What pulmonology 4 bpd and copd

Pulmonology
BDP and COPD
Attilio Boner
University of Verona, Italy
attilio.boner@univr.it
WHAT YOU SOULD HAVE READ BUT ………………… 2018

Bronchopulmonary
Dysplasia •Genetic Risk
•predisposing factors

Antenatal Determinants of Bronchopulmonary Dysplasia
and Late Respiratory Disease in Preterm Infants.
Morrow LA, Am J Respir Crit Care Med. 2017;196(3):364-374.
RATIONALE:
Mechanisms contributing to chronic
lung disease after preterm birth
are incompletely understood.
OBJECTIVES:
To identify antenatal risk factors
associated with increased risk
for bronchopulmonary dysplasia (BPD)
and respiratory disease during early
childhood after preterm birth,
we performed a prospective, longitudinal study of 587 preterm infants
with gestational age less than 34 weeks and birth weights
between 500 and 1,250 g.

 longitudinal study of 587
preterm infants with
gestational age < 34 weeks
and birth weights between
500 and 1,250 g.
 longitudinal follow-up by
questionnaire until 2 years
of age.
Maternal smoking prior to preterm birth
increased the odds of having an infant
with BPD by twofold (P = 0.02).
Maternal smoking was associated with
prolonged mechanical ventilation and
respiratory support during the neonatal
intensive care unit admission.
Preexisting hypertension was associated
with a twofold (P = 0.04) increase in odds
for BPD.
Lower gestational age and birth weight
z-scores were associated with BPD

 longitudinal study of 587
preterm infants with
gestational age < 34 weeks
and birth weights between
500 and 1,250 g.
 longitudinal follow-up by
questionnaire until 2 years
of age.
Ors for bronchopulmonary dysplasia

OR for Bronchopulmonary Dysplasia

Prenatal Factors by Respiratory Diagnosis Status
22% of infants diagnosed with BPD and
34% of preterm infants without BPD
had no clinical signs of late
respiratory disease during
early childhood.

Model Results of Logistic Regression for Respiratory Diagnosis over the first 2 years of life

Preterm Birth, Bronchopulmonary Dysplasia, and
Long-Term Respiratory Disease. Editorial
Shepherd EG, Am J Respir Crit Care Med. 2017;196(3):264-265.
•Preterm birth interferes with the normal in utero fetal development of major organ
systems, including the lungs.
•Infants born before 32 completed weeks gestational age are at high risk for
abnormal postnatal lung development, and this risk increases with decreasing
gestational age at birth.
•Bronchopulmonary dysplasia or BPD, was first described in 1967 by Northway.
•Although significant advances in neonatal intensive care have reduced mortality,
there has been no decrease in the incidence of BPD.
•Clearly, a better understanding of risk factors for BPD and late respiratory disease
is vital to allow insights into disease pathogenesis, potential preventative strategies,
and better prognostic reliability.

Preterm Birth, Bronchopulmonary Dysplasia, and
Long-Term Respiratory Disease. Editorial
Shepherd EG, Am J Respir Crit Care Med. 2017;196(3):264-265.
•In this issue of the Journal, Morrow and colleagues (pp. 364–374) confirmed
previous observations; for example, lower gestational age and lower birth weight
z-scores were associated with a greater risk of developing BPD.
•One particularly striking finding, however, was that maternal smoking during
pregnancy was not only associated with a twofold increase in the odds of having a
child with BPD but was also associated with a twofold increase in late respiratory
disease.
•The authors provide an excellent discussion of potential biological mechanisms that
may result in maternal smoking altering in utero lung development.
•However, we would add that antenatal risk factors may be influenced by postnatal
events and/or associations, such as environment, degree of stimulation,
socioeconomic status, and other currently unknown variables.

Vascular Endothelial Mitochondrial Function Predicts
Death or Pulmonary Outcomes in Preterm Infants.
Kandasamy J, Am J Respir Crit Care Med. 2017;196(8):1040-1049.
RATIONALE:
Vascular endothelial mitochondrial dysfunction contributes
to the pathogenesis of several oxidant stress-associated disorders.
Oxidant stress is a major contributor to the pathogenesis of
bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity
that often leads to sequelae in adult survivors.
OBJECTIVES:
This study was conducted to identify whether differences in mitochondrial
bioenergetic function and oxidant generation in human umbilical vein
endothelial cells (HUVECs) obtained from extremely preterm infants were
associated with risk for BPD or death before 36 weeks postmenstrual age

bioenergetic function
and oxidant generation in
human umbilical vein
endothelial cells
(HUVECs) obtained
from 69 extremely
preterm infants
Compared with HUVECs from infants who survived
without BPD, HUVECs obtained from infants who
developed BPD or died had:
a lower maximal oxygen consumption rate
(mean ± SEM, 107 ± 8 vs. 235 ± 22 pmol/min/30,000 cells;
P < 0.001),
produced more superoxide after exposure to
hyperoxia
(mean ± SEM, 89,807 ± 16,616 vs. 162,706 ± 25,321 MitoSOX
Red fluorescence units; P < 0.05), and
released more hydrogen peroxide into the
supernatant after hyperoxia exposure
(mean ± SEM, 1,879 ± 278 vs. 842 ± 119 resorufin arbitrary
fluorescence units; P < 0.001).

bioenergetic function
and oxidant generation in
human umbilical vein
endothelial cells
(HUVECs) obtained
from 69 extremely
preterm infants
CONCLUSIONS:
Our results indicating that endothelial cells
of premature infants who later develop BPD
or die have
impaired mitochondrial bioenergetic
capacity and produce more oxidants at
birth suggest that the vascular endothelial
mitochondrial dysfunction seen at birth
in these infants persists through their
postnatal life and contributes to adverse
pulmonary outcomes and increased early
mortality.

Prevention possibilities
Bronchopulmonary
Dysplasia

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.

Diagnosis
Bronchopulmonary
Dysplasia

treatment
Bronchopulmonary
Dysplasia

Long-Term Effects of Inhaled Budesonide
for Bronchopulmonary Dysplasia.
Bassler D, N Engl J Med. 2018;378(2):148-157.
•Bronchopulmonary dysplasia (BPD) is associated with higher mortality rates,
and among survivors it confers a predisposition to chronic respiratory and
cardiovascular impairment, growth failure, and neurodevelopmental delay.
•Late (> 7 days) postnatal corticosteroids or early (< 8 days) postnatal
systemic glucocorticoids are effective for the prevention of BPD
but can increase the risk of neurodevelopmental impairment.
•Many preterm infants receive inhaled glucocorticoids for the prevention or
treatment of bronchopulmonary dysplasia during routine clinical care.

863 infants (gestational age,
23 weeks 0 days to 27 weeks
6 days) to receive early
(within 24 hours after birth)
inhaled budesonide or placebo.
neurodevelopmental disability
among survivors,
(cerebral palsy, cognitive delay,
deafness, or blindness
at a corrected age
of 18 to 22 months.
The dose of budesonide was 2 puffs
(200 μg per puff) administered every
12 hours in the first 14 days of life
and 1 puff administered every
12 hours from day 15 until the infants
no longer required supplemental
oxygen and positive-pressure support
or until they reached a postmenstrual
age of 32 weeks, regardless
of ventilatory status.

among survivors,
at a corrected age
of 18 to 22 months.
% infants with
neurodevelopmental disability
60 –
50 –
40 –
30 –
20 –
10 –
0
48.1%
budesonide placebo
51.4%
ns

among survivors,
at a corrected age
of 18 to 22 months.
% infants death
60 –
50 –
40 –
30 –
20 –
10 –
0
19.9%
budesonide placebo
14.5%
P=0.04
relative
risk,
1.37

•Most infants had died in the first weeks of life; thus, the difference in
mortality observed at a corrected age of 18 to 22 months largely reflected
the differences in mortality before hospital discharge.
•Respiratory infections were suggested as a potential explanation for any
excess in mortality in the glucocorticoid group, but a post hoc analysis of our
data did not support this hypothesis.
•In summary, we found no effect of budesonide on the risk of
neurodevelopmental disability among surviving extremely preterm infants
at 18 to 22 months of age.
•However, the mortality rate was higher in the budesonide group for
unexplained reasons.

Two-Year Follow-Up Outcomes of Premature Infants
Enrolled in the Phase I Trial of Mesenchymal Stem Cells
Transplantation for Bronchopulmonary Dysplasia
So Yoon Ahn, J Pediatr. 2017;185:49-54
 Serious adverse events, somatic
growth, and respiratory and
neurodevelopmental outcomes
at visit 1 (4-6 months of CA),
visit 2 (8-12 months of CA),
and visit 3 (18-24 months of CA)
in a prospective follow-up study
up to 2 years' corrected age
(CA) of infants who received
human umbelical cord bloody
MSCs (MSC group).
• 1 of 9 infants in the MSC
group died of
Enterobacter cloacae
sepsis at 6 months of CA,
the remaining 8 infants
survived without any
transplantation-related
adverse outcomes,
including tumorigenicity.

• No infant in the MSC
group was discharged
with home supplemental
oxygen compared with
22% in the comparison
group.
MSCs (MSC group).

• No infant in the MSC
group was discharged
with home supplemental
oxygen compared with
22% in the comparison
group.
MSCs (MSC group).
Intratracheal
transplantation of
MSCs in preterm
infants appears
to be safe.

 Recently, we and others demonstrated that the exogenous
transplantation of mesenchymal stem cells (MSCs) significantly
attenuate hyperoxic lung injury in newborn animal models.
 Based on this promising experimental evidence, a phase I clinical trial
was conducted, which revealed that single intratracheal transplantation
of allogenic (from a donor) MSCs in very preterm infants at high risk for
developing BPD was safe, feasible, and potentially efficacious in
attenuating BPD compared with that in a historical control group
matched for gestational age, birth weight, and respiratory severity

Bronchopulmonary Dysplasia: Where Have All the Stem
Cells Gone?: Origin and (Potential) Function of Resident
Lung Stem Cells. Möbius MA, Chest. 2017 Nov;152(5):1043-1052.
•BPD is postulated to be a misdirection of many functions in the developing
lung, including growth factor signalling and matrix as well as cellular
composition, resulting in impaired alveolar and lung vascular growth.
•Despite improvements in understanding the mechanisms that regulate
normal lung development, BPD remains without therapies.
•Insights into stem cell biology have identified
the repair potential of stem cells.
•Promising preclinical studies demonstrated the lung protective effects of
stem cell-based therapies in animal models mimicking BPD,
leading to early-phase clinical trials.

Symmetric and
asymmetric division
of stem cells.
Highpotent,
low-differentiated
stem cells give raise
to a quiescent stem
cell (blue) to self-
renew as well as to
an active, less
potent, highly
differentiated
organ-specific cell
(red) which
contributes to organ
growth,
maintenance, or
repair.

Stem Cell Terminology
The distinction between unipotent lung stem cells and lung progenitor cells remains blurred and subject
to further research. Some unipotent cells can become multipotent in response to an injury. Conversely,
obligatory unipotent progenitors lose their proliferation and differentiation potential once committed.

Concepts of endogenous (lung) stem cell impairment
(A)Stem cell dedifferentiation and onset of malignancies.
Over cycles of self renewal, endogenous stem cells (blue) acquire genetic
aberrations, which lead to more or less aberrant daughter cells (red) and
eventually to dedifferentiation of the stem cell into a cancer stem cell,
giving rise to a malignant cell population (black).
(B) Functional stem cell impairment.
Stem cells (blue) giving raise to physiologic amounts of differentiated cells
(red). Following damage (gray), stem cells yield either too few or too many
differentiated cells, leading to, for example, COPD or bronchiolitis obliterans
syndrome (BOS), respectively.

Concepts of exogenous and endogenous stem cell function
in normal and impaired lung development.
Normal function of the
lung’s endogenous stem
cell pool is required to
facilitate normal lung
growth, alveolarization,
and vascularization.

Impairment of the
endogenous cell
populations by
premature birth
and its consequences
(gray cells, upper right
scheme) leads to
impaired lung
development and
bronchopulmonary
dysplasia (BPD).

Exogenous stem or
progenitor cells from
mesenchymal,
endothelial, and
epithelial lineages
introduced into this
environment provide
various small
molecules, cytokines,
exosomes, and even
whole organelles,
including mitochondria
(left scheme).

This may protect
and/or rescue the
function of the lung-
resident cells, allowing
a normal transition
toward alveolarization
and vascularization of
the developing lung
with healthy
endogenous stem and
progenitor cells (blue
cells/red cells, right
lower scheme).

Can We Prevent Bronchopulmonary Dysplasia?
JL Aschner, J Pediatr. 2017;189:26-30
Windows of opportunities for prevention of BPD

• Antenatal and postnatal factors can predispose
the structurally and biochemically immature lung
to the development of BPD.
• BPD most commonly occurs in extremely low gestational age newborns born
during the canalicular or early saccular phases of lung development.
• However, not all extremely premature infants develop BPD, suggesting BPD
can be prevented.
• Figure identifies potential windows of opportunity for primary prevention
of BPD.
• IUGR intrauterine growth retardation.
Reprinted with permission of the American Thoracic Society. Copyright © 2017 American Thoracic
Society. McEvoy CT, Jain L, Schmidt B, Abman S, Bancalari E, Aschner JL. NHLBI Workshop on the
primary prevention of chronic lung disease: Bronchopulmonary dysplasia. Ann Am Thorac Soc 2014;
11: S146-S153.

Pharmacologic Interventions
• A meta-analysis of 10 trials of early inhaled steroids in infants <1500 g
showed decreased BPD among survivors (RR 0.76).
• Infants receiving surfactant with budesonide had a lower incidence of BPD
(42% vs 66%; RR 0.58; CI 0.44-0.77; P < 0.001) without evidence of
neurologic side effects.
• A recent meta-analysis showed a small reduction in incidence of BPD with
vitamin A supplementation as compared with placebo (RR 0.87).

Pharmacologic Interventions
• Clara cell protein (CC10) has strong anti-inflammatory and
immunomodulatory properties.
• A pilot study of recombinant human CC10 in preterm infants showed
significant anti-inflammatory effects in the lung and was well tolerated.
• Stem cell therapy is a promising intervention for BPD prevention.

And asthma
Bronchopulmonary
Dysplasia

Differences and similarities between bronchopulmonary
dysplasia and asthma in schoolchildren
B Nordlund, Pediatr Pulmonol 2017;52:1179-1186
Lung function measures
• (FEV1% 77 vs 84,
• FEV1/FVC% 85 vs 91,
• FEF50% 61 vs 80) and
• carbon monoxide diffusion
capacity (DLCO%, 81 vs 88)
were all reduced in children with
BPD compared to asthma
(P values <0.042).
 30 schoolchildren with
bronchopulmonary dysplasia
(BPD) (10.4 years/born
at 26.6 weeks’ gestation)
and 30 age- and sex-
matched children with
asthma and sensitized
to airborne allergens
(IgE >0.35 kUA/L).

Lung function measures
• (FEV1% 77 vs 84,
• FEV1/FVC% 85 vs 91,
• FEF50% 61 vs 80) and
• carbon monoxide diffusion
capacity (DLCO%, 81 vs 88)
were all reduced in children with
BPD compared to asthma
(P values <0.042).
 30 schoolchildren with
(BPD) (10.4 years/born
at 26.6 weeks’ gestation)
and 30 age- and sex-
matched children with
asthma and sensitized
to airborne allergens
(IgE >0.35 kUA/L).
FENO values were also
significantly lower in
children with BPD
(12 vs 23, P = 0.019).
The proportion of positive
methacholine tests
(74% vs 93%, P = 0.14) was
comparable between BPD
and asthma.

• The hallmarks of BPD in ex-preterm schoolchildren were reduced lung
function.
• BPD was different to atopic asthma with regard to greater impairments
in airflow and diffusion capacity, and with less evidence of ongoing airway
inflammation.
• The development of BPD is characterized by airflow limitation, although
inflammation later in life seems less apparent.
• Low dynamic flow values such as FEV1, along with low FEV1/FVC ratios,
raise concerns about lung growth and long-term respiratory health,
especially as BPD is known to increase the risk of later chronic obstructive
pulmonary disease.

• Our study also found that DLCO% was reduced in children with BPD
compared to asthma.
• Carbon monoxide transfer capacity is determined both by lung flow and the
surface area available for diffusion, affected by pulmonary capillary blood
volume and the thickness of the alveolar capillary membrane.
• A complication of BPD is impaired
alveolar development with fewer and
larger alveoli, which reduces the surface
area and diffusion capacity of the aveoli.

Increasing airway obstruction from 8 to 18 years
in extremely preterm/low-birthweight survivors born
in the surfactant era. Doyle LW, Thorax 2017;72:712–719
Background
• The evolution of airway obstruction into late adolescence
of extremely preterm
(gestational age <28 weeks) or
extremely low-birthweight
(birth weight <1000 g) survivors
in the era after surfactant
was introduced is unclear.
Objective
• To compare changes in spirometry from 8 to 18 years of age of a
geographical cohort of preterm survivors with normal birth weight
controls, and to determine higher risk groups within the preterm cohort.

 297 extremely preterm/
low-birthweight survivors
born in 1991–1992.
 Spirometry at
8 and 18 years of age.
 260 normal birth weight
controls.
• The preterm group had
substantial impairments
in airflow at both ages
compared with controls.
• The preterm group had
a greater increase in small
airway obstruction between
8 and 18 years
compared with controls.

born in 1991–1992.
 Spirometry at
controls.
• Within the preterm group,
those who had bronchopulmonary
dysplasia in the newborn period
and
• those who were smokers at
18 years had airway obstruction
that increased over time
compared with those who did not.

born in 1991–1992.
 Spirometry at
controls.
• Within the preterm group,
those who had bronchopulmonary
dysplasia in the newborn period
and
• those who were smokers at
18 years had airway obstruction
that increased over time
compared with those who did not.
At-risk preterm
participants include
those who had
bronchopulmonary
dysplasia, and smokers
at 18 years.

Preterm respiratory disease in the modern era:
the value of cohort studies
Montgomery GS, Thorax 2017;72:680–681 Editorial
• In this issue of Thorax, two Australian research teams delineate
phenotypic features of the respiratory system in school age children
and adolescents born prematurely.
• Both preterm populations consisted of children with and without the
diagnosis of BPD.
• Unlike the two reports in this issue of Thorax, few prior studies evaluated
participants born in the so-called postsurfactant or ‘new BPD’ era.
• The most significant finding from both studies is the similar degree of
obstructive lung disease in children born prematurely when compared with
matched control participants, with more significant reduction seen in
individuals meeting the diagnosis of BPD based on the NHLBI definition.

• However, even those without BPD had reductions in airflow, highlighting
the often silent airway obstruction that occurs in this preterm population.
• These findings highlight that the trajectory of lung function impairment
in preterm children may be determined prior to discharge from the
neonatal intensive care unit.
• Our current therapeutic approach to these preterm infants remains
insufficient to meaningfully impact the severity and progression of lung
disease later in childhood, despite improvements in overall mortality.
• The severity of lung function abnormalities in former preterm school age
children are not static, but rather progressive in nature.

• FVC continues to increase while these spirometric measures of airway
obstruction diminish.
• The authors state that
dysanaptic pulmonary
development (slower growth
of the airway compared
to lung parenchyma)
may be a possible
explanation for this
observation.

Long-term consequences
Bronchopulmonary
Dysplasia

Altered lung structure and function in mid-childhood
survivors of very preterm birth
Simpson SJ, Thorax 2017;72:702–711
Rationale
• Survivors of preterm birth are at risk of chronic and lifelong pulmonary
disease. Follow-up data describing lung structure and function are scarce
in children born preterm during the surfactant era.
Objectives
• To obtain comprehensive data on lung structure and function
in mid-childhood from survivors of preterm birth.
• We aimed to explore relationships between lung structure, lung function
and respiratory morbidity as well as early life contributors
to poorer childhood respiratory outcomes.

 Lung function at 9–11 years
in children born at term
(58 controls) and at
≤32 weeks gestation.
 163 preterm children
(99 with bronchopulmonary
dysplasia).
FEV1 was improved:
• by 0.10 z-scores for every
additional week of gestation
(p=0.008) and
• by 0.34 z-scores per z-score
increase in birth weight
(p=0.002).

Lung function expressed as z-scores, plotted against neonatal factors for children born
preterm with a neonatal classification of bronchopulmonary dysplasia (BPD) (black)
and those without BPD (grey)

• Structural lung changes were
present in 92% of preterm
children,
• with total CT score
decreased by 0.64 (p<0.001)
for each additional week
of gestation.
 Lung function at 9–11 years
in children born at term
(58 controls) and at
≤32 weeks gestation.
 163 preterm children
(99 with bronchopulmonary
dysplasia).

Chest CT abnormalities in contemporary bronchopulomary
dysplasia.
• Images A and B are from an 11-year-old male (27 wks gestation)
highlighting triangular subpleural (red) and linear (blue)
opacities, areas of hypoattenuation/mosaic perfusion (yellow)
and emphysema (green).
• Image C is from an 11-year-old male (25 weeks gestation)
and highlights bronchial wall thickening (orange).

•Neonatal factors influencing
lung structure in preterm
children at 9–11 years.
•Total CT score (max 50)
and extent score for linear
and triangular subpleural
opacities (max 6) are plotted
against gestational age, and
days of mechanical
ventilation for children born
preterm with a neonatal
classification of
(BPD) (black) and those
without BPD (grey).

Relationships between lung function and lung structure in preterm children. Lung function,
expressed as z-scores, is plotted against chest CT outcomes for preterm children with
(black) and without (grey) bronchopulmonary dysplasia.

KCO score of Gas exchange (DLCO)

Abnormal lung structure in mid-childhood resulting from preterm birth
in the contemporary era has important functional consequences.
KCO score of Gas exchange (DLCO)

• We show significant airway obstruction in children born very preterm
with reductions in FEV1, FEF25–75 and FEV1/FVC, and further reductions
in children with BPD.
• Findings of reduced forced expiratory flows and
volumes with stable FVC are suggestive of reduced
airway calibre in this population and likely results
from chronic airway inflammation,
airway remodelling and/or
reduced parenchymal tethering.

• Almost half of the very preterm children in this study
had evidence of bronchial wall thickening on chest CT
that we speculate reflects postinflammatory changes
and/or ongoing airway inflammation.
• Children with bronchial wall thickening had significantly worse obstructive
lung disease and more respiratory symptoms than their peers.
• Additionally, the small airways may be particularly at risk from oxygen
toxicity during the neonatal period, with reduced midexpiratory flows
evident in those with longer exposures to oxygen.

Sleep disordered breathing in bronchopulmonary dysplasia
LE Ortiz, Pediatr Pulmonol 2017;52:1583-1591
 140 retrospective study
of overnight polysomnogram
data of 140 children enrolled
in our bronchopulmonary
dysplasia (BPD) registry
between 2008 and 2015.
• The mean respiratory
disturbance index (RDI) was
elevated at 9.9 events/hr.
• The mean obstructive apnea-
hypopnea index (OAHI) was
6.5 events/hr.
• The mean central event rate
of 3.0 (3.7) events/hr.

6.5 events/hr.
RDI had decreased
by 22% or 1.5
events/hour with
each year of age
(P = 0.005).

6.5 events/hr.
Subjects with more
severe respiratory
disease had 38% more
central events
(P = 0.02).

Respiratory Disturbance Index (RDI)
was elevated in a selected BPD population
compared to norms for non-preterm
children.
BPD severity, smoke exposure, and race
may augment the severity of sleep
disordered breathing (SDB).
RDI improved with age but was still
elevated by age 4, suggesting that this
population is at risk for the sequelae
of SDB.

•COPD
• Definition
• Diagnosis
• Pathogenesis

• COPD
• Risk
Factors
Failure to reach
optimal Lung function

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
a population-based prospective
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

• COPD
• Risk
Factors
Lung function decline
with age

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.
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.

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.

Progress in disease progression genetics: dissecting the
genetic origins of lung function decline in COPD
Busch R, Thorax 2017;72:389-390. Editorial
• Lung function is a heritable trait.
• Heritability estimates posit that
approximately 30%–50% of the
phenotypic variation in FEV1
is explained by genetics.
• Longitudinal change in lung function (ΔFEV1, ΔFEV1/FVC) is also heritable.
• Low maximum attained lung function and accelerated
lung function decline are distinct processes that
can exert independent effects on the risk
for chronic airflow obstruction.

Progress in disease progression genetics: dissecting the
genetic origins of lung function decline in COPD
Busch R, Thorax 2017;72:389-390. Editorial
• Lung function is a heritable trait.
• Heritability estimates posit that
approximately 30%–50% of the
phenotypic variation in FEV1
is explained by genetics.
• Longitudinal change in lung function (ΔFEV1, ΔFEV1/FVC) is also heritable.
• Low maximum attained lung function and accelerated
lung function decline are distinct processes that
can exert independent effects on the risk
for chronic airflow obstruction.
Therefore, it would not be surprising if different genetic determinants
influenced cross-sectional and longitudinal lung function change.

Genetic variants affecting cross-sectional lung function
in adults show little or no effect on longitudinal lung
function decline. John C, Thorax 2017;72:400-408
Genome-wide data from
4167 individuals.
Spirometry
(12 695 observations
across 8 time points).
• The 26 genome regions previously
associated with cross-sectional
lung function jointly showed
a strong effect on baseline lung
function (p=4.44×10−16 for FEV1/FVC)
• but no effect on longitudinal
decline (p=0.160 for FEV1/FVC).

Genetic variants affecting cross-sectional lung function
in adults show little or no effect on longitudinal lung
function decline. John C, Thorax 2017;72:400-408
Genome-wide data from
4167 individuals.
Spirometry
(12 695 observations
across 8 time points).
• The 26 genome regions previously
associated with cross-sectional
lung function jointly showed
a strong effect on baseline lung
function (p=4.44×10−16 for FEV1/FVC)
• but no effect on longitudinal
decline (p=0.160 for FEV1/FVC).
These findings emphasise
the continuing public health
importance of focusing on
the key environmental
determinants of lung
function decline,
particularly smoking
and diet.

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

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.

Inhaled resveratrol treatments slow ageing-related
degenerative changes in mouse lung
Navarro S, Thorax 2017;72:451-459
Background
• Lung ageing, a significant risk factor
for chronic human lung diseases such as
COPD and emphysema, is characterised
by airspace enlargement and
decreasing lung function.
• Likewise, in prematurely ageing telomerase null (terc−/−) mice, (a mouse
with accelerated lung function decline), p53 stabilisation within diminishing
numbers of alveolar epithelial type 2 cells (AEC2) accompanies reduced
lung function.

Background
• Resveratrol (RSL) is a plant phytoalexin that
has previously showed efficacy in enhancing
invertebrate longevity and supporting mammalian
muscle metabolism when delivered orally.
• Here, we tested whether inhaled RSL could protect young, terc−/− mice
from accelerated ageing of the lung.

RSL treatments
• delayed the loss of lung
compliance (p<0.05),
• maintained lung structure
(p<0.001) and
• blocked parenchymal cell
DNA damage.
Terc−/− mice (a mouse with
accelerated lung function
decline) aged 2 months
inhaled 1 mg/kg RSL instilled
intratracheally once per
month for 3 months.
One month after the last
inhalation, whole lung
function, structure and
cellular DNA damage and
AEC2 survival.

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