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European protocols for the diagnosis and initial

treatment of interstitial lung disease in children
Andrew Bush,1 Steve Cunningham,2 Jacques de Blic,3,4 Angelo Barbato,5
Annick Clement,6 Ralph Epaud,7 Meike Hengst,8 Nural Kiper,9 Andrew G Nicholson,10
Martin Wetzke,11 Deborah Snijders,5 Nicolaus Schwerk,12 Matthias Griese,13
on behalf of the chILD-EU collaboration

▸ Additional material is ABSTRACT approaches and treatment protocols were harmo-

published online only. To view Interstitial lung disease in children (chILD) is rare, and nised across Europe. This manuscript reports on
please visit the journal online
(http://dx.doi.org/10.1136/ most centres will only see a few cases/year. There are our agreed approach, including standard operating
thoraxjnl-2015-207349). numerous possible underlying diagnoses, with specific protocols, and the Delphi consensus process used
and non-specific treatment possibilities. The chILD-EU to harmonise our approach to treatment, across the
For numbered affiliations see
end of article. collaboration has brought together centres from across entire childhood age range. The reader is also
Europe to advance understanding of these referred to an official American Thoracic Society
Correspondence to considerations, and as part of this process, has created statement, which covers only the 0–2 years age
Professor Andrew Bush, standard operating procedures and protocols for the range.8 The aim is not to dictate to clinicians
Department of Paediatric
Respiratory Medicine, Royal investigation of chILD. Where established consensus whether to undertake trials of particular treatments
Brompton Hospital, Sydney documents exist already, for example, for the but to encourage and enable the use of the same
Street, London SW3 6NP, UK; performance of bronchoalveolar lavage and processing of protocol for treatments where there is no evidence.
[email protected] lung biopsies, these have been adopted. This manuscript
Received 1 June 2015
reports our proposals for a staged investigation of chILD, THE STARTING POINT: WHEN TO SUSPECT
Accepted 14 June 2015 starting from when the condition is suspected to CHILD—TYPICAL PRESENTATIONS
Published Online First defining the diagnosis, using pathways dependent on Shortly after birth
1 July 2015 the clinical condition and the degree of illness of the The earliest presentation of chILD is shortly after
child. These include the performance of genetic testing, birth, with unexplained respiratory distress in a
echocardiography, high-resolution CT, bronchoscopy term baby. This frequently and rapidly proceeds to
when appropriate and the definitive investigation of lung intubation and ventilation, with relentlessly pro-
biopsy, in order to establish a precise diagnosis. Since no gressive respiratory failure8 9 leading to death or
randomised controlled trials of treatment have ever been lung transplantation, if the latter is available. The
performed, we also report a Delphi consensus process to usual causes are surfactant protein gene muta-
try to harmonise treatment protocols such as the use of tions9 10 and the alveolar-capillary dysplasia spec-
intravenous and oral corticosteroids, and add-on trum;11 some of the former may make a partial
therapies such as hydroxychloroquine and azithromycin. recovery10 and the baby may survive in chronic
The aim is not to dictate to clinicians when a therapeutic respiratory failure. The same conditions should be
trial should be performed, but to offer the possibility to considered in preterm babies with respiratory dis-
collaborators of having a unified approach when a tress which does not run the normal clinical
decision to treat has been made. course, but the yield of positive results is much less.

First 2 years of life

INTRODUCTION Later presentations of chILD are very non-specific.
Interstitial lung disease in children (chILD) is rare; In the first 2 years of life, symptoms in descending
there are no reliable estimates, but prevalence is order of frequency are fast breathing, failure to
likely <1 per 100 000, as against 60–80 per thrive, typically dry cough and wheeze (this last in
100 000 in adults;1 the average European Hospital 25% of cases) in the absence of respiratory tract
will see no more than 5 cases/year.2 chILD is more infection.3 Suggested protocols for the clinical
diverse than interstitial lung disease in adults, com- assessment of these infants are available on the
prising more than 200 different conditions with a chILD-EU website (http://www.klinikum.uni-
variety of proposed classifications.3–6 Since individ- muenchen.de/Child-EU/en/index.html). SpC muta-
ual centres see so few chILD patients, it is unsur- tions may present as respiratory syncytial virus
prising that there are no randomised controlled (RSV)-positive bronchiolitis, which fails to
trials of treatment. To address this, a proposal was resolve;12 there is animal evidence that RSV causes
funded by the European Union FP7 stream7 to (a) increased inflammation and worse outcomes in
create a pan-European registry; (b) peer review all animals with SpC mutations.13 14 Signs of chILD
potential chILD diagnoses; (c) gather prospective include hypoxia, tachypnoea, recession, crackles,
longitudinal data from well-defined groups of chil- pulmonary hypertension and gastro-oesophageal
To cite: Bush A, dren, including the results of N of 1 therapeutic reflux.3 Auscultation can be normal in more than a
Cunningham S, de Blic J, trials; (d) set up and perform the first randomised third. Chest deformity, particularly pectus excava-
et al. Thorax controlled trials of chILD treatment. In order to tum, has been reported especially with ABCA3
2015;70:1078–1084. achieve this, it was essential that the diagnostic mutations.15
1078 Bush A, et al. Thorax 2015;70:1078–1084. doi:10.1136/thoraxjnl-2015-207349
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2–16 years of age respiratory disease; deciding if reflux may be contributory is

There are no large series from this age group, but it is likely that difficult even in the presence of a barium swallow reflux
the clinical picture will not be dissimilar. In older children, study and a pH study.
exercise-induced breathlessness may be the presentation, 3. Physiological testing: Lung function testing in infants has
although other, commoner causes need to be considered. little general availability and the role in infants is unclear.
The USA group have coined the term ‘chILD syndrome’7 Neuroendocrine cell hyperplasia of infancy (NEHI) is char-
which is a label mandating further evaluation in a child with acterised by a pattern of hyperinflation and airflow obstruc-
diffuse lung disease who has had common causes excluded (eg, tion,21 but there is insufficient experience to rely on
cystic fibrosis, uncoordinated swallow leading to aspiration) and physiological patterns in infancy in chILD. In older children,
who has at least three of four criteria, namely (a) respiratory the usual pattern is classically restrictive, with a reduced
symptoms; (b) respiratory signs, including digital clubbing and FEV1 and FVC, a normal or even elevated FEV1/FVC ratio
failure to thrive; (c) hypoxaemia; and (d) diffuse radiological and reduced lung volumes. Carbon monoxide transfer (dif-
changes. Clearly, another important part of the initial work-up fusing capacity or transfer factor of the lung for carbon
is a full clinical evaluation of the child, looking for signs of a monoxide, DLCO) is usually reduced, and if elevated, pul-
systemic disease (especially renal, skin, liver, eyes, joints), evi- monary haemorrhage should be suspected.22 The occasional
dence of pulmonary hypertension and signs of reflux and chILD may have a more obstructive pattern of physiology.
aspiration. 4. Echocardiogram: Should be an early investigation to estimate
In all cases, a careful history is mandated, including a family pulmonary artery pressure, and exclude cardiac mimics of
history, which may lead to suspicion of genetic causes of chILD, interstitial lung disease, such as cor triatrium leading to pul-
and environmental exposures if there is any possibility of hyper- monary oedema.23 Pulmonary hypertension, where present,
sensitivity pneumonitis; the recent outbreak of ILD in adults should be diagnosed and treated accordingly in liaison with
and children in Korea emphasises the importance of the envir- paediatric cardiology colleagues.
onmental history.16–18 Simple laboratory testing may give clues 5. Blood studies: A focused approach is recommended. Tests
to the diagnosis. Anaemia and reticulocytosis are seen in pul- can be grouped into (a) genetic abnormalities; (b) immune
monary haemorrhagic syndromes. Peripheral eosinophilia sug- function (especially if the follicular bronchiolitis-lymphoid
gests parasitic disease, hypersensitivity, eosinophilic lung disease interstitial pneumonia spectrum is suspected); (c) auto-
and systemic eosinophilic diseases. Stool occult blood results antibody studies (cases of pulmonary haemorrhage, alveolar
may be positive in patients with pulmonary haemorrhage; proteinosis, or if there is evidence of a systemic disease); (d)
indeed these children may have undergone extensive diagnostic environmental organic dust exposures (hypersensitivity
work-up for iron deficiency without the possibility of pulmon- pneumonitis); (e) miscellaneous, that is, ACE inhibitors in
ary haemorrhage having been considered.19 cases of suspected sarcoidosis. Note that novel genetic
chILD entities with multisystem disease are being
INITIAL INVESTIGATIONS described,24 25 and the younger the child is the more care-
Given the non-specific nature of the presentation of chILD the fully new or established genetic diagnoses are sought. In all
probability of a diagnosis can be enhanced by structured investi- cases of chILD, DNA of the patient and parents should be
gation. A simple severity score has been proposed (table 1),20 stored for future analyses. The clinical situation will dictate
which sadly has yet to be superseded by more sophisticated which tests are performed, and whether it is realistic to
biomarkers: await results before proceeding to a CT or lung biopsy.
1. Clinical: Evidence of hypoxaemia is often the first abnormal- A proposed diagnostic pathway is shown in figure 1. In terms
ity to raise concern and should be noted whether it is of timing of enrolment of suspected chILD patients in the regis-
present at rest both awake and asleep breathing room air. In try, a preliminary discussion at an early stage would be valuable
older children exercise testing should be used to unmask for the patient. The use of, for example, standardised scanning
desaturation which is not present at rest, following standard protocols is to be preferred.
protocols; there is insufficient evidence to recommend a par-
ticular method over others. It is unwise and uninformative IF CHILD IS SUSPECTED CLINICALLY: THE ROLE OF CHEST
to exercise a child who is desaturated at rest, without giving CT SCANNING
supplemental oxygen. CT chest is invariably performed in the investigation of a pos-
2. Radiology: The chest radiograph may be normal, but more sible case of ChILD. The purpose of chest CT is to evaluate the
likely reveals non-specific abnormalities. Gastro-oesophageal presence and extent of disease. In some cases it can be diagnos-
reflux is common in young children and also in patients with tic,26 but is more usually supportive of a diagnosis that takes
account of clinical history, blood results and sometimes bronch-
oalveolar lavage and/or biopsy material.
Table 1 Staging the severity of childhood interstitial lung disease CT scanning for chILD should only be performed in centres
(chILD)20 experienced in paediatric radiology. The general principles of
scanning are to minimise radiation dosage to the child while
Hypoxaemia maximising the information obtained; a very low dose scan
<90% sleep or Hypoxaemia Pulmonary
Score Symptoms exercise <90% rest hypertension which is diagnostically useless benefits no one.27 Detailed proto-
cols for reducing radiation exposure while maintaining image
1 No No No No quality are given online, and these should be audited regularly.
2 Yes No No No The optimal CT scan is a volumetric scan during inspiration,
3 Yes Yes No No performed in tandem with a high-resolution CT (HRCT)
4 Yes Yes Yes No fine-cut spaced expiratory scan. Ventilation should be controlled
5 Yes Yes Yes Yes to ensure satisfactory, interpretable, scan output. In young chil-
dren this necessitates a general anaesthetic (ie, under 5 years of
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Figure 1 Proposed flow chart for investigating interstitial lung disease in children (chILD). If the child is well and stable, progress to the more
invasive investigations may not be indicated. HRCT, high-resolution CT.

age), although some centres advocate sedation and controlled, respiratory movements made by the child and (2) the variance
bag and mask ventilation.28 As always, the risk of anaesthesia or in lung volumes during an uncontrolled respiratory cycle will
sedation should be weighed against the risk of not obtaining reduce the value of the scans obtained and the reliability of CT
diagnostic information. Older children should be able to reliably to provide the supportive evidence for a diagnosis of ChILD.
hold breath in inspiration and expiration for 6–10 s. In children Whatever the timing of investigations, planning to avoid the
who are ventilated under a general anaesthetic it is important to child having multiple general anaesthetics is essential. So fibre-
attain appropriate ventilation pressures in both inspiration and optic bronchoscopy should only be done as a separate procedure
expiration; these details are provided in our online standard if it is likely to be diagnostic; otherwise, it is better performed
operating procedure (SOP). under the same anaesthetic as the lung biopsy.
The administration of contrast medium will make the assess-
ment of ground glass shadowing almost impossible, and so INVASIVE TESTING: FLEXIBLE BRONCHOSCOPY
careful consideration should be given as to the risk/benefit of Bronchoscopy with bronchoalveolar lavage (BAL) may be diag-
using a contrast medium based on the anticipated diagnosis. nostic in pulmonary haemorrhage syndromes, alveolar proteino-
The need to assess the pulmonary vasculature will require the sis and eosinophilic lung disease, and a normal cell differential
use of contrast, with detrimental effects on the interpretation of can rule out hypersensitivity pneumonitis. BAL target site
some lung components. should be chosen on the basis of radiological abnormality or
The three outcomes of HRCT scanning (figure 1) are (1) airway inspection. If BAL is to be performed during the same
chILD unlikely including that the CT is normal. Although a anaesthetic as CT, then it should follow the imaging; where it is
normal CT scan is unusual in ChILD, it may occur in some to be performed at the time of lung biopsy, the lobe designated
cases early in the course of the disease process where there are for a lung biopsy should be avoided. Where possible flexible
very few non-diagnostic CT features; (2) chILD present and a bronchoscopy should be performed via endotracheal or laryn-
specific diagnosis can be made26; and (3) chILD present, with geal mask to reduce suction channel contamination from the
or without possible evidence of a comorbidity such as aspiration upper airway. BAL volume is adjusted to body weight using
(eg, consolidation in a typical distribution), but a specific diag- 3 mL/kg of sterile normal saline divided into three equal frac-
nosis cannot be made. If chILD is unlikely then appropriate tions in children weighing <20 kg and 3 mL/kg in 20 mL por-
diagnostic algorithms to investigate possible non-chILD findings tions in children weighing >20 kg.29 Negative suction pressure
are deployed; these are beyond the scope of this article. A spe- should be adjusted to avoid visible airway collapse. The first
cific diagnosis of chILD may allow immediate action; however, bronchoalveolar lavage fluid aliquot should be unfiltered and
the ability for CT to be completely diagnostic is limited to rela- used for microbiological studies, and the other aliquots should
tively few conditions (ie, pulmonary alveolar proteinosis, extrin- be pooled (unless one is bloodstained), filtered through sterile
sic allergic alveolitis and NEHI), and these too are usually gauze only if a lot of mucus is present, which is unlikely in
supported by other diagnostic tests, that is, environmental aller- chILD, and used for analysis of cellular and non-cellular compo-
gen and prednisolone response in hypersensitivity pneumonitis nents. Transport and preparation of samples is provided in our
(figure 2A) ,or granulocyte-macrophage colony-stimulating fac- online SOP. Clinicians should liaise with their laboratories to
torreceptor auto-antibody or gene mutation studies, surfactant ensure appropriate investigation of samples, to include appropri-
protein gene mutations and an immunological work-up in cases ate microbiological analysis and culture (bacterial, fungal, virus),
of pulmonary alveolar proteinosis (figure 2B). Oil Red O staining (fat-laden macrophages), periodic acid–
It is recognised that although faster CT scanners may enable Schiff staining ( pulmonary alveolar proteinosis) and iron
chest CT without the need for anaesthetic, we do not recom- staining (ie, Prussian blue for haemosiderin within macrophages)
mend this unless anaesthesia is thought to be unsafe, as (1) the to diagnose pulmonary haemorrhage syndrome. CD1a-positive
technique frequently provides suboptimal results from cells are consistent with Langerhans cell histiocytosis. A
1080 Bush A, et al. Thorax 2015;70:1078–1084. doi:10.1136/thoraxjnl-2015-207349
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Figure 2 Diagnostic high-resolution CTs (HRCTs) in childhood interstitial lung disease (chILD). (A) There is diffuse ground glass shadowing with a
widespread soft centrilobular nodular pattern. This is virtually diagnostic of hypersensitivity pneumonitis, in this case due to pet doves. (B) There is
generalised ground glass opacification with thickening of the interlobular septa, giving the classical cobblestone appearance of pulmonary alveolar
proteinosis. It is not possible to distinguish the different aetiologies from the HRCT appearances.

lymphocyte-predominant BAL with an elevated CD4/CD8 ratio wound healing and to expedite specific chILD treatments, ie,
(>2) suggests sarcoidosis with involvement of the lung.30 TNF-α antagonist infliximab combined with methotrexate for
Metabolic abnormalities may be diagnosed by BAL, for sarcoidosis, and cyclophosphamide for angiitis with granulo-
example, sea-blue macrophages.31 matosis). The dilemma posed by the sick patient with chILD
Endobronchial (EBx) and transbronchial (TBB) biopsies are who is on the verge of ventilation (and biopsy would most
rarely performed in ChILD and are not recommended unless a likely tip to requiring ventilation) or is unstable on a ventilator
specific diagnosis that could be made by these techniques is sus- often dictates that a steroid trial before a biopsy may be
pected. Specific conditions such as pulmonary alveolar micro- appropriate. If the child is already ventilated, unless the venti-
lithiasis may be diagnosed by TBB,32 but the samples are too latory requirements are very high, a biopsy can safely be
small to diagnose most chILDs. Blind EBx may detect sarcoid performed.
granulomas,33 but is not useful for diagnosing NEHI.34 Our The site of biopsy should be guided by a recent CT chest.
protocols for these procedures can be found online if needed. There should be liaison between the surgeon, pathologist and
paediatrician. Any other procedures which may merit general
INVASIVE TESTING: SURGICAL LUNG BIOPSY anaesthesia (eg, bronchoalveolar lavage, mucosal biopsy, place-
The timing and need for lung biopsy is controversial. chILD ment of a vascular access device or gastrostomy) should be care-
patients who are well and thriving may not merit biopsy even fully planned. The tip of the middle lobe and lingula should be
if the CT scan appearances are not typical. Some would con- avoided, and biopsy should preferably be from two sites, and
sider that an oxygen requirement warrants a diagnostic lung sample areas of varying disease severity. Increasingly, biopsy is
biopsy, while others would wait and see. There is clearly merit using video-assisted thoracoscopic surgery rather than a mini-
in performing an invasive procedure only if treatment will be thoracotomy. Whatever technique is used, the procedure must
changed as a result. Steroids are a mainstay of treatment for only be undertaken by an experienced surgeon, who is confident
chILD and the timing of biopsy related to their initiation is of obtaining adequate biopsies (at least 10×10×10 mm); a very
often dictated by circumstance. Where possible, biopsy prior superficial biopsy, which does not contain distal airways, may
to steroid treatment is recommended (to minimise risk to result in diagnostic error.
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Samples should be rapidly transported to a waiting patholo-

Table 3 Staining of lung biopsy specimens
gist working in an accredited laboratory working to inter-
national standards.35 There should be access to light microscopy Stain Purpose
and common special stains, immunohistochemistry, genetics ser-
Always: H&E Overview of extent, distribution and nature of
vices, microbiology and virology services and photographic any pathology
equipment. Table 2 describes the postbiopsy sample processing. Always: Elastic Van Gieson Collagen/pulmonary vasculature
The remaining tissue should be fixed in formalin. Table 3 As indicated: CD34 Vascular marker
describes the routine stains to be used. Details of transport of As indicated: Perls stain Iron-laden macrophages
specimens can be found online. As indicated: Bombesin Diagnosis of NEHI
As indicated: Periodic Schiff Glycogen-positive cells: PIG
OTHER SOURCES OF LUNG TISSUE If infection suspected Ziehl–Neelsen, Grocott, others
Postmortem and explanted lung tissue should be accessed if at As indicated: Langerhans cells (S-100, CD1a)
all possible, and handled in the same way as a lung biopsy. Even immunohistochemistry
if permission for autopsy is refused, it may be possible to obtain NEHI, neuroendocrine cell hyperplasia of infancy.
permission for percutaneous, transthoracic True-cut needle biop-
sies. DNA of the patient and both parents should be stored with and related questions. All scenarios related to children with
the family’s permission, if this has not already been done. proven or highly suspected ILD. The survey was in English.
Another valuable source of tissue is the explanted lungs after Survey 1 consisted of 8 scenario stems with 75 responses
lung transplantation. required, survey 2 of 9 lead statements with 11 individual
responses required. Clinicians were asked to score according to
THE ROLE OF PEER REVIEW agreement: 1 Strongly Agree; 2 Agree; 3 Neutral; 4 Disagree; 5
chILD is a spectrum of very rare conditions, and no centre will Strongly Disagree; 6 Don’t know.
see many cases. The diagnosis may be obvious, as, for example, Survey 1 was approached by 173 clinicians. Twenty-nine
a suspected surfactant protein gene mutation when known responders who provided fewer than 50% of responses were
disease causing mutations are detected. However, in many cases removed from the analysis. Data is presented from 144 clinician
the interpretation of CT scans and lung biopsy material is diffi- responders: Australia 14, Canada 3, France 5, Germany 15,
cult. We believe that the best practice is to peer review these Italy 1, USA 61, UK 37 and other 8. There were 127 respon-
cases so that patients have the benefit of a consensus view from dents to the second round of Delphi. Twelve provided insuffi-
different specialists who can pool and increase their expertise. cient data responses (fewer than 50% responses) and so were
This is an integral part of our protocols. In chILD-EU, cases are removed from the complete analysis. The 115 consultant/attend-
peer reviewed at point of diagnosis and revisited at 12 monthly ing pulmonologist respondents contributing to the second
intervals to gauge the precision of diagnosis and patient round of Delphi were from the UK (36), USA (30), Germany
outcome. (22), Australia (9), France (6), Italy (5), Canada (2) and other
countries (5).
PROPOSED TREATMENT PROTOCOLS: THE DELPHI Delphi 1 consisted of four scenarios related to the care of a
PROCESS patient who was very sick and ventilated or close to ventilation
In the absence of any randomised controlled trial data, a Delphi for whom no specific treatment was known. Delphi 2 provided
process was undertaken to achieve a consensus on treatment statements derived from the consensus of opinion from the first
protocols to harmonise treatment approaches. The full details Delphi round and asked how clinicians viewed the statement.
are given in the online supplementary material. Briefly, we con- Options, provided for varying doses and medicines, are sum-
ducted a two-round web-based Delphi consensus of clinicians marised as (a) usual practice or (b) could happily use it if it is
caring for chILD. Clinicians were identified from registered the consensus of the Delphi, or (c) not usual practice and would
email addresses with national paediatric respiratory society not wish to use it even if it is the consensus of the Delphi.
groups, including the paediatric assembly of the American In all scenarios, we were clear that the suggested doses should
Thoracic Society. The questions were derived by the chILD-EU be considered starting doses and could be changed at the discre-
core management team, with adaptation by the lead representa- tion of the treating clinician at any time. The final consensus for
tives for clinicians in North America (Robin Deterding) and treatment reached is summarised in table 4, and the consensus
Australia (Adam Jaffe). The survey consisted of a scenario stem for a significant response in table 5.

Table 2 Handling of lung biopsy specimens

Type of
processing Tissue material used Processing procedure Purpose

1 Majority of the sample (about 80%) 4% Formalin For wax blocks and staining studies and storage
2 Several 1–2 mm cuboidal pieces Glutaraldehyde-buffer Electron microscopy, esp Sp mutations
3 10 to 20% of tissue Snap frozen in liquid nitrogen, place Genetic, biochemical studies, conserve RNA and proteins
in −80 freezer
RNAlater solution Same as snap frozen, except enzyme activity studies; however, more
convenient as can be shipped at room temperature
4 Fresh tissue (can be the remnant on the None Microbiology
proximal side of the staple line)
Clearly all necessary clinical samples need to be taken before any is allocated for research.

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Table 4 Doses of medication to be used and anticipated time to assess if there has been a clinical response
chILD ventilated or close to ventilation chILD not ventilated or close to ventilation

Methylprednisolone
Dose Intravenous 10 mg/kg or 500 mg/m2 Intravenous 10 mg/kg or 500 mg/m2
Response rate 7 days 28 days
Comment 30 mg/kg used by some centres As alternative to oral prednisolone. Use before other therapies and judge response
Prednisolone
Dose Oral 1 mg/kg, used in between pulses of Oral 2 mg/kg, as alternative to methylprednisolone pulses. Use before other therapies and
methylprednisolone judge response
Response rate 7 days 28 days
Hydroxychloroquine
Dose 10 mg/kg 10 mg/kg
Response rate 21–28 days 3 months
Comment In children <6 years 6.5 mg/kg in some centres to In children <6 years 6.5 mg/kg in some centres to reduce toxicity.
reduce toxicity No preference over azithromycin as second line.
54% would consider Hydroxychloroquine as sole therapy in mild stable chILD
Azithromycin
Dose 10 mg/kg 3 days per week 10 mg/kg 3 days per week
Response rate 3 months 3 months.
Comment No preference over hydroxychloroquine as second line.
51% would consider azithromycin as sole therapy in mild stable chILD
Results are simple majority assessed by median?/mean?.
chILD, childhood interstitial lung disease; IV, intravenous; PIG, pulmonary interstitial glycogenosis.

OTHER POTENTIAL THERAPIES and body plethysmography recommended as indicated but at

There is even less evidence for other regimes and no recommen- least once per year.
dations are made. If there is evidence of systemic disease, and if
cytotoxic or biological therapies are contemplated, it would PULMONARY EXACERBATIONS
usually be wise to involve a paediatric rheumatologist. Acute pulmonary events associated with instability are a charac-
teristic of many chronic diseases. Although recognised, they are
MONITORING CHILD often difficult to define. No definition exists for a pulmonary
The variety of ChILD diagnoses makes a single common moni- exacerbation in chILD and so we have sought, through the
toring plan of little value. chILD-EU has looked to enable refer- Delphi process and a review of the evidence, to define what is a
ence across diagnoses by the development of an observational clinically significant change in chILD as a first step towards a
trial protocol focused on the first year of diagnosis. Monitoring definition of a pulmonary exacerbation (table 5). The period of
is at months 1, 2, 3, 6 and 12 and annually thereafter. Key stability before and between exacerbations must be defined; for
observations are clinical (respiratory rate, heart rate, weight, ChILD this is arbitrarily considered to be at least 7 days of sta-
oxygen saturation in air awake, oxygen saturation including bility at baseline values. More work is ongoing to define the def-
overnight while asleep and on exercise, evidence of pulmonary inition of a pulmonary exacerbation and its relationship with
hypertension) and radiological monitoring (chest X-ray at diag- other respiratory events such as upper respiratory tract infection
nosis, 6 and 12 months; CT not recommended, however, if con- and aspiration.
sidered justifiable, a limited cut thin-section HRCT of areas of
interest should provide sufficient information). In older children SUMMARY AND CONCLUSIONS
spirometry at each observational monitoring visit should be We have proposed a sequence of investigations for chILD, and
recorded, with DLCO ( pulmonary haemorrhage monitoring) provided SOPs for performance of these tests. We aim to har-
monise investigation of chILD to facilitate future research; this
manuscript is the framework on which this will be based.
Table 5 Improvement in physiological outcomes considered to be
a treatment response Author affiliations
1
Imperial College, National Heart and Lung Institute, Royal Brompton Harefield NHS
Possible Response Best Foundation Trust, London, UK
2
response (%) (%) response NHS Lothian and University of Edinburgh, Edinburgh, UK
3
Pediatric Pulmonary Department, Hôpital Universitaire Necker Enfants Malades,
Heart Rate 10 20 – Paris, France
4
Respiratory Rate 5 10 20% Université Paris Descartes, Paris, France
5
Department of Women’s and Children’s Health, University of Padova, Padua, Italy
SpO2 5 10 – 6
Hôpital Armand-Trousseau, Pneumologie pédiatrique, Centre National de Référence
Loss of need for – – Yes des Maladies Respiratoires Rares, Paris, France
supplemental oxygen 7
Faculté de Médecine, Centre Intercommunal de Créteil, Service de Pédiatrie,
Loss of need for mechanical – – Yes INSERM, U955, Université Paris-Est, Créteil, France
8
ventilation Children’s Hospital of Ludwig, Maximilians University, Munich, Germany
9
Conversely, a deterioration of this size would be considered a significant decline.
Faculty of Medicine, Department of Pediatric Pulmonology, Hacettepe University,
SpO2, arterial oxygen saturation. Ankara, Turkey
10
Imperial College & Royal Brompton Harefield NHS Foundation Trust, London, UK

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11
Department of Pediatrics, Pediatric Pulmonology, Allergology and Neonatology, 13 Glasser SW, Witt TL, Senft AP, et al. Surfactant protein C-deficient mice are
Hannover Medical School, Hannover, Germany susceptible to respiratory syncytial virus infection. Am J Physiol Lung Cell Mol
12
Department of Pediatric Pulmonology and Pediatric Lung Transplantation, Physiol 2009;297:L64–72.
Hannover Medical School, Clinic for Pediatric Pneumology, Allergology and 14 Glasser SW, Senft AP, Maxfield MD, et al. Genetic replacement of surfactant protein-C
Neonatology, Hannover, Germany reduces respiratory syncytial virus induced lung injury. Respir Res 2013;14:19.
13
Lung Research Group, Children’s Hospital of Ludwig, Maximilians University, 15 Doan ML, Guillerman RP, Dishop MK, et al. Clinical, radiological and pathological
Munich, Germany features of ABCA3 mutations in children. Thorax 2008;63:366–73.
16 Hong S-B, Kim HJ, Huh JW, et al. A cluster of lung injury associated with home
Acknowledgements We are grateful to Professor Robin Deterding, ChILD humidifier use: clinical, radiological and pathological description of a new
Foundation and Children’s Hospital Colorado, USA, and Professor Adam Jaffe, syndrome. Thorax 2014;69:694–702.
Sydney Children’s Hospital, Australia, for their assistance co-ordinating national 17 Kim HJ, Lee M-S, Hong S-B, et al. A cluster of lung injury cases associated
responses via their respective networks (American Thoracic Society Paediatric Section with home humidifier use: an epidemiological investigation. Thorax
and Australian Paediatric Medicine Respiratory Group). 2014;69:703–8.
18 Kim KW, Ahn K, Yang HJ, et al. Humidifier disinfectant-associated children’s
Contributors AB drafted the manuscript, all authors reviewed it and agreed on the
interstitial lung disease. Am J Respir Crit Care Med 2014;189:48–56.
contents. SC led the Delphi consensus, and wrote the online supplement.
19 Bush A, Sheppard M, Warner JO. Chloroquine in idiopathic pulmonary
All authors reviewed it and agreed with the contents.
haemosiderosis. Arch Dis Child 1992;67:625–7.
Funding This project (“Orphans Unite: chILD better together – European 20 Fan LL, Deterding RR, Langston C. Pediatric interstitial lung disease revisited.
Management Platform for Childhood Interstitial Lung Disease”) was funded by the Pediatr Pulmonol 2004;38:369–78.
FP7-305653-chILD-EU grant. In addition, AB and AGN were supported by the NIHR 21 Kerby GS, Wagner BD, Popler J, et al. Abnormal infant pulmonary function in young
Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield children with neuroendocrine cell hyperplasia of infancy. Pediatr Pulmonol
NHS Foundation Trust and Imperial College London. 2013;48:1008–15.
Competing interests None declared. 22 Greening AP, Hughes JM. Serial estimations of carbon monoxide diffusing capacity
in intrapulmonary haemorrhage. Clin Sci (Lond) 1981;60:507–12.
Provenance and peer review Not commissioned; internally peer reviewed. 23 Sondheimer HM, Lung MC, Brugman SM, et al. Pulmonary vascular
Data sharing statement Original data from the Delphi consensus available disorders masquerading as interstitial lung disease. Pediatr Pulmonol
through SC. 1995;20:284–8.
24 Has C, Spartà G, Kiritsi D, et al. Integrin α3 mutations with kidney, lung, and skin
disease. N Engl J Med 2012;366:1508–14.
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1084 Bush A, et al. Thorax 2015;70:1078–1084. doi:10.1136/thoraxjnl-2015-207349

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European protocols for the diagnosis and

initial treatment of interstitial lung disease in
children
Andrew Bush, Steve Cunningham, Jacques de Blic, Angelo Barbato,
Annick Clement, Ralph Epaud, Meike Hengst, Nural Kiper, Andrew G
Nicholson, Martin Wetzke, Deborah Snijders, Nicolaus Schwerk, Matthias
Griese and on behalf of the chILD-EU collaboration

Thorax 2015 70: 1078-1084 originally published online July 1, 2015

doi: 10.1136/thoraxjnl-2015-207349

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