Eating Plate’ as a guide for
creating healthy and balanced meals,
with a special focus on diet quality.
• The first message of this ‘healthy plate’
is that half of our plate should comprise fruits
and vegetables, which resonates with the current
report of Kaluza et al.

Naso elettronico
VOC
metabolomica

Background
• Hereditary Hemorrhagic Telangiectasia (HHT)
is an autosomal dominant disease
with multi-systemic vascular dysplasia.
• Early diagnosis through screening is important
to prevent serious complications.
• How best to screen children of affected parents for pulmonary
arteriovenous malformations (PAVMs) is often subject to debate.
• Transthoracic contrast echocardiogram (TTCE) is considered optimal
in screening for PAVMs in adults.
• Guidelines for the screening of children are not specific, reflecting the
lack of scientific evidence on the best method to use.
Screening children for pulmonary arteriovenous
malformations: Evaluation of 18 years of experience
AE Hosman, Pediatr Pulmonol 2017;52:1206-1211

40%
(175/436)
40 –
30 –
20 –
10 –
00 –
% children had a
diagnosis of HHT
 Current screening method,
consisting of history,
physical examination,
pulse oximetry
saturation <96%,
and chest radiography.
 436 children from
Hereditary Hemorrhagic
Telangiectasia (HHT)
families.

• Pulmonary arteriovenous
malformations (PAVMs) were
detected in 39/175 (22%) children,
33/39 requiring treatment by
embolotherapy.
• None of the screened children
suffered any PAVM-associated
complications with this screening
method.
pulse oximetry
saturation <96%,
families.

• Pulmonary arteriovenous
malformations (PAVMs) were
detected in 39/175 (22%) children,
33/39 requiring treatment by
embolotherapy.
• None of the screened children
suffered any PAVM-associated
complications with this screening
method.
pulse oximetry
saturation <96%,
families.
Postponing TTCE and
subsequent chest CT
scanning until
adulthood to detect
any smaller PAVMs
does not appear to
be associated with
major risk.

Assessing hypoxia risk during air travel after a severe
asthma exacerbation in children
JA Pena-Zarza, Ann Allergy Asthma Immunol,2017;119:389-390
• Decreased atmospheric cabin pressure in commercial aircrafts
(cruising altitude 9,000–13,000 m), requiring cabin pressurization from
1,530 to 2,440 m, is equivalent to breathing a fraction of inspired oxygen
(FiO2) of 15.1% at sea level.
• These conditions can cause severe hypoxia in patients with chronic
respiratory disease.
• The normobaric hypoxic challenge test (HCT) is the recommended method
to estimate the risk of in-flight hypoxia in patients with respiratory
disease, allowing symptom observation and titration of oxygen (O2)
requirements.
S. Ahmedzai, Thorax 2011;66 (suppl 1):i1ei30

• The HCT was performed by introducing nitrogen (50 L/min) in a sealed
body plethysmograph (Jaeger MasterScreen Body) that lowered FiO2 from
21% to 15%, simulating hypoxia during air travel.
• SpO2 and heart rate were monitored by continuous pulse oximetry.
• If SpO2 decreased to lower than 90%, we titrated O2 until hypoxia was
resolved (SpO2 > 92%).
• Patients who remained with an SpO2 higher than 90% at an FiO2 of 15%
for 20 minutes were considered a “no in-flight hypoxia risk.”
• Those who did not were requested to repeat the HCT after 24 hours.

 Hypoxia risk during air travel
after hospitalization for severe
asthmatic exacerbation by
performing the HCT in children.
 51 patients (2–15 years old)
hospitalized for severe asthma
exacerbation with O2 dependence
(baseline O2 saturation < 92%)
who were planning a flight after
discharge.
% children passing the HCT after 24 hours
without O2 therapy and were considered
a no in-flight hypoxia risk.
90%
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00 –

discharge.
% children passing the HCT after 24 hours
without O2 therapy and were considered
a no in-flight hypoxia risk.
90%
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00 –
Those who did not pass,
the HCT was repeated
after 48 hours without
O2 and all (100%) passed
the test.

hypoxic challenge test Results in Asthmatic Patients
Abbreviations: FEV1, forced expiratory volume in 1 second; FiO2 max, maximum fraction
of inspired oxygen during hospitalization; HCT, hypoxic challenge test; NS, not significant

FEV1 % predicted
Yes No
P = 0.04
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00 –
89%
69%
Pass the HCT within
the first 24 hours
discharge.

FEV1 % predicted
Yes No
P = 0.04
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00 –
89%
69%
Pass the HCT within
the first 24 hours
discharge.
No differences were
found in SpO2 before
the HCT

 Most guidelines consider pulse oximetry or
arterial gasometry values when selecting
patients with hypoxia risk during flights.
 In fact, patients with PaO2 higher than
70 mm Hg or SpO2 higher than 95% are
considered fit to fly in most cases.
 Nevertheless, in recent years, different
studies have shown that the “fit-to-fly criteria”
based on basal PaO2 are insufficient.

 In our study, the group who did not
pass the HCT in the first 24 hours
after O2 therapy showed lower
pretest FEV1 values, and although
this it does not seem to be a
sufficiently reliable indicator, an
FEV1 lower than 70% has to be
taken into account.

Trans-nasal flexible bronchoscopy in wheezing children:
Diagnostic yield, impact on therapy,
and prevalence of laryngeal cleft.
Boesch RP, Pediatr Pulmonol. 2018 Mar;53(3):310-315.
AIM:
Persistent or recurrent wheezing
is a common indication for flexible
bronchoscopy, as anatomic and
infectious or inflammatory changes
are highly prevalent.
We sought to evaluate the
prevalence of anatomic, infectious, and inflammatory disease in a cohort
of children undergoing flexible bronchoscopy for wheezing
or poorly controlled asthma.

retrospectively reviewed all
children <18 years old who
underwent flexible
bronchoscopy for wheezing
(persistent, frequently
recurring, or atypical)
101 procedures in 94 patients,
aged 3 months to 18 years
% patients with identified
potential anatomic causes
for wheezing
50 –
40 –
30 –
20 –
10 –
0
45.7%

underwent flexible
for wheezing
50 –
40 –
30 –
20 –
10 –
0
45.7%
Tracheomalacia in 18%.
Among these subset
of subjects 38.5%
also had visible bronchitis,

underwent flexible
for wheezing
50 –
40 –
30 –
20 –
10 –
0
45.7%
a laryngeal cleft in 11%
for which half required
medical or surgical
management.

underwent flexible
for wheezing
50 –
40 –
30 –
20 –
10 –
0
45.7%
medical or surgical
management.
transnasal flexible
bronchoscopy
has high yield
in children with recurrent,
persistent, or atypical
wheezing and those
with poorly
controlled asthma.

underwent flexible
for wheezing
50 –
40 –
30 –
20 –
10 –
0
45.7%
medical or surgical
management.
Laryngeal cleft
has a reasonably
high prevalence
that warrants
specific evaluation
in this population.

A decade of pediatric tracheostomies:
Indications, outcomes, and long-term prognosis
ML McPherson, Pediatr Pulmonol 2017;52:946-953
• The median patient age was
1.5 years (3 days–24 years).
 Retrospective chart review
of 426 patients admitted
to a Pediatric Intensive
Care Unit who underwent
a tracheostomy
between 2001 and 2011.

• Primary indications for
tracheostomy included:
a) airway obstruction,
b) congenital neurologic disease,
c) acquired neurologic disease,
d) congenital respiratory disease,
e) acquired respiratory disease.
a tracheostomy

% patients who died
during the study period
23%
25 –
20 –
15 –
10 –
05 –
00
Patients with
acquired neurologic
disease were most
likely to die
a tracheostomy

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