The understanding of the mechanisms underlying the development and progression of ILD remains elusive 13 14 . Indeed, for a long time, chronic ILD and pulmonary fibrosis were believed to result mainly from chronic inflammation following an initial injury to the alveolar epithelial lining 15 16 . In cases of limited injury, it was thought that the reparative attempt could reverse the trend toward fibrosis. By contrast, in situations of continuing injury, the repair process driven by inflammatory molecules produced by the local cells will result in scarring and structural changes. Therefore, by targeting the inflammatory response, the belief was that fibrosis could be prevented or controlled. This theory explains the large use of anti-inflammatory therapy with, however, limited clinical efficacy.

Based on clinical and experimental observations, a new paradigm has progressively emerged with the alveolar epithelium being viewed as a key actor in the development of ILD 17 18 19 . Following injury, alveolar epithelial cells (AEC) may actively participate in the restoration of a normal alveolar architecture through a coordinated process of re-epithelialization, or in the development of fibrosis through a process known as epithelial-mesenchymal transition (EMT) 20 . Complex networks orchestrate EMT leading to changes in cell architecture and behaviour, loss of epithelial characteristics and gain of mesenchymal properties. The reasons for epithelial cell loss and inappropriate re-epithelialisation are still debated, but ongoing apoptosis is believed to be a key component in the progression of the disorder 21 . Prolonged denudation of the basement membrane contributes to altered interactions and cross-talk between AECs and mesenchymal cells, resulting in profound modifications of cell functions with imbalanced production of oxidants, proteases, and polypeptide mediators including cytokines and growth factors such as Transforming Growth Factor (TGF)-β and Endothelin (ET)-1. A consequence is the perpetuation of a vicious cycle with TGF-β promoting epithelial cell apoptosis, which in turn increases the local production of TGF-β 22 . ET-1 is also considered to be an important actor, based on the current knowledge of its numerous functions including fibroblast and smooth muscle cell mitogen, and stimulant of collagen synthesis 23 24 . Recent studies showed that ET-1 is produced by AEC, and could induce alveolar EMT via stimulation of endogenous TGF-β production.

ILD may be caused by myriad etiologies with differing prognoses and natural history. Indeed, multiple factors may injure the alveolar epithelium and initiate the development of ILD 25 . The initiating injury can be introduced through the airways and the circulation, or can occur as a result of sensitization. Consequently, the mechanisms underlying disease progression will be influenced by the causative event as well as by the host and the environment. These mechanisms are developed through interactions of multiple pathways, which include apoptotic pathways, developmental pathways, and endoplasmic reticulum (ER) associated pathways (Figure 1).

Apotosis plays a central role in lung remodeling associated with ILD 26 . An important molecule in the events associated with epithelial cell apoptosis is TGF-β, which is overexpressed in ILD. Downstream events linked to upregulation of TGF-β include modifications in the expression of various components of the cell cycle machinery, mainly the cyclin-dependent kinases (CDK) system that plays an essential role in ensuring proper cell cycle progression. Recently, much work has been focused on the protein p21cip1, a member of the CDK inhibitor family. This protein promotes cell cycle arrest to apoptosis in cases of cellular DNA damage. Interestingly, upregulation of p21cip1 has been reported in the lung tissues of patients with pulmonary fibrosis, primarily in hyperplastic alveolar epithelial cells 27 The increased expression of p21cip1 can favour the process of epithelial cell apoptosis. Apoptotic cells can also produce TGF-β. A consequence would be the perpetuation of a vicious cycle with TGF-β promoting epithelial cell apoptosis, which in turn increases the local production of TGF-β.

Recently, it has been suggested that genes associated with lung development and embryonic pathways could be involved in aberrant epithelium-mesenchymal crosstalk and epithelial plasticity, and could therefore participate in the development of chronic ILD. Selman and coworkers reported that lung fibrosis is characterized by enrichment for genes associated with cell adhesion, extracellular matrix, smooth muscle differentiations, and genes associated with lung development 28 29 30 31 . During EMT in the embryonic period, cells undergo a switch from a polarized epithelial phenotype to a highly motile mesenchymal phenotype 32 . Molecular processes governing EMT are induced by a cooperation of receptor tyrosine kinases or oncogenic Ras (RTK/Ras) pathway and TGF-β signaling 33 . Recently, additional pathways and effectors have been reported to play a role in the induction of EMT, such as Wnt//β-catenin, Notch and Sonic hedgehog signalling 34 .

Recent reports strongly suggest that the ER stress may represent an important mechanism of the altered repair process observed in the alveolar epithelium of fibrotic lung 35 . Situations associated with abnormal regulation of the cascade of events leading to the formation of mature protein result in either misfolding or mistargeting of the protein. These events trigger induction of intracellular aggregate formation and ER stress, which can lead to cell death through apoptosis and autophagic pathways 36 37 . Several stimuli including oxidant-antioxidant imbalance, viral proteins, inflammatory molecules, nutrient deprivation may induce ER stress 38 39 (Figure 2). Among the cytoprotective mechanisms available are the ER chaperones such as binding immunoglobulin protein (BiP). Interestingly, mutant BiP mice have been reported to die within several hours of birth from respiratory failure due to impaired secretion of pulmonary surfactant by type 2 AEC. In these animals, expression of surfactant protein (SP)-C was reduced and the lamellar bodies were malformed, indicating that BiP plays a critical role in the biosynthesis of surfactant 40 . Several recent reports suggest the possible implication of ER stress in ILD, with activation of stress response markers in fibrotic lung tissues.

It is now well established that surfactant dysfunction plays an important role in the development and progression of ILD. Pulmonary surfactant is a multimolecular complex constituted of phospholipids and proteins secreted by type 2 AEC into the alveolar space. It assures alveolar stability by reducing surface tension along the epithelial lining and this role involves mainly the lipids and the specific hydrophobic SP, SP-B and SP-C. Other important players in surfactant metabolism include the ATP-binding cassette, sub-family A, member 3 (ABCA3) and the thyroid transcription factor 1 (TTF-1).

Surfactant deficiency can be induced by a number of primitive and secondary mechanisms. Among them are genetic defects with mutations in SP-B gene (SFTPB) as well as genes coding for SP-C (SFTPC), ABCA3, and TTF-1 41 42 43 . More than 30 SFTPB (located on chromosome 2) mutations have been identified among patients with a congenital deficiency in SP-B. For SFTPC located on chromosome 8, at least 35 mutations have been described, localized primarily in the COOH- terminal Brichos domain 44 45 . A proposed function of the Brichos domain is a chaperone-like activity, which could prevent misfolding and aggregation of the parent protein. Alterations in the Brichos domain could therefore lead to diseases through mechanisms related to abnormal protein processing and cell toxicity 46 . Recently, several studies have also documented the role of ABCA3 deficiency in ILD. ABCA3 functions in the transport of surfactant lipids into lamellar bodies and is required to maintain pulmonary surfactant phospho-lipid homeostasis. Another contributor of ILD is TTF-1 (NK2 homeobox 1) dysfunction. TTF-1 is a critical regulator of transcription for the surfactant protein SP-B and SP-C. It is encoded by a gene located on chromosome 14q13 and is composed of three exon and two introns 47 . It is expressed in the thyroid, brain and lung.

Stem cell dysfunction represents a new domain of investigation. Alveolar epithelium regeneration and repair requires activation and proliferation of tissue-resident (progenitor) cells and their differentiation to replace the damaged cells 48 . However, unlike cancer cells, stem cells are not immortal and display decreasing telomere length with aging 49 . Telomere shortening has been documented to be associated with reduced capacity for stem cell renewal, and decreased activity of telomerase, the polymerase responsible for telomere maintenance. The stem cells of the alveolar epithelium are the type 2 AEC, and expression of telomerase has been documented in these cells 48 . Experimental studies have also indicated that telomerase is expressed mainly during lung development with a peak expression before birth followed by a decrease to nearly undetectable levels in mature alveolar epithelium. Interestingly, telomerase expression and activity could be reinduced in normal quiescent type 2 AEC exposed to oxidative stress 50 . The current understanding is that a population of type 2 AEC may have the capacity to survive injury through telomerase activation, and consequently may be responsible for repopulation of the damaged alveolar epithelium. On the basis of reports of pulmonary disorders in dyskeratosis congenita (a rare hereditary disease of poor telomere maintenance), recent and exciting findings have documented mutations in the telomerase gene in familial idiopathic pulmonary fibrosis 51 . In addition, it is likely that environmental factors such as inflammation, oxidative stress, or virus infection may modify telomerase activity and account for the development of organ-specific disease associated with telomerase dysfunction. In this view, new data in chronic respiratory diseases support the concept that alveolar stem cell dysfunction may play an important role in the rate of progression or severity in ILD 52 . The question whether telomerase mutations or telomere dysfunction may be implicated in pediatric ILD needs to be addressed in prospective studies, one possible tool being determination of telomere length in circulating leukocytes.

The frequency of lung fibrotic disorders is much lower in children than in adults. Some clinical situations have features certainly unique to children, but many of these diseases overlap their adult counterparts with the primary event being injury and damage of the alveolar epithelium 11 13 . Yet, the overall outcome and prognosis of the diseases in children are thought to be less severe than in adult patients. In addition, pediatric ILD is more responsive to therapeutic strategies than adult ILD 9 . These differences may be explained by the types of initial injury, which may not be similar due to changes in the host environment. Another explanation is the modifications of the process of wound healing with age. Comparison of the response to injury in foetal and adult skin shows clear differences 53 . Skin wound healing in the foetus is characterized by complete regeneration of the skin and the absence of scar formation. Progressively with age, the skin looses the capacity to regenerate the original tissue architecture with the result being scar formation that extends outside the wound bed. The process of healing involves the coordinated regulation of cell proliferation and migration and tissue remodeling, predominantly by polypeptide growth factors 54 . The slowing of wound healing that occurs in the aged may be related to changes in the activity of these various regulatory factors. In a study on the role of aging in the development of cardiac fibrosis in the rabbit, differences in the cascade of events leading to myocardial remodeling were observed, with mainly the presence of more myofibroblasts synthesising collagen and expressing high levels of TGF-β in older animals 55 . A study of growth factors involved in skin wound healing in young and aged mice also showed age-dependent changes. Expression of all the fibroblast growth factors was diminished in aged mice, even in healthy skin. In addition, the post-wound regulation of expression of these factors and of TGF-β was less pronounced and slower than in young mice. These findings are in agreement with data observed in muscle that indicated significant alterations in the TGF-β production with age 56 57 . Other potential mechanism is linked to the observation that injury in adult tissues does in certain circumstances stimulate tissue regeneration, depending on the presence of small subsets of primitive stem cells. Stem cells are the self-renewing, primitive, undifferentiated, multipotent source of multiple cell lineages 49 . While such cells are critical for development and growth through childhood, residual pools of adult stem cells are hypothesized to be the source of the frequently limited tissue regeneration and repair that occurs in adults 58 . Unlike embryonic stem cells, adult stem cells are not immortal, and show decreasing telomere length with increasing age. The naturally limited replacement capacity of such endogenous stem cell pools may occur via exhaustion of the stem cell pool or arise as a consequence of inherited or acquired mutations that alter proper stem cell function 59 . The limited life span of cells may result from replicative senescence in response to various stresses including DNA damage, oxidants, and telomere erosion 52 . All these forms of injury have been documented in the lung from adult patients with ILD.

The prevalence of children ILD is higher in the younger patients: more than 30% of patients are less than 2 years at diagnosis, as recorded by the recent ERS Task Force. 7% have parental consanguinity and nearly 10% of case siblings were affected by similar diseases. There is a male predominance with a sex ratio of 1.4. The presenting clinical manifestations are often subtle and non-specific. The onset of symptoms is, in most cases, insidious and many children may have had symptoms for years before the diagnosis of ILD is confirmed. However, the majority of patients has symptoms for less than one year at the time of initial evaluation. The clinical manifestations vary from asymptomatic presentation with radiological features suggestive of ILD to more characteristic presence of respiratory symptoms and signs such as cough, tachypnea and exercise intolerance 9 60 . These varying presentations are also reflected in the report published by Fan et al. who systematically evaluated the clinical symptoms and physical findings of 99 consecutive children with ILD 2 . Common symptoms at presentation included cough, dyspnea, tachypnea and chest wall retraction, exercise limitation and frequent respiratory infections. Cough is observed in almost 75% of the patients, is normally non-productive and does not disturb sleep. Tachypnea is observed in 80% of patients and is usually the earliest and most common respiratory symptom. Unexplained fever is also reported in almost one third of infants. Failure to thrive (37%), tiring during feeding and weight loss are also common symptoms, mainly in young patients. Although a history of wheezing may be elicited in almost 50% of the patients, wheezing is documented by physical examination in only 20% of the cases.

The frequent clinical findings are inspiratory crackles (44%), tachypnea and retraction. In a child with a normal birth history, these are strongly suggestive of ILD. Other findings associated with an advanced stage of lung disease include finger clubbing (13%) and cyanosis during exercise or at rest (28%) 9 61 . During physical examination it is essential to check the presence of associated non-respiratory symptoms such as joint disease, cutaneous rashes, and recurrent fever suggestive of collagen-vascular disorders. Details should also be obtained on precipiting factors such as feeding history, infections, or exposure to dust and drugs. In addition, information on relatives or siblings with similar lung conditions should be gathered.

Plain radiographs are usually performed in a child suspected of ILD at first presentation, but the information provided is often limited and the key chest imaging tool for diagnosis is the High Resolution Computed Tomography (HRCT), which can visualize the parenchymal structure to the level of the secondary pulmonary lobule.

HRCT technique for ILD diagnosis has been extensively discussed 62 63 64 . To optimise spatial resolution, there is a general agreement to use thin sections, the smallest field of view and a sharp resolution algorithm. The most common HRCT feature of ILD is widespread ground-glass attenuation. Intralobular lines, irregular interlobular septal thickening and honeycombing are less common findings. Large subpleural air cysts in the upper lobes adjacent to areas of ground-glass opacities have been also reported in young children with ILD. These cysts are interpreted as paraseptal or irregular emphysema. HRCT is useful for ILD diagnosis and selection of lung area to be biopsied. It is proposed that it also may contribute to monitor disease activity and/or severity. However, evaluation is still needed to support a role of HRCT as a follow up tool in pediatric patients.

Pulmonary function testing (PFT) techniques are well established in children and adolescents. However, children aged 2-6 years represent a real challenge in pulmonary function assessment as they cannot be sedated and find it difficult to cooperate with all respiratory manoeuvres. In 2007, an ATS and ERS statement on PFT in preschool children summarized the current knowledge on the PFT techniques suitable for young children 65 66 .

Although PFT does not provide specific information, it represents a useful investigation for both the diagnosis and the management of ILD 11 . Generally, in ILD, pulmonary function abnormalities reflect a restrictive ventilatory defect with reduced lung compliance and decreased lung volumes 67 68 69 . Vital capacity (VC) is variably diminished; the decrease in total lung capacity (TLC) in general is relatively less than in VC. Functional residual capacity (FRC) is also reduced but relatively less than VC and TLC, and residual volume (RV) is generally preserved; thus the ratios of FRC/TLC and RV/TLC are often increased. Airway involvement is observed only in a minority of patients. Lung diffusing capacity of carbon monoxide (DLCO) or transfer factor (TLCO) is often markedly reduced and may be abnormal before any radiological findings. However, DLCO corrected for lung volume may also be normal in many children. Hypoxemia as defined by a reduced resting arterial oxygen saturation (SaO₂) or a reduced resting arterial oxygen tension is often present. Hypercarbia occurs only late in the disease course. During exercise the above described dysfunctions become even more pronounced. Thus, gas exchange during exercise might be a more consistent and sensitive indicator of early disease 3 .

Bronchoalveolar lavage (BAL) usefully provides specimens for cytological examination, microbial cultures, and molecular analysis. Besides infections, BAL can be of diagnostic value in several situations. In the context of pulmonary alveolar proteinosis, BAL abnormalities are characterized by milky appearance fluid, abundant proteinaceous periodic acid schiff positive material, and presence of foamy alveolar macrophages (AM) 70 . BAL can also be diagnostic for pulmonary alveolar haemorrhage 11 . This diagnostic is easy when the BAL fluid has a bloody or pink color, but its gross appearance may be normal. Microscopic analysis may then be of value by documenting the presence of red blood cells in AM or haemosiderin laden AM 71 . Among other situations, the diagnosis of Langerhans cell histiocytosis can be performed with the use of the monoclonal antibodies revealing the presence of CD1a positive cells (in more than 5% of the BAL cells) 72 . Lipid disorders with lung involvement represent another indication of BAL. This includes congenital lipid-storage diseases (Gaucher's disease and Niemann-Pick disease) or chronic lipid pneumonia due to chronic aspiration 73 74 . However, in cases of aspiration syndromes, the presence of lipid laden AM is sensitive but not specific 75 .

In other pathological situations, BAL can usefully serve to direct further investigations. Accumulation of BAL T-lymphocytes with prevalence of CD4+ cells is suggestive of sarcoidosis, whilst prevalence of CD8+ cells is suggestive of hypersensitivity pneumonitis 76 . Also, an increase in BAL eosinophils suggests pulmonary infiltrates associated with eosinophilia syndromes 77 . Depending of the underlying diseases, a number of cellular and molecular investigations can be proposed including the studies of various surfactant components, phospholipids and apoproteins 78 .

With increasing recognition of the different patterns of ILD and their clinical significance, histological investigation has become increasingly important. Depending on disorder presentation, biopsy may concern more accessible organs than the lung such as the skin or the liver in sarcoidosis. Histological evaluation of lung tissue usually represents the final step in a series of diagnostic approaches.

Different methods may be used to obtain lung tissue. The major difference between individual methods lies mainly in balancing invasiveness against the potential for obtaining adequate and sufficient tissue for diagnosis. The techniques of choice are open lung biopsy and video assisted thoracoscopy biopsy. In children, open lung biopsy usually provides sufficient tissue with few complications related directly to the biopsy procedure 79 . Video assisted thoracoscopy biopsy is an alternative to open lung biopsy, and it has been shown that the procedure can be safely performed, even in small children 80 . The place of other methods like transbronchial lung biopsy and percutaneous needle lung biopsy in appropriate diagnosis of pediatric patients with ILD has to be established 81 82 83 .

The lung histological patterns that can be observed in ILD have been reviewed by the ATS/ERS 5 . In children, they include mainly: DIP, NSIP, and LIP. DIP is characterized by airspaces filled with AM, thickened alveolar septa, scattered mixed inflammatory cells and minimal fibrosis. Many alveolar spaces are lined by hyperplastic type 2 AEC. Recently, association with surfactant disorders has been reported 41 84 85 86 . NSIP encompasses a broad spectrum of abnormalities with varying degrees of alveolar wall inflammation or fibrosis. The cellular pattern of NSIP is characterized by mild to moderate interstitial chronic inflammation and type 2 AEC hyperplasia in inflammation areas. It has been reported in a variety of underlying conditions including connective tissues diseases and surfactant disorders. LIP features include a marked diffuse infiltrate of mature lymphocytes, plasma cells and histiocytes within the pulmonary interstitium, particularly the alveolar walls. They are often associated with either connective tissues disorders or immunodeficiency states, both congenital and acquired 9 . Another pattern described mainly in adults is diffuse alveolar damage (DAD), which includes diffuse homogeneous thickening of alveolar interstitial walls with myofibroblast accumulation, prominent type 2 AEC hyperplasia and atypia, and hyaline membranes containing surfactant proteins and cellular debris 87 . Usual interstitial pneumonia (UIP) is rare in children 88 . It is characterized by severe remodeling of the alveolar structure with heterogeneous appearance consisting of contiguous areas of normal lung, dense scarring, and bronchiolar abnormal proliferation. Interstitial inflammation is usually mild to moderate. Histologic patterns of ILD unique to infancy are described below.

Laboratory tests are used to exclude a number of respiratory diseases in childhood that does not typically present with ILD such as chronic aspiration syndromes, resolving acute respiratory distress syndrome, tuberculosis, cystic fibrosis, bronchopulmonary dysplasia and diffuse pulmonary disease such as cystic fibrosis. Laboratory tests also verify the absence of immunodeficiencies 3 .

When these conditions have been eliminated, the spectrum of investigations that should be performed for the diagnostic approach will be guided by the history and clinical presentation in each individual child. These investigations are discussed below for the various disorders. In addition, an increasing number of blood and BAL biomarkers for evaluation of disease severity and progression is currently investigated. The studied molecules include various cytokines and chemokines, surfactant protein D, Krebs von den Lungen-6 antigen (KL-6), matrix metalloproteinases MMP1 and MMP7 and defensins 89 90 91 92 .

Exposure-related disease refers to diseases caused by a sufficient level of exposure (dose) to components with target organ contact, and subsequent biologic changes and clinical expression. Many agents have been associated with pulmonary complications of various types including ILD. The adult literature has provided extensive lists of candidate molecules 93 . In children, the potential involvement of these molecules is not similar as the environmental conditions and the use of therapeutic drugs differ. It is important to point out that exposure-related diseases are certainly under-estimated in the pediatric age. One reason is linked to the fact that the diagnosis is less often discussed than in adults as pediatricians and other child health care providers do not usually have the expertise necessary to take an environmental history. In this review, the most frequent causes of exposure-related ILD are discussed.

Depending on the causes, the components of the alveolar structure (the epithelium and the alveolar space, the interstitium, and the pulmonary capillary endothelium) can be involved differently and can serve as primary targets of the underlying pathological processes. Based on history, clinical presentation, BAL data, and, most important, on information from lung tissue studies, the disorders can be gathered in groups according to predominant structural targets (Figure 4).

In the context of ILD, pulmonary interstitial glycogenosis, neuroendocrine cell hyperplasia, and chronic pneumonitis in infancy have been reported to be exclusively observed in very young children 8 .

Pulmonary interstitial glycogenosis (PIG) is a non lethal disease, reported in neonates with respiratory distress syndrome developed shortly after birth 193 194 . Very few cases are described so far but it seems to have a male preponderance 195 . The histological hallmark of pulmonary interstitial glycogenosis is the accumulation of monoparticulate glycogen in the interstitial cells on lung biopsy. It is thought to represent a maturation defect of interstitial cells that leads them to accumulate glycogen within their cytoplasm 8 196 . It is discussed that PIG could meet "chronic pneumonitis in infancy" as this remains a generalized term 87 . As well, PIG could be considered as a premature lung disease, but more than half of published cases were in term infants 195 197 198 . The long term consequences in these infants need to be ascertained.

Neuroendocrine cell hyperplasia of infancy (NCHI) is also a non lethal disease characterized by tachypnea without respiratory failure. The human airway epithelium contains highly specialized pulmonary neuroendocrine cells (PNEC) system. It's function remains unknown but is hypothysed to act in modulation of fetal lung growth and in post-natal stem cell condition 199 . The PNEC system permits synthesis and release of serotonin and neuropeptides such as bombesin 200 . As normal bombesin levels decrease after mid-gestation, its overexpression in NCHI could be attributed to a non-regression of neuroendocrine cells 201 . Clinical presentation is typically a respiratory distress in post-natal young infant (mean age 3.8 months in a large serie, but cases in older children have been reported 202 . HRCT shows patchy centrally ground-glass opacifications and air trapping 203 . On lung biopsy, the histological abnormality is hyperplasia of neuroendocrine cells within bronchioles documented by bombesin immunohistochemistry. The follow-up reveals in some cases the persistence of tachypnea and oxygen requirement for several months. Usually, there is a good prognosis 7 8 196 202 .

Chronic pneumonitis in infancy was first described by Katzenstein et al. 4 . The clinical and radiologic features are similar to those observed in other forms of ILD. Specific histologic abnormalities include diffuse thickening alveolar septa, hyperplasia of type 2 AEC, and presence of primitive mesenchymal cells within the alveolar septa. In some cases, foci of pulmonary proteinosis-like material have been observed in air spaces. The prognosis has been reported to be poor with a high mortality rate.

Other disorders associated with pulmonary development and growth abnormalities encompass a broader spectrum of respiratory manifestations and are more adequately integrated in the classification of diffuse lung diseases 8 .

Management of children with ILD includes administration of oxygen for chronic hypoxaemia, and maintenance of nutrition with an adequate energy intake, Immunization with influenza vaccine on an annual basis is recommended along with other routine immunizations against major respiratory pathogens 11 . In addition, aggressive treatment of intercurrent infections and strict avoidance of tobacco smoke and other air pollutants are strongly recommended.

A very few children do not require any treatment and recover spontaneously. In the majority of cases, treatment with immunosuppressive, anti-inflammatory, or anti-fibrotic drugs is required for weeks, months or even years 1 9 61 . Various drugs discussed below can be used, but no guidelines for treatment of ILD in children have been proposed so far. The major reason is the very limited number of pediatric patients available for a prospective clinical trial. In addition, controlled studies with a placebo arm are unacceptable because of the poor prognosis of untreated cases and the reported efficacy of anti-inflammatory therapies in a number of pediatric ILD.

At the present time, the main therapeutic strategy is based on the concept that suppressing inflammation may most likely prevent progression to fibrosis. Among the anti-inflammatory agents used in pediatric ILD, steroids are the preferred choice, administered orally and/or intravenously. This has been well illustrated by the results of the ERS Task Force on pediatric ILD 9 . Oral prednisolone is most commonly administered at a dose of 1-2 mg/kg/day 1 . Children with significant disease are best treated with pulsed methylprednisolone at least initially 61 204 . This is usually given at a dose of 10-30 mg/kg/day for 3 days consecutively at monthly intervals. The minimum number of cycles recommended is 3 but treatment may need to be continued for a longer period of 6 months or more depending on response. When the disease is under control, the dosage of methylprednisolone can be reduced or the time between cycles can be spaced out. The disease may then be controlled with oral prednisolone preferably given as an alternate day regime. In few cases oral prednisolone is used from the beginning simultaneously with intravenous methylprednisolone but this is only recommended in those with very severe disease. Methylprednisolone may be effective when other forms of steroids administration fail without significant side effects.

An alternative to steroids is hydroxychloroquine with a recommended dose of 6-10 mg/kg/day. Individual case reports have described a response to hydroxychloroquine even in the presence of steroid resistance 1 205 206 . Some groups have proposed to base the decision as to which agent to use on the lung biopsy findings, with a preference for steroids in case of large amount of desquamation and inflammation and for hydroxychloroquine if increased amounts of collagen representing pre-fibrotic change are found. However, as documented in the ERS Task Force on pediatric ILD, the preferred choice between steroids or hydroxychoroquine in children is highly dependent on the expertise of the center in charge of the patient, and does not seem to be oriented by the histopathological pattern 9 . In case of severe disease, steroids and hydroxychloroquine may be associated. In situations of inefficiency of steroids and hydroxychloroquine, other immunosuppressive or cytotoxic agents such as azathioprine, cyclophosphamide, cyclosporine, or methotrexate may be used. These treatments have been used mainly in situation of autoimmune disorders.

Promising therapeutic options include macrolides. Indeed, these antibiotics have been shown to display a number of anti-inflammatory and immunomodulatory actions. Although the mechanisms and cellular targets specific to macrolide activity remain to be elucidated, beneficial effects in several chronic lung diseases including chronic obstructive pulmonary diseases (COPD) and cystic fibrosis have been reported 207 208 . Of interest is the ability of macrolides to accumulate in host cells including epithelial cells and phagocytes. In a recent report, a favorable response to treatment with clarithromycine has been described in an adult patient with DIP 209 . Other new therapeutic strategies currently proposed in adult patients target fibrogenic cytokines. The Th1 cytokine interferon-γ has an antifibrotic potential through suppression of Th2 fibrogenic functions. Antagonists to TGF-β include pirfenidone and decorin. The use of molecules directed against TNF-α such as the soluble TNF-α receptor agent etanercept is also under investigation. To date, there are no reports on the use of these novel therapies in pediatric ILD. Finally, in the coming years, it is likely that an expanding number of molecules aimed at favoring alveolar surface regeneration and repair through activation and proliferation of tissue-resident (progenitor) cells will come out.

Depending on the underlying diseases, several specific treatment strategies needs to be considered. These include whole lung lavage for pulmonary alveolar proteinosis, which has been reported to be effective by removing the material from the alveolar space 210 . GM-CSF has also been shown of interest in this disease 171 . Other strategies such as interferon-α for pulmonary haemangiomatosis are effective 211 .

In recent years, lung transplantation has emerged as a viable option in children of all ages, even in young infants, and lung or heart-lung transplantation may be offered as an ultimate therapy for end-stage ILD 11 . The outcome and survival do not seem to be different from those reported in conditions others than ILD, although comparisons are difficult to establish due to the limited number of reported cases.

Response to treatment and outcome can be evaluated in children based on several criteria such as decrease in cough and dyspnea, increase in oxygenation at rest and sleep, and changes in pulmonary function tests 1 11 . Improvement on thoracic HRCT may also be seen, but tends to occur over a much longer period of time. Reports in pediatric ILD have not shown a good correlation between histological findings and outcome. Some children with relatively severe fibrosis on lung biopsy make good progress, whereas others with mild desquamation have a poor outcome. This is probably due to the variable severity of the disease in different parts of the lung especially in relation to the particular area biopsied, despite HRCT guidance. Overall a favorable response to corticosteroid therapy can be expected in 40-65% of cases, although significant sequelae such as limited exercise tolerance or the need for long-term oxygen therapy are often observed. Reported mortality rates are around 15%. The outcome for infants is more variable 1 61 .