The approach to childhood interstitial lung disease
Ernst Eber, MD
Correspondence
Prof. Dr. Ernst Eber
Respiratory and Allergic Disease Division
Paediatric Department
Medical University of Graz
Auenbruggerplatz 30
A-8036 Graz, AUSTRIA
Tel.: +43 316 385 12620
Fax: +43 316 385 14621
ernst.eber@medunigraz.at
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Summary
Presentation of childhood interstitial lung disease (ILD) is usually nonspecific, and a
systematic approach to diagnosis is essential. In most cases, confirmation of the
presence of ILD is obtained by a high-resolution computed tomography, and the
assessment of severity by lung function testing (inluding blood gas analysis). Lung
biopsy usually represents the final step in a series of diagnostic methods. Childhood
ILD is difficult to diagnose, but precise diagnosis is crucial because of genetic and
therapeutic implications. There are no randomised, double-blind, placebo-controlled
therapeutic trials in childhood ILD. A few children do not require any treatment or only
oxygen therapy, and recover spontaneously. Most children will need corticosteroid
therapy which may be combined with hydroxychloroquine. For the future, there is an
urgent need for international collaboration which will allow to collect sufficiently large
cohorts of patients with specific entities in order to perform proper therapeutic trials.
As a prerequisite, a clear and standardised classification of the histopathology of the
underlying conditions has to be developed. Such multicentre trials will help to reduce
the still considerable morbidity and mortality in children with ILD.
Key words
Bronchoalveolar lavage (BAL), imaging, lung biopsy, lung function testing,
monitoring, treatment
Presentation of childhood interstitial lung disease and approach to
diagnosis
Childhood interstitial lung disease (ILD) represents a heterogeneous group of
respiratory disorders that are mostly chronic and associated with high morbidity and
mortality. The frequency of ILD is much lower in children than in adults, but in
children ILD comprises a broader spectrum of disorders. This is linked to the fact that
the disease occurs in the context of lung growth at the various stages of alveolar
development and maturation. ILD frequently occurs in young children (often with
neonatal onset of symptoms), the prevalence of chronic ILD is higher in boys than in
girls, and a substantial proportion of patients have a family history of lung disease.
Presentation of ILD in infants and children is usually nonspecific. Presenting features
are hypoxaemia, tachypnoea, subcostal retractions and other signs of respiratory
distress, failure to thrive, crackles, cough and also wheeze.
History and physical examination
A systematic approach to diagnosis is essential, and should start with an accurate
clinical history and physical examination. The presence and onset of respiratory signs
and symptoms should be noted, and the presence of ILD in other family members
should be sought as well as any relationship to feeding, possible inhalant triggers in
the environment, and features suggestive of a multi-system disease. Physical
examination may reveal signs of respiratory distress, such as tachypnoea and
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subcostal retractions, and crackles. Rarer findings associated with an advanced
stage of the disease include digital clubbing and cyanosis during exercise or at rest.
Laboratory tests
While laboratory tests are rarely diagnostic, in most cases a panel of tests will be
performed in an attempt to determine the cause of ILD. A selective approach is
recommended, with the spectrum of investigations being guided by the history and
clinical presentation of the child. As an example, precipitating immunoglobulin G
antibodies against airborne allergens would suggest hypersensitivity pneumonitis if
there is a compatible history. In most children with ILD, searching for mutations in the
surfactant protein (Sp)-B, Sp-C, and ABCA3 genes will be indicated. Further,
laboratory tests may be helpful to exclude systemic disorders (such as
immunodeficiencies or collagen vascular diseases that can be associated with
interstitial lung involvement), and more common respiratory diseases in childhood
that do not typically present with diffuse pulmonary disease (such as cystic fibrosis or
tuberculosis).
Imaging
The chest radiograph may show ground-glass, nodular, reticular, or reticulonodular
shadowing, and honeycombing in advanced disease. However, in some children with
ILD the chest radiograph may be normal. In general, chest radiographs have poor
sensitivity and poor specificity, and correlate poorly with symptoms, histology, and
response to treatment. Consequently, the key chest imaging tool for both diagnosis
and management of a child with ILD is high-resolution computed tomography
(HRCT). In most cases, confirmation of the presence of ILD is obtained by an HRCT
scan. HRCT may allow specific diagnoses (e.g. Langerhans cell histiocytosis,
hypersensitivity pneumonitis) to be established only in very few cases. With the most
common HRCT feature being widespread ground-glass attenuation, HRCT is not a
diagnostic investigation for most children with ILD. In addition, HRCT may be used to
determine the site of a lung biopsy, and it may also contribute to monitor disease
activity and/or severity.
Lung function testing
Lung function testing does not provide specific information, but represents a useful
tool for assessing severity and monitoring therapy. Generally, in older children lung
function abnormalities reflect a restrictive ventilatory defect with decreased lung
volumes, reduced forced expiratory volume in 1 s (FEV1) and forced vital capacity
(FVC), with a normal or increased FEV1/FVC ratio. Lung function testing in infants
and pre-school children is still considered a research technique.
The majority of patients show hypoxaemia; hypercarbia occurs only late in the
disease course. Pulse oximetry and blood gas analysis (arterial or arterialised blood)
should be performed at room air at rest in every child with (suspected) ILD. In
addition, oxygen saturation (SaO2) and/or blood gases may also be determined
during exercise (e.g. cycle ergometer, treadmill).
Bronchoalveolar lavage (BAL)
Flexible bronchoscopy and BAL are diagnostic in only a few specific conditions (such
as Langerhans cell histiocytosis, pulmonary alveolar proteinosis and lipoid
pneumonia), and may be useful in several diseases (such as sarcoidosis and
hypersensitivity pneumonitis). BAL is very good for the diagnosis of opportunistic
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infections in immunocompromised children, in particular if there was no prior
antibiotic or antifungal therapy. Usually, BAL is carried out in the most affected area
(identified radiologically). In diffuse ILD, BAL is mostly performed in the middle lobe,
or, for infants, in the lower lobe.
Lung biopsy
Histological evaluation of lung tissue usually represents the final step in a series of
diagnostic methods. It is recommended to perform a lung biopsy ahead of blind trials
of treatment unless the child is too sick, or a specific diagnosis has been made by
other techniques. Available techniques include transbronchial biopsy, percutaneous
CT-guided needle lung biopsy, video-assisted thoracic surgery (VATS) and lung
biopsy via a mini-thoracotomy. Samples from transbronchial biopsies are usually
small and thus not adequate for the pathologist to make a diagnosis; for both
transbronchial and percutaneous biopsies there is a considerable risk of bleeding
and pneumothorax. Thus, a surgical biopsy is the method of choice, with a number of
centres now confirming VATS to be a safe procedure even in small children. ILD is
frequently patchy and it is, therefore, essential that representative areas are sampled.
HRCT scanning provides a reliable guide in this respect, directing the surgeon to
areas with active disease and avoiding those where the process is burnt-out. Close
collaboration between surgeon and pathology laboratory is essential.
Treatment
There are no randomised, double-blind, placebo-controlled trials in childhood ILD.
Thus, current treatment regimens for children are based on anecdote and/or are
derived from information provided by studies in adult patients, although expression
and outcome of ILD in children differ from adult ILD.
General measures
Supportive care includes administration of oxygen for chronic hypoxaemia, adequate
nutrition, annual immunisation with influenza vaccine along with other routine
immunisations against respiratory pathogens, aggressive treatment of intercurrent
infections, strict avoidance of tobacco smoke and other air pollutants, and the
selective use of bronchodilators. Further, the treatment of associated gastrooesophageal reflux, whether it is a primary or secondary phenomenon, may be
important.
Pharmacologic therapy
A few children with very mild disease do not require any treatment and recover
spontaneously. In the majority, however, treatment with immunosuppressive, antiinflammatory, or anti-fibrotic drugs is required for months to years. Although
responses to steroids are highly variable, a trial of corticosteroids for at least six to
eight weeks should be considered in every child with idiopathic ILD. The most
commonly used treatment consists of oral prednisolone in a start dose of 2
mg/kg/day. Alternatively, intravenous methylprednisolone may be given at a dose of
10-30 mg/kg (or 500 mg/m2) for three consecutive days at monthly intervals, usually
for six months. As pulsed steroid therapy may be associated with fewer side effects,
today this therapeutic strategy is preferred by a number of authors. Morbidity and
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mortality associated with ILD has to be balanced against the treatment risks; thus,
any medication has to be titrated to the lowest dose resulting in clinical stability.
There are no evidence-based criteria available that may be used for discontinuation
of corticosteroid treatment.
A number of alternative or steroid-sparing agents has been used with anecdotal
success in children with ILD; of these, the anti-malarial drug hydroxychloroquine (610 mg/kg/day in two doses) is the preferred agent. However, similar to steroids,
responses to hydroxychloroquine are highly variable. Patients with severe disease
may benefit from a combination of corticosteroids and hydroxychloroquine.
When steroids and hydroxychloroquine are not successful, or when there is evidence
of severe steroid side effects, other immunosuppressive or cytotoxic agents such as
azathioprine, cyclophosphamide, cyclosporin, or methotrexate may be used, but
evidence is even more anecdotal.
Specific treatment strategies
Patients with underlying systemic disorders require primary treatment for these
disorders, e.g. chemotherapy for malignancy, or intravenous gamma globulin for
hypogammaglobulinaemia. Specific therapeutic strategies include anti-infective
therapy for chronic respiratory infections (e.g. cytomegalovirus or Epstein-Barr virus
infection), interferon- for pulmonary haemangiomatosis, pulsed cyclophosphamide
for Wegener’s granulomatosis, and whole lung lavage and inhaled or subcutaneous
GM-CSF in idiopathic pulmonary alveolar proteinosis. In patients with hypersensitivity
pneumonitis, avoidance of the causative environmental antigen is of fundamental
importance. Furthermore, in patients treated with corticosteroids or cytotoxic agents
chronically,
prophylaxis
against
Pneumocystis
jirovecii
with
trimethoprim/sulfamethoxazole should be considered.
Transplantation
Lung or heart-lung transplantation may be offered as ultimate therapy for end-stage
ILD and for some lethal diseases such as those caused by mutations in the Sp-B and
ABCA3 genes. In recent years, transplantation has been shown to be a viable option
in children of all ages, even in young infants. There have been a few reports on the
recurrence of ILD in the recipient lung (e.g. Langerhans cell histiocytosis,
sarcoidosis).
Novel therapeutic approaches
New approaches to treatment of ILD involve substances directed against the action
of cytokines, growth factors and oxidants. Several of these agents (e.g. interferon-γ,
pirfenidone) have shown promise at the clinical trial stage in adult patients with
idiopathic pulmonary fibrosis.
Another cytokine-based approach is inhibition of tumour necrosis factor (TNF)- in
patients with pulmonary sarcoidosis; infliximab, pentoxifylline, etanercept, and
thalidomide have been studied in adult patients.
Monitoring
There are no well established guidelines to monitor the course of illness in children
with ILD. Usually, patients are assessed at regular intervals of three to six months or
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more frequently if severely ill. While in older children the response to treatment can
be assessed by lung function testing, in infants and small children decrease in
tachypnoea, return of weight gain and growth to normal levels, improved exercise
tolerance, and an increase in resting oxygen saturation levels of 3-4% are considered
to indicate a favourable response. As improvements on HRCT scans tend to occur
only over longer periods of time and radiation exposure should be minimised,
imaging plays a limited role. Repeat BAL appears to be indicated in pulmonary
haemorrhagic syndromes only.
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