What pulmonology 2 rare diseases

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

• Discinesia ciliare
clinica

Validation of a health-related quality of life instrument
for primary ciliary dyskinesia (QOL-PCD)
Behan L, Thorax 2017;72:832-839
• This analysis led to 9 items
being dropped; the validated
measure now comprises
40 items.
• 2-week test–retest
demonstrated stability
for all scales (intraclass
coefficients 0.73 to 0.96).
 72 adults (mean (range) age:
33 years with PCD;
 mean FEV1% pred. 68%.
 49-item QOL-PCD and generic
QOL measures: Short-Form
36 Health Survey, Sino-Nasal
Outcome Test 20 (SNOT-20)
and St George Respiratory
Questionnaire (SGRQ)-C.
 35 participants repeated QOL-
PCD 10–14 days later to measure
stability or reproducibility
of the measure.

Behan L, Thorax 2017;72:832-839
• Significant correlations
were obtained between
QOL-PCD scores and
age and FEV1.
• Strong relationships were
also found between
QOL-PCD scales lower
respiratory symptoms and
SGRQ-C (r=0.72, p<0.001),
33 years with PCD;
of the measure.

Behan L, Thorax 2017;72:832-839
• Significant correlations
were obtained between
QOL-PCD scores and
age and FEV1.
• Strong relationships were
also found between
QOL-PCD scales lower
respiratory symptoms and
SGRQ-C (r=0.72, p<0.001),
33 years with PCD;
of the measure.
QOL-PCD has
demonstrated good
internal consistency,
test–retest reliability,
convergent and
divergent validity.

diagnosi

genetica

prognosis

treatment

Introduction
• Flexible bronchoscopy (FB) is the current
gold standard for diagnosing
tracheobronchomalacia.
• However, it is not always feasible
and virtual bronchoscopy (VB),
acquired from chest multi-detector CT (MDCT) scan is an alternative
diagnostic tool.
• We determined the sensitivity, specificity, and positive and negative
predictive values of VB compared to FB in diagnosing
tracheobronchomalacia.
A comparison of virtual bronchoscopy versus flexible
bronchoscopy in the diagnosis of tracheobronchomalacia
in children. S Choo Su, Pediatr Pulmonol 2017;52:480-486

Detected at FB
% children with
tracheomalacia
70%
(37/53)
 53 children
(median age = 2.5 yrs)
evaluated for airway
abnormalities.
 Flexible bronchoscopy
(FB) and chest multi-
detector CT (MDCT)
were undertaken within
30-min to 7-days
of each other.
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00 –

Detected at FB
% children with
tracheomalacia
70%
(37/53)
 53 children
abnormalities.
detector CT (MDCT)
30-min to 7-days
of each other.
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00 –
Of these, Virtual
Bronchoscopy detected
tracheomalacia in
20 children, with a
sensitivity of 54.1%,
specificity = 87.5%

Detected at FB
% children with
tracheomalacia
70%
(37/53)
 53 children
abnormalities.
detector CT (MDCT)
30-min to 7-days
of each other.
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00 –
Of these, Virtual
Bronchoscopy detected
tracheomalacia in
20 children, with a
sensitivity of 54.1%,
specificity = 87.5%
VB cannot replace
FB as the gold
standard for detecting
tracheobronchomalacia
in children.

Mild tracheomalacia at the junction between middle
and lower third of trachea detected in both FB and VB
during inspiration during expiration virtual bronchoscopy (VB)

FB revealed severe left upper lobe bronchomalacia (A), which was
categorized as moderate left upper lobe bronchomalacia on VB (B)

Eight years 11 months old girl with history of repaired tracheo-
esophageal fistula and esophageal atresia with chronic wet cough
Flexible bronchoscopy shows
the presence of a diverticulum
and pig's bronchus
Virtual bronchoscopic view
of the carina with similar
findings as FB

Detected at FB
% children with
bronchomalacia
79%
(45/53)
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
 53 children
abnormalities.
detector CT (MDCT)
30-min to 7-days
of each other.

Detected at FB
% children with
bronchomalacia
79%
(45/53)
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
 53 children
abnormalities.
detector CT (MDCT)
30-min to 7-days
of each other.
VB had a
sensitivity = 45.2%,
specificity = 95.5%
compared to FB
in detecting
bronchomalacia

Detected at FB
% children with
bronchomalacia
79%
(45/53)
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
00
 53 children
abnormalities.
 FB and MDCT were
undertaken within
30-min to 7-days of
each other.

Summary of Data From Existing Studies Comparing Virtual Bronchoscopy (VB) to Flexible (FB)
or Rigid Bronchoscopy (RB) in Children
Author (year)
Diagnostic modalities
compared
Diagnosis
Sensitivity (%)
(true +)
Specificity (%)
(true -)
Our current study (2016) VB versus FB
Tracheomalacia 54.1 87.5
Bronchomalacia 45.2 95.5
Abd-ElGawad et al. (2014) VB versus RB Tracheobronchial foreign body 94.4 75
Lee et al. (2013) 3D CT versus FB
Tracheomalacia 37.5 100
Bronchomalacia 75 90.6
Bhat et al. (2010) VB versus RB Tracheobronchial foreign body 92.3 85.7
Heyer et al. (2007) VB versus FB
Tracheobronchial anomalies
(both fixed and dynamic
anomalies)
86.8 85.7
Haliloglu et al. (2004) VB versus RB Tracheobronchial foreign body 100 100

Dynamic expiratory CT: An effective non-invasive
diagnostic exam for fragile children with suspected
tracheo-bronchomalacia
N Ullmann, Pediatr Pulmonol 2018;53:73-80
Background
• Tracheobronchomalacia, defined as variable collapse
of the airways, has been recognized as an important
cause of respiratory morbidity but still widely
underdiagnosed.
• Bronchoscopy is still considered as the gold standard, but
numerous limitations are known, especially for fragile sick children.
• Moreover, information on parenchymal lung disease cannot be described.
• There is a real need for a reliable, non-invasive test to help detection
of airway and parenchymal malformations in children,
specifically when bronchoscopy cannot be performed.

 34 paediatric patients
underwent cine
multidector CT for
ongoing respiratory
symptoms.
Bronchomalacia
alone
Trachea
broncomalacia
% children with
53%
29%
60 –
50 –
40 –
30 –
20 –
10 –
00

 34 paediatric patients
underwent cine
multidector CT for
ongoing respiratory
symptoms.
Bronchomalacia
alone
Trachea
broncomalacia
% children with
53%
29%
60 –
50 –
40 –
30 –
20 –
10 –
00
Moreover, CT allowed
identification of
parenchymal disease
in 10 patients.

• The majority of patients (85%) underwent also bronchoscopy
for clinical decision.
• The agreement between CT and bronchoscopy was explored.
The two examinations did not agree only in two cases.
• CT dynamic showed an excellent
sensitivity of 100% (81.47-100 %),
a great specificity of 82% (48.22-97.72 %),
NPV 100%, and
PPV 90% (72-96.9 %).

Conclusion
• Dynamic CT results an effective and highly sensitive diagnostic exam
for children with tracheo-bronchomalacia.
• CT is especially indicated for those small and fragile patients
that cannot undergo an invasive investigation.
• Moreover, CT allows a detailed evaluation both of the airways
and the lungs which is useful for the clinical management.

The natural history of prenatally diagnosed congenital
cystic lung lesions: long-term follow-up of 119 cases
J Cook, Arch Dis Child. 2017;102:798-803
What is already known on this topic?
• Incidental identification of
cystic lung lesions on prenatal scans
is increasingly common.
• A paucity of evidence regarding the natural history of the lesions
has contributed to divergent management strategies.
• The majority of surgical centres worldwide
resect all identified lesions.

 Long-term clinical course of
119 children diagnosed with
congenital pulmonary airway
malformations (CPAMs)
treated at Great Ormond
Street Hospital (GOSH).
 Patients followed up
for at least 5 years.
43%
(51/119)
50 –
40 –
30 –
20 –
10 –
00
% children
managed surgically

• 8 (6.7%) as an emergency during the neonatal period,
• 6 (5.1%) electively due to concerning features on CT scan,
• 20 (17%) following medical advice,
• 1 (0.8%) following a severe respiratory infection,
• 5 (4.2%) the indication was unclear.
• The indication in 11 (9.2%) was recurrent respiratory infection and
median age at surgery was 1.6 years (range 0.4 to 4.6 years).
children managed surgically

• No cases of malignancy were identified on histological examination
of resected lesions.
• 68 (57%) patients were managed conservatively for a median period
of 9.9 years (range 5.2 years to 18 years), of these:
o 7 (10%) were discharged, 1 was followed-up elsewhere (1.5%) and 8 (11%)
were lost to follow-up.
o In 4 patients (5.9%), the lesion resolved spontaneously.
o 52 (76%) continue to be followed-up and remain asymptomatic.

• No cases of malignancy were identified on histological examination
of resected lesions.
• 68 (57%) patients were managed conservatively for a median period
of 9.9 years (range 5.2 years to 18 years), of these:
o 7 (10%) were discharged, 1 was followed-up elsewhere (1.5%) and 8 (11%)
were lost to follow-up.
o In 4 patients (5.9%), the lesion resolved spontaneously.
o 52 (76%) continue to be followed-up and remain asymptomatic.
Conservative management is a reasonable
option in selected cases.

Surgically managed cases
Total, n (% of all cases) 51 (43)
Surgery in neonatal period, n (% of all cases) 8 (6.7)
Median age at surgery, days (range) 6 (2–20)
Surgery beyond neonatal period, n (% of all cases) 43 (36)
Median age at surgery, years (range) 1.2 (0.2–5.1)
Indication for surgery beyond neonatal period, n (% of all cases)
Concerning features on initial CT 4 (3.4)
Concerning features on surveillance CT 2 (1.7)
Reported recurrent respiratory infections 11 (9.2)
Single respiratory infection 1 (0.8)
Elective (medical advice) 20 (17)
Unclear 5 (4.2)

Surgically managed cases
Histological classification, n (% of surgical cases)
CPAM (type 1) 23 (45)
CPAM (type 2) 09 (18)
CPAM (not typed) 04 (7.8)
PS 7 (13)
Hybrid lesion 1 (2.0)
Bronchial atresia 3 (5.9)
Lobar emphysema 1 (2.0)
Bronchogenic cyst 2 (3.9)
Tracheal diverticulum 1 (2.0)
Histological evidence of malignancy, n (% of surgical cases) 0 (0)
Histological evidence of inflammation, n (% of surgical cases)
None 27 (53)
Acute 20 (39)
Chronic 4 (7.8)
CPAM, congenital pulmonary airway malformation; PS, pulmonary sequestration.

Great Ormond Street Hospital (GOSH) approach to assessment and follow-up of
asymptomatic CPAM/PS during the paediatric period and features that may
trigger intervention

* DICER1 mutation analysis
is not offered as a routine
screening test

CLM, congenital lung malformation; CPAM, congenital pulmonary airway malformations; PS, pulmonary sequestration

Great Ormond Street Hospital (GOSH)
approach to assessment and follow-up
of asymptomatic CPAM/PS during the
paediatric period and features
that may trigger intervention

What this study adds?
• This is the first long-term follow-up of asymptomatic,
conservatively managed lesions (median 9.9 years).
• The risk of recurrent infection is less than 10%
and decreases following the second year.
• No cases of malignancy were identified.

• With the increasing rate of prenatal diagnosis, it has become clear that
the vast majority of congenital pulmonary malformations (CPMs) are
actually asymptomatic.
• The paper by Cook et al in this issue confirm:
o First, severe neonatal complications are rare.
o Second, postnatal disappearance of the CPM occurs only in rare cases.
o Finally, infection is not the predominant indication for surgery.
Postnatal management of asymptomatic
congenital pulmonary malformations:
moving towards evidence-based decisions. Editorial
C Delacourt, Arch Dis Child. 2017; Sep;102(9):789-790

• Do all CPMs follow the same natural
course and how should
we classify them?
• Clinically, it is tempting to assume
that the rate of long-term complications may differ between small CPM
limited to a pulmonary segment with hyperlucent aspect and large
macrocystic malformations.

• How should we deal with the issue of the potential malignant
transformation of CPM?
• But would parents be willing to accept an undefined risk of early cancer
for their child, even if this risk is considered to be very low?
• If we can confirm, in large series, that KRAS mutations, associating
bronchioloalveolar carcinoma and cystic CPM, are actually found only
in mucinous islets of large macrocystic malformations CPMs, this
would facilitate a move towards consensual guidelines for surgical
removal or conservative management, depending on imaging results.
• We must avoid switching abruptly from a dogma of ‘all surgery’
to the diametrically opposite dogma of ‘no surgery’.

Exercise capacity is not decreased in children who have
undergone lung resection early in life for congenital thoracic
malformations compared to healthy age-matched children
A Dunn, Pediatr Pulmonol 2017;52:1340-1348
• Congenital Pulmonary Airway Malformations (CPAM) are due to abnormal
embryological lung formation that takes place throughout the different
stages of fetal development, with a reported incidence of one case per
10 000 to 35 000 live births.
• CPAMs that cause any symptoms, are large, or suspicious of a carcinoma or
pleuropulmonary blastoma are surgically removed in the first year of life.
• There is some controversy regarding the treatment of asymptomatic
children born with smaller lesions, though strong evidence suggests
elective resection surgery should be performed.

• If left untreated, there is a risk for subsequent complications, such as
sudden enlargement of cysts, pneumothorax, infection, or malignancy
occurring later in life.
• Compensatory lung growth has been reported to occur in children who
have undergone lung resections due to CPAM, however it is uncertain
whether this resembles normal lung growth.

Purpose
• The purpose of this study was to compare
• (i) the exercise capacity and
• (ii) lung function prior to and immediately post cardiopulmonary exercise
tests (CPET)
of children who underwent early life lung resection for Congenital
Pulmonary Airway Malformations (CPAM) to healthy control children.

 8 children with CPAM and
8 control children.
 Cardiopulmonary exercise
tests (CPET) on a cycle
ergometer, during which
maximal oxygen consumption
(VO2max) and heart rate were
measured.
• No significant between group
differences in
pre CPET lung function or
maximal exercise capacity
(VO2max).



8 control children.
measured.
• No significant between group
differences in
pre CPET lung function or
maximal exercise capacity
(VO2max).


Early life lung
resection for CPAM
does not appear
to have negative
implications for
exercise capacity
later in childhood.

• Post CPET, FEV1 was
significantly lower in the CPAM
group, with 2 participants
diagnosed subsequently with
exercise induced bronchospasm
based on post-CPET spirometry
and follow-up clinical
investigations.
8 control children.
measured.

• Post CPET, FEV1 was
significantly lower in the CPAM
group, with 2 participants
diagnosed subsequently with
exercise induced bronchospasm
based on post-CPET spirometry
and follow-up clinical
investigations.
8 control children.
measured.
Clinicians should be
aware that dyspnoea
following exercise may
be due to asthma
rather than residual
effects of CPAM
in these children

Congenital Diaphragmatic Hernia and Growth to 12 Years
Leeuwen L, Pediatrics 2017;140:e20163659
Objectives
• Growth problems are reported in patients
with congenital diaphragmatic hernia during
the first years of life.
• However, it is unknown if poor growth
persists during childhood.
• We therefore evaluated growth of patients
longitudinally until 12 years of age.

 172 patients
(43 treated with
extracorporeal membrane
oxygenation [ECMO]).
 Z scores of height-for-age
(HFA), weight-for-height,
and distance-to-target
height (DTH)
at 6 months of age and
at 1, 2, 5, 8, and 12 years
of age.
At 12 years of age, the mean
HFA z score was still less
than the norm in both groups:
• ECMO (-0.67) vs
• non-ECMO (-0.49; P<0.01).

height-for-age (HFA) in patients with CDH
treated with
and without ECMO until 12 years of age
The data indicate a significant difference between ECMO and non-ECMO patients
Non-ECMO
ECMO
 172 patients
(43 treated with
height (DTH)
at 1, 2, 5, 8, and 12 years
of age.

height-for-age (HFA) in patients with CDH
treated with
and without ECMO until 12 years of age
The data indicate a significant difference between ECMO and non-ECMO patients
Non-ECMO
ECMO
 172 patients
(43 treated with
height (DTH)
at 1, 2, 5, 8, and 12 years
of age.
Adjusting for target
height improved the
mean height z scores
but did not bring them
to normal range.

 172 patients
(43 treated with
height (DTH)
at 1, 2, 5, 8, and 12 years
of age.
• Poor linear growth persisted
at 12 years of age.
• The pattern of early deterioration
of weight gain followed by a decline
in linear growth is suggestive of
inadequate nutrition during infancy.
• Therefore, nutritional assessment
and intervention should be started
early and should be continued
during childhood.

Flowchart for dietary consultation and intervention in patients with CDH
Use HFA if DTH is not available. Modified nutritional risk screening tool STRONGkids for patients with CDH (see Table 3)

Modified Nutritional Risk Screening Tool STRONGkids for Patients With CDH
Score if Yes
1. Subjective clinical assessment 1 point
Is the patient in a poor nutritional status judged by subjective
clinical assessment (diminished subcutaneous fat and/or muscle mass and/or hollow face)?
2. High-risk disease state 2 points
Are one of the following items present?
ECMO treatment?
Chronic lung disease?
Recurrent (pulmonary) infections requiring antibiotics or hospitalization?
Recent major surgery?
High-risk CDH judged by clinical assessment of physician?
3. Nutritional intake and losses 1 point
Are one of the following items present?
Excessive diarrhea (≥5 times per day) and/or vomiting (>3 times per day) the last few days?
Preexisting dietetically advised nutritional intervention (for example calorie-enriched feeds or tube feeding)?
Obvious reduced food intake during the last few days?
Inability to consume adequate intake (for example, because of GERD)?
4. Weight loss or poor weight gain? 1 point
Is there weight loss or no weight gain (infants <1 y) during the last weeks/months?

Objectives:
• Growth problems are reported in patients with
congenital diaphragmatic hernia during the first years of life.
• However, it is unknown if poor growth persists during childhood.
We therefore evaluated growth of patients longitudinally until 12 years
of age.
• Poor linear growth persisted at 12 years of age.
• The pattern of early deterioration of weight gain followed by a decline in
linear growth is suggestive of inadequate nutrition during infancy.
• Therefore, nutritional assessment and intervention should be started early
and should be continued during childhood.

We assume that the decline in
growth during infancy might be
explained by inadequate nutritional
intake to meet energy needs, and
this possible cause should be
explored as an initial step.
In patients with CDH, feeding
difficulties and increased resting
and active energy expenditure due
to respiratory morbidity and work
of breathing contribute to impaired
growth.

Impact of Objective Echocardiographic Criteria for
Timing of Congenital Diaphragmatic Hernia Repair
S Deeney, J Pediatr. 2018;192:99-104
• Congenital diaphragmatic hernia is a severe birth
defect characterized by herniation of abdominal
contents into the thorax caused by a defect
in the diaphragm.
• It occurs in 2 in 10 000 births and presents
with a wide range of severity.
• Historically, congenital diaphragmatic hernia was
considered a surgical emergency, until a study
in the late 1980s revealed that repair after
a period of stabilization of 1-5 days did not
worsen outcomes.

• The severity of pulmonary hypertension in congenital diaphragmatic hernia
is a major determinant of patient survival.
• Pulmonary hypertension can be estimated
noninvasively using Doppler echocardiogram,
with a composite of tricuspid regurgitant jet,
interventricular septal configuration,
and ductal and atrial shunt.

• Clinical experience has led to the observation that congenital
diaphragmatic hernia repair during the phase when pulmonary hypertension
is severe and the pulmonary vascular bed most reactive may precipitate
an acute postoperative decompensation.
• Acute changes in pulmonary compliance following congenital diaphragmatic
hernia repair may also contribute to cardiopulmonary interactions during
acute postoperative decompensation.
• Acute pulmonary decompensation and pulmonary hypertensive crisis often
requires an escalation in care and even the need for extracorporeal
membrane oxygenation (ECMO) support.

The primary study outcome was acute postoperative decompensation
within the first 24 hours, defined as an overall sustained escalation in care
for >12 hours compared with the immediate preoperative period, and which
included:
• initiation of or increase in pulmonary vasodilators,
• paralytics,
• pressor requirements,
• ventilator requirements including respiratory rate, positive end expiratory
pressure,
• fraction of inhaled oxygen, or c
• hange to high frequency ventilation, or
• placement on ECMO.

 The multidisciplinary congenital
diaphragmatic hernia management
team instituted a protocol in 2012
requiring the specific criterion of
echocardiogram-estimated pulmonary
artery pressure ≤80% systemic blood
pressure before repairing congenital
diaphragmatic hernias.
 A retrospective review of 77 neonatal
patients with Bochdalek hernias
repaired between 2008 and 2015
were reviewed:
group 1 included patients repaired
before protocol implementation
(n = 25);
after implementation (n = 52).
Group 1 Group 2
48%
17%
P=0.01
% patients with postoperative
decompensation
50 –
40 –
30 –
20 –
10 –
00

were reviewed:
(n = 25);
Group 1 Group 2
48%
17%
P=0.01
decompensation
50 –
40 –
30 –
20 –
10 –
00
Group 2 displayed
a trend toward
improved survival
to 30 days
postoperatively

were reviewed:
(n = 25);
Group 1 Group 2
48%
17%
P=0.01
decompensation
50 –
40 –
30 –
20 –
10 –
00
The implementation of
a protocol requiring
echocardiogram-estimated
pulmonary arterial pressure
≤80% of systemic pressure
before congenital
diaphragmatic hernia repair
may reduce the incidence
of acute postoperative
decompensation.

• Children performed a maximal
cardiopulmonary exercise test
after the lung function assessment,
that is, 1-2 h after inhalation of
salbutamol.
• A motor-driven treadmill was used,
programmed for increases in angle
of inclination and speed according
to the Bruce protocol.
van der Cammen-van Zijp MHM,
Scand J Med Sci Sports. 2010; 20:e130–e130
Determinants of exercise capacity in school-aged
esophageal atresia patients
LCC Toussaint-Duyster, Pediatr Pulmonol 2017;52:1198-1205
 Exercise capacity of
63 children with esophageal
atresia (EA) born 1999-2007
evaluated at the age of 8 yrs.
 Lower respiratory tract
infections (RTIs), symptoms
of gastroesophageal reflux,
weight-for-height, and
sports participation.

• The children were encouraged
to perform to exhaustion.
• Heart rate and transcutaneous
oxygen saturation were monitored.
• Heart rate of ≥185 beats per min
or loss of coordination because
of excessive fatigue was taken
as maximal performance.
Karila C, Chest. 2001; 120:81–87

• Eight-old children with EA
had reduced exercise
capacity which was only
associated with the
reduction in total lung
capacity (TLC) and higher
SDS weight-for-height.

Chronic interstitial lung
diseases CHild

Surgical Lung Biopsy for Interstitial Lung Diseases.
Raj R. Chest. 2017 May;151(5):1131-1140.
Suggested
algorithm outlining
the role of surgical
lung biopsy in
interstitial lung
diseases.
CTD-ILD = connective
tissue disease–
associated
interstitial lung
disease;
HP = hypersensitivity
pneumonitis;
HRCT = high-
resolution CT;
IPF = idiopathic
pulmonary fibrosis

Raj R. Chest. 2017 May;151(5):1131-1140.
Usual interstitial pneumonitis pattern.
(A) Axial and (B) coronal images through the chest show peripheral-predominant,
basal-predominant reticular abnormality with small areas of honeycombing (arrows).

Raj R. Chest. 2017 May;151(5):1131-1140.
Possible usual interstitial pneumonitis pattern.
A) Axial and (B) coronal images through the chest show peripheral-predominant,
basal-predominant reticular abnormality without honeycombing.
Biopsy revealed usual interstitial pneumonitis.

Raj R. Chest. 2017 May;151(5):1131-1140.
Atypical usual interstitial pneumonitis.
A) Axial and (B) coronal images through the chest in a patient with scleroderma show basal predominant,
reticular and ground-glass abnormality without honeycombing. There is slight peripheral predominance,
but the extent of ground-glass abnormality is greater than would be expected for usual interstitial
pneumonitis. However, biopsy revealed usual interstitial pneumonitis.

Pulmonary hypertension in childhood interstitial lung
disease: A systematic review of the literature
S Bromley, Pediatr Pulmonol 2017;52:689-698
 20 articles
Patients with PH had a significantly
higher risk (up to 7X) of death
compared with those without PH.
Estimates of pulmonary hypertension
(PH) in chILD ranged from 1% to 64%

Air pollution and subclinical interstitial lung disease: the
Multi-Ethnic Study of Atherosclerosis (MESA) air-lung
study.Sack C, Eur Respir J.2017 Dec 7;50(6). pii: 1700559.
•Interstitial lung diseases (ILDs), a heterogeneous group of chronic lung
diseases characterised by inflammation and fibrosis of the pulmonary
parenchyma that affect nearly one out of 200 older adults in the USA.
•ILD is often diagnosed after the onset of irreversible parenchymal fibrosis.
•Early symptoms are nonspecific and frequently attributed to other chronic
pulmonary or cardiac diseases.
•Owing to the late presentation of clinical manifestations and the presumed
long latency between exposure and disease development, the underlying
aetiologies of many of the ILDs are unknown.

ambient pollution PM2.5)
nitrogen oxides (NOx), nitrogen
dioxide (NO2) and ozone (O3)
at each home.
5495 participants underwent
serial assessment by cardiac CT;
2671 participants assessed for
interstitial lung abnormalities
(ILAs) using full lung CT
at the 10-year follow-up.
OR of subclinical
interstitial lung disease
2.0 –
1.0 –
0.0
1.77
p=0.03
per 40 ppb increment in NOx

Predicted risk of interstitial lung abnormalities (ILAs) with increasing levels of pollutants
Associations of ambient fine particulate matter (PM2.5), NOx and NO2 concentrations with
progression of HAAs varied by race/ethnicity (p = 0.002, 0.007, 0.04, respectively, for
interaction) and were strongest among non-Hispanic white people.

•The associations we found were strongest and most consistent for NOx,
which is predominantly a mixture of nitrogen monoxide (NO) and NO2.
•NOx levels are highest in the near road environment, and may serve as a
proxy for a suite of other traffic-related air pollutants (TRAP), including
polyaromatic carbons, ultrafine particles and other products of fossil fuel
combustion.
•During inhalation, NOx and TRAP combine with ammonia and other small
particles, to penetrate deep within the terminal bronchioles where particles
can be phagocytised by airway macrophages, activate pulmonary nocioceptive
fibres or cause direct epithelial damage.

•The associations we found were strongest and most consistent for NOx,
which is predominantly a mixture of nitrogen monoxide (NO) and NO2.
•NOx levels are highest in the near road environment, and may serve as a
proxy for a suite of other traffic-related air pollutants (TRAP), including
polyaromatic carbons, ultrafine particles and other products of fossil fuel
combustion.
•During inhalation, NOx and TRAP combine with ammonia and other small
particles, to penetrate deep within the terminal bronchioles where particles
can be phagocytised by airway macrophages, activate pulmonary nocioceptive
fibres or cause direct epithelial damage.
nitrate exposure causes cellular injury,
epithelial proliferation, hyperplasia, inflammation
and fibrotic changes

The association between air pollution and the incidence
of idiopathic pulmonary fibrosis in Northern Italy.
Conti S, Eur Respir J 2018;51:1700397
association between
chronic exposure to
NO2, O3 and PM10
and IPF incidence
in Northern Italy
between 2005 and 2010.

an increment
of 10 μg·m−3
in NO2
concentration
was associated
with an
increase
between 7.93% and 8.41% in IPF incidence
rate, depending on the season.
association between
chronic exposure to
NO2, O3 and PM10
and IPF incidence
in Northern Italy
between 2005 and 2010.

possible mechanisms by which NO2 might have a role in the development of
IPF include:
1) proinflammatory response in bronchial epithelial cells,
2) alteration of the distribution of leukocyte subsets in both blood and
bronchoalveolar lavage
3) telomere shortening
The telomeric DNA regions at the ends of chromosomes are
particularly sensitive to the damage caused by reactive oxygen species,
which are also generated by NO2, and telomere shortening can be
accelerated by chronic inflammation and increased oxidative stress, two
major mechanisms involved in mediating NO2 effects on human health.

Is chronic exposure to air pollutants a risk factor
for the development of idiopathic pulmonary fibrosis?
Editorial Siroux V. Eur Respir J 2018; 51: 1702663
•In this issue of the European Respiratory Journal,
CONTI et al. provide evidence for the association
between chronic exposure to ambient air pollutants
(NO2, PM10 and ozone) and the incidence
of idiopathic pulmonary fibrosis (IPF)
in Lombardy, Northern Italy.
•These findings expand recent results from the Multi-Ethnic Study of
Atherosclerosis (MESA) cohort, which reported that higher exposure to
oxides of nitrogen and NO2 increased risk of interstitial lung abnormalities
and the 6-year progression of high attenuation areas, two measurements of
subclinical interstitial lung disease. Sack C, Eur Respir J 2017; 50: 1700559.

•The pathophysiology of pulmonary fibrosis
is that alveolar epithelial cell injury drives
abnormal repair with recruitment of
mesenchymal cells to the lung leading to
accumulation of extracellular matrix and
destruction of the normal architecture
of the lung.
•Exogenous factors (such as air pollutants,
drugs or viruses) or endogenous factors
(such as an altered microbiome) may
contribute to alveolar epithelial cell injury,
and thus fibrosis development, in individuals
susceptible to fibrosis due to genetic
predisposition and ageing.
Is chronic exposure to air pollutants a risk factor
for the development of idiopathic pulmonary fibrosis?
Editorial Siroux V. Eur Respir J 2018; 51: 1702663

Eosinophilic pneumonia
HYPEREOSINOPHILIC
SYNDROMES

 Pulmonary hypertension (PH)
retrieved from the Swedish
Registry of Congenital Heart
Disease (N = 67).
 6 controls randomly selected
and matched to each case.
Risk factors for pulmonary arterial hypertension
in children and young adults
E Naumburg, Pediatr Pulmonol 2017;52:636-641
Preterm birth
≤ 36 weeks
OR of
pulmonary hypertension
8.46
10 –
09 –
08 –
07 –
06 –
05 –
04 –
03 –
02 –
01 –
00
P<0.0001

Risk of Pulmonary Hypertension
95% CI
Risk factor OR Lower Upper
Maternal age 1.08 1.01 1.58
Acute pulmonary disease 3.58 1.33 9.55
Congenital diaphragm herniation 94.26 6.58 999.99
Congenital heart defect 4.26 1.13 16.10
Chromosome disorder 22.47 1.44 351.28
Gestational age ≤36 weeks 8.46 2.97 24.10
Multiple logistic regression

Risk of Pulmonary Hypertension
95% CI
Risk factor OR Lower Upper
Maternal age 1.08 1.01 1.58
Acute pulmonary disease 3.58 1.33 9.55
Congenital diaphragm herniation 94.26 6.58 999.99
Congenital heart defect 4.26 1.13 16.10
Chromosome disorder 22.47 1.44 351.28
Gestational age ≤36 weeks 8.46 2.97 24.10
Multiple logistic regression
Other factors, such as acute pulmonary diseases,
congenital heart defects, congenital diaphragm
herniation, and chromosomal disorders were also
associated with PH in the multivariate analysis.

Pulmonary hypertension
Oxidative stress

Impact of the mitochondria-targeted antioxidant MitoQ
on hypoxia-induced pulmonary hypertension.
Pak O, Eur Respir J. 2018 Feb 1. pii: 1701024
•Hypoxic pulmonary vasoconstriction (HPV)
is a reaction of the pre-capillary pulmonary
vessels to alveolar hypoxia and serves
to maintain ventilation–perfusion matching,
thereby optimising the oxygenation of blood.
•In contrast, generalised chronic hypoxia
(e.g. in chronic obstructive pulmonary disease)
leads to the development of pulmonary
hypertension, which is a progressive
disorder characterised by pulmonary
vascular remodelling, ultimately resulting
in right heart failure.

•Pulmonary arterial smooth muscle cells
(PASMCs) are key players in these responses,
as they react
to acute hypoxia with contraction and
to chronic hypoxia with proliferation.
•Mitochondrial reactive oxygen species
(ROS) have been suggested
to play a crucial role in both processes.
•Additionally, ROS may be involved
in the development
of right ventricular remodelling.

•MitoQ is an orally available mitochondria-targeted
antioxidant, consisting of a ubiquinone moiety
(a vital respiratory cofactor)
linked to a triphenylphosphonium
(TPP+) molecule.
•The lipophilic TPP+ cation allows MitoQ
to pass through the phospholipid bilayers
and to accumulate within the mitochondrial
inner membrane driven by the
mitochondrial membrane potential.

•The active antioxidative form of MitoQ,
ubiquinol, is oxidised by ROS to the inactive form,
ubiquinone, which is continually recycled
by complex II of the respiratory chain
to its active ubiquinol form.
•MitoQ is an effective antioxidant against
lipid peroxidation, peroxynitrite,
the hydroperoxyl radical and superoxide,
although its reactivity with H2O2 is negligible.
•As superoxide and H2O2 are suggested to regulate the development
of chronic hypoxia-induced pulmonary hypertension, MitoQ offers the
possibility to specifically target mitochondrial ROS and oxidative damage
therapeutically.

Mice exposed to chronic
hypoxia (10% O2 for 4 weeks)
or after banding of the
main pulmonary artery
right ventricular
remodelling

Mice exposed to chronic
hypoxia (10% O2 for 4 weeks)
or after banding of the
main pulmonary artery
right ventricular
remodelling
MitoQ did not affect
the development of
chronic hypoxia-
induced pulmonary
hypertension but
attenuated
right ventricular
remodelling
(-)

Pulmonary hypertension
treatment

Sickle cell disease
and the lung

What pulmonology 2 rare diseases

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