Approach to the infant and child with diffuse lung disease (interstitial lung disease)

INTRODUCTION — Diffuse lung disease (DLD), traditionally known as interstitial lung disease (ILD), consists of a diverse group of disorders that involve the pulmonary parenchyma and interfere with gas exchange. Although some of the conditions that cause DLD in children and adults are similar, they occur in different proportions in each population. In addition, certain diseases are unique to infants [1-6].

Children with DLD may present with respiratory failure, or with more indolent or chronic symptoms including tachypnea, retractions, cough, persistent unexplained hypoxemia with an otherwise uncomplicated respiratory infection, exercise intolerance, failure to thrive, or other nonspecific symptoms. Thus, the differential diagnosis is broad, and the first approach is to exclude more common causes for this presentation, including infection, immunodeficiency, structural airway abnormalities, congenital heart disease, and cystic fibrosis [7].

Once more common explanations are excluded, a child with unexplained pulmonary symptoms and diffuse pulmonary infiltrates should be given a provisional diagnosis of DLD, and further investigations to determine a specific cause are warranted [7]. Establishing a definitive diagnosis may inform prognosis, genetic counseling for families, and in some cases may alter treatment decisions. However, for many forms of DLD, treatment options are limited and often include drugs of unproven efficacy with substantial side effects. Thus, DLD presents a diagnostic and therapeutic challenge, even to the most experienced pediatric pulmonologist.

This topic review provides an approach to the diagnosis and management of DLD (including ILDs) in infants and children. Other topic reviews with related content include:

●(See "Classification of diffuse lung disease (interstitial lung disease) in infants and children".)

●(See "Genetic disorders of surfactant dysfunction".)

●(See "Neuroendocrine cell hyperplasia of infancy (NEHI)".)

●(See "Pulmonary alveolar proteinosis in children".)

●(See "Approach to the adult with interstitial lung disease: Clinical evaluation".)

TERMINOLOGY — The term "diffuse lung disease" (DLD) describes a diverse group of disorders that involve the pulmonary parenchyma and interfere with gas exchange. This term reflects the spectrum of underlying pathology, which often includes extensive alteration of alveolar and airway architecture, in addition to changes in the interstitial compartment. These disorders have traditionally been described as "interstitial lung disease" (ILD), but that term is less accurate because the interstitium is not involved in some types, such as neuroendocrine cell hyperplasia of infancy. Another term used in the literature is "diffuse parenchymal lung disease" [8].

The term childhood ILD (chILD) syndrome is sometimes used to describe a case in which ILD or DLD is suspected based on clinical and radiologic features but a specific cause has not yet been established.

EPIDEMIOLOGY — DLD is rare in childhood. Epidemiologic studies vary in their prevalence estimates, in part due to use of different case definitions and ascertainment methods. A study from Germany reported 1.32 cases per million children ≤16 years of age, excluding those secondary to underlying systemic disease (autoimmune or immunodeficiency) [9]. An earlier study from the United Kingdom and Ireland estimated a prevalence of 3.6 cases per one million children; this study included only patients who were diagnosed with ILD after lung biopsy by a specialist and may have failed to capture cases with mild symptoms [10]. Other studies suggest that these disorders disproportionately present in the first year of life [9-12], and are slightly more common among boys than girls, particularly in children younger than two years of age [11]. Each of these studies focused on a somewhat narrower spectrum of disease compared with the more current definition of DLD.

It is likely that estimates of DLD prevalence will increase as more current and broader definitions of DLD are used (table 1) and as these disorders are increasingly recognized by clinicians. Studies using rigorous case ascertainment methods typically detect higher rates of these diseases than those reported to registry studies [13-15]. As an example, a prospective study in France collected 205 cases of childhood DLD in three years, suggesting that targeted case identification efforts may provide new information about the epidemiology of these disorders [15]. A publication from Spain reported 381 cases in a two-year period, 209 of which (55 percent) were in infants [16].

The identification of genetic causes of childhood DLD, including those due to mutations in genes involved in surfactant production and metabolism, have led to more definitive estimates of the population frequency of these specific subtypes [17-19] (see "Genetic disorders of surfactant dysfunction"). Improved coding for childhood DLD in the International Classification of Diseases may also facilitate improved estimates of the frequency of childhood DLD [20].

CLASSIFICATION — DLD comprises a heterogeneous group of disorders that are classified together because of similar clinical, radiographic, physiologic, or pathologic manifestations.

There are several potential ways in which to classify DLD in children, and the frameworks continue to evolve, driven in part by increased understanding of the underlying genetic and molecular mechanisms [7,13,21]. Age at presentation is a key organizing principle of this classification structure. The classification is broadly divided into "disorders more prevalent in infancy" and "disorders not specific to infancy" (table 1). Within this classification, it is also useful to distinguish between DLD that is primarily a pulmonary-specific process and forms that occur in association with a systemic disorder (table 2). For types of DLD that have no recognized causes and are not associated with a systemic disease, histopathologic patterns remain important components of classification (table 3). A discussion of the classification of DLD in infants and children is presented separately. (See "Classification of diffuse lung disease (interstitial lung disease) in infants and children".)

CLINICAL PRESENTATION — The possibility of DLD should be considered in the following situations:

●Any neonate who presents with unexplained respiratory failure.

●Late preterm or preterm infants who present with chronic lung disease out of proportion to the degree of prematurity or other known comorbidities [22,23].

●Infants and children with a normal birth history who present with persistent tachypnea, crackles, hypoxemia, chronic cough, or clubbing of the digits. Feeding difficulties, poor weight gain, and gastroesophageal reflux are also common presenting features [13,24]. Exercise intolerance may be the presenting feature in older children.

●A young infant with tachypnea in the early months who is hospitalized with an acute viral respiratory infection and more severe morbidity (respiratory failure, hypercapnia or persistent hypoxemia) than would be expected. This is particularly true if there is a family history of a similarly affected sibling (see "Classification of diffuse lung disease (interstitial lung disease) in infants and children", section on 'Disorders more prevalent in infancy') [10,22].

●Chest imaging showing persistent diffuse infiltrates of otherwise unknown etiology.

Outside of the neonatal age group, the onset of symptoms usually is insidious and their duration before presentation often is substantial. In a retrospective study of 48 children with DLD, 44 percent were symptomatic for more than one year before diagnosis [25]. In a study from the European Respiratory Society Task Force (ERSTF), the mean duration of symptoms before diagnosis was 6.6±0.5 months [11]. More than 25 percent of children with DLD have pulmonary hypertension at presentation [26], and 35 percent have been treated for asthma before undergoing a definitive evaluation [25].

Some groups have used a definition of DLD that requires symptom duration of three or more months [11]. Such an approach likely helps exclude more common infectious and transient causes of similar symptoms, but fails to capture some of the forms of DLD most prevalent in infancy that may present at birth and need prompt evaluation. Furthermore, for older children, if symptoms are persistent, severe, and otherwise unexplained, it is not necessary to wait for a period of three months before pursuing further investigations for possible DLD.

DIAGNOSTIC APPROACH — The overall approach to the diagnostic evaluation is guided by an assessment of the clinical context and disease severity, taking into consideration factors such as the presence of hypoxemia, pulmonary hypertension, failure to thrive, immunocompetence, family history, and trend toward worsening or improvement [7]. Diagnostic studies are used to evaluate for predisposing disorders, to assess the extent and severity of disease, and to identify the primary DLD disease, if possible (table 4). The most useful approach to diagnosis is obtaining a history and physical examination, followed by noninvasive tests and invasive studies if needed. Genetic testing may obviate the need for more invasive studies such as lung biopsy and, thus, should be considered early in the evaluation in the appropriate clinical context. (See "Genetic disorders of surfactant dysfunction".)

Even with a thorough evaluation, it is not always possible to identify a specific disorder. In a series of children with DLD, a staged approach similar to the one described above provided a specific diagnosis in approximately 70 percent [27]. Among the 51 patients, the diagnosis was based on history and physical examination alone in one patient, noninvasive tests in eight (16 percent) patients, and invasive studies (including lung biopsy) in 26 patients (51 percent). Of the remaining patients, eight (16 percent) had a suggestive diagnosis and eight (16 percent) had no specific diagnosis. Similarly, in a multicenter survey regarding the diagnostic evaluation of 131 children with DLD, an etiologic or histologic diagnosis was achieved in 89 percent; only 4 percent of patients were diagnosed with noninvasive techniques alone [12]. In another large multicenter study, 11 percent of lung biopsy cases were not classifiable despite expert pathology review, largely due to technical limitations of limited tissue sampling and processing [13].

History

●History of respiratory symptoms – The history should include details about the duration and severity of symptoms of possible restrictive lung disease, including tachypnea and dyspnea, retractions, exercise intolerance, and/or dry cough. However, these historical features are neither sensitive nor specific for DLD diagnosis.

Presenting symptoms of chronic DLD in immunocompetent children (185 cases overall, 58 in children <2 years) were documented in a retrospective review by the European Respiratory Society Task Force (ERSTF) [11]. The most common symptoms of chronic DLD included:

•Cough (78 percent overall, 73 percent of those <2 years)

•Tachypnea/dyspnea (76 percent overall, 84 percent of those <2 years)

•Failure to thrive (37 percent overall, 62 percent of those <2 years)

•Fever (20 percent overall, 29 percent of those <2 years)

Presenting symptoms in children <2 years undergoing lung biopsy for DLD were further described in a separate multicenter study by the Children's Interstitial and Diffuse Lung Disease Research Network (ChILDRN) network [13]. Hypoxemia, tachypnea, and retractions were present in the majority but not all cases. Gastroesophageal reflux and failure to thrive were documented in one-half of cases, while crackles, cough, and wheezing were present in less than one-half of cases.

●Other symptoms – The history should also seek details about symptoms that may suggest an underlying cause, including the following:

•Feeding difficulties – Aspiration

•Hemoptysis – Pulmonary hemorrhage

•Febrile or acute respiratory illness – Infection

•Exposure to birds or organic dusts – Hypersensitivity pneumonitis

●Associated medical problems – In addition, the clinical context may greatly help focus further investigations. In patients with a history of connective tissue disease, autoimmune disease, or immune deficiency, the DLD is likely to be secondary to the systemic disorder (table 2). Patients without these diagnoses but with suggestive symptoms (eg, recurrent fever, arthritis, rash, nail dystrophy, or anemia) should be further evaluated for the suspected underlying disorder. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis" and "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis" and "Approach to the child with recurrent infections".)

●Family history – A family history of chronic lung disease may reveal an inherited form of DLD. In the ERSTF study described above, 10 percent of children with chronic DLD had affected siblings [11]. A history of unexplained neonatal respiratory failure raises suspicion for surfactant dysfunction disorders and other forms of DLD more prevalent in infancy (table 1). A family history of bone marrow hypoplasia or premature hair graying raises the possibility of dyskeratosis congenita. (See 'Extrapulmonary manifestations' below.)

Physical examination — The physical examination in patients with DLD is frequently abnormal, but the findings are nonspecific. Tachypnea and retractions typically are present in young children. Failure to thrive signifies chronic or advanced disease.

●Crackles or "velcro rales" are common in most forms of DLD; in the ERSTF study, they were present in 44 percent of patients overall but only 9 percent of those <2 years [11].

●Wheezing has been reported in approximately 20 percent of children with DLD [13,25].

●Cardiac examination usually is normal except in the late stages of DLD, when findings of pulmonary hypertension and cor pulmonale (augmented P2, right-sided lift, right-sided gallop) may become evident.

●Cyanosis is indicative of more severe disease; in the ERSTF study, it was present in 28 percent of patients overall and 54 percent of those <2 years [11].

●Clubbing of the digits (ie, the distal part of the finger is enlarged compared with the proximal part) is a late manifestation suggesting advanced disease (figure 1). In the ERSTF study, it was present in 13 percent of patients overall and 9 percent of those <2 years [11].

●Chest wall deformities may include either pectus excavatum or signs of hyperinflation [24,28].

Extrapulmonary manifestations — Extrapulmonary manifestations may be helpful in narrowing the differential diagnosis, particularly in older children where the features and subtypes of DLD overlap more substantially with forms of DLD in adults (table 5). These include skin, eye, and nail findings; anemia or pancytopenia; lymphadenopathy; arthritis; and hepatosplenomegaly. As an example, dyskeratosis congenita may be associated with pulmonary fibrosis, which has occasionally presented during late childhood or early adolescence [29]. Dyskeratosis congenita is characterized by bone marrow hypoplasia or failure, reticulated skin hyperpigmentation, nail dystrophy, and mucosal leukoplakia (picture 1). (See "Dyskeratosis congenita and other telomere biology disorders".)

Diagnostic testing — The first step is to exclude other more common causes for the respiratory signs and symptoms (table 4). The differential diagnosis of DLD in infants and children varies depending on the clinical setting [21]. However, the more common diagnoses to consider include:

●Cystic fibrosis (see "Cystic fibrosis: Clinical manifestations and diagnosis")

●Congenital or acquired immunodeficiency (see "Approach to the child with recurrent infections")

●Congenital heart disease (see "Identifying newborns with critical congenital heart disease")

●Bronchopulmonary dysplasia (see "Bronchopulmonary dysplasia (BPD): Clinical features and diagnosis")

●Pulmonary infection (see "Neonatal pneumonia" and "Pneumonia in children: Epidemiology, pathogenesis, and etiology")

●Recurrent aspiration (eg, gastroesophageal reflux, swallowing dysfunction, or anatomic abnormalities of the larynx, trachea, or esophagus) (see "Aspiration due to swallowing dysfunction in children")

●Structural airway abnormalities (see "Congenital anomalies of the intrathoracic airways and tracheoesophageal fistula")

It is important to recognize that children with DLD may have some of the above comorbidities. Therefore, DLD investigations may be considered in children with the above diagnoses if disease is persistent despite addressing the above factors or if the respiratory symptoms are out of proportion to the underlying disease [7]. This is particularly true for infants or children with gastroesophageal reflux and suspected aspiration because it is often difficult to determine whether aspiration is occurring secondary to lung disease or is instead the primary cause of symptoms. (See "Aspiration due to swallowing dysfunction in children".)

Laboratory studies — Routine laboratory evaluation rarely establishes the diagnosis of a specific DLD. Nonetheless, the overall purpose is to screen for evidence of systemic or multiorgan system disease, to assess complicating factors, and to potentially provide supportive evidence in the context of the clinical presentation. Considerations for laboratory testing include hematologic tests, evaluation for infectious etiologies, evaluation of immune function, serologic studies investigating possible autoimmune disorders, and testing for hypersensitivity pneumonitis (table 4 and table 6). A complete blood count and general chemistries are appropriate in almost all infants. Quantitative immunoglobulins should be strongly considered in most cases, except those presenting at birth. Rheumatologic evaluations are generally reserved for older children, for infants presenting with pulmonary hemorrhage, or for toddlers with multiorgan manifestations.

Genetic testing — Analysis of blood can identify the common genetic mutations that cause surfactant dysfunction [22] and thus avoid the need for more invasive evaluations such as lung biopsy [7,17,30]. This testing is suggested for infants presenting with acute respiratory failure in the absence of other explanations or in older children with chronic presentation or family history of DLD, especially if the diagnostic imaging is consistent with DLD [7,31].

A growing number of genetic etiologies are being identified as causes of DLD in children:

●Mutations in the SFTPB, SFTPC, ABCA3, and NXK2-1 genes affect the quantity and/or quality of surfactant production. Mutations in the CSF2RA, CSF2RB, SLC7A7, MARS1, GATA2, STAT5B, and OAS1 genes impact the catabolism of surfactant via macrophage dysfunction [31,32]. (See "Genetic disorders of surfactant dysfunction".)

●Mutations and deletions in the FOXF1 gene are associated with alveolar capillary dysplasia (ACD), with or without misalignment of the pulmonary veins (ACD-MPV), and genetic testing for these mutations is particularly appropriate in a neonate with severe pulmonary hypertension without other explanation. (See "Classification of diffuse lung disease (interstitial lung disease) in infants and children", section on 'Alveolar capillary dysplasia with or without misalignment of the pulmonary veins'.)

●Mutations in the FLNA gene cause X-linked periventricular nodular heterotopia and have also been associated with severe DLD with alveolar simplification (mimicking emphysema) and pulmonary hypertension, with a variety of extrapulmonary manifestations [33-36].

●Mutations in the TBX4 and ITGA3 genes are also associated with altered lung development [37,38].

●Mutations in the SMPD1 gene cause acid sphingomyelinase deficiency (Niemann-Pick types A and B), in which lung disease is related to accumulation of sphingomyelin in macrophages [39]. Niemann-Pick type C is also associated with lung disease, through a different mechanism. (See "Overview of Niemann-Pick disease", section on 'Classification and clinical features'.)

●Mutations in the COPA gene are associated with an immune dysregulation, arthritis, and pulmonary hemorrhage syndrome [40].

●A growing list of genetic causes have been associated with DLD associated with immunodeficiency or primary immune regulatory disorders [41]. For example, mutations in the STAT3 gene have been shown to lead to autoimmunity and lymphocytic interstitial pneumonia [42]. Mutations in the LRBA gene, which encodes a protein involved in trafficking of CTLA4 in Treg cells, have also been identified in patients with common variable immunodeficiency and lymphocytic interstitial pneumonia [43]. In addition, mutations in the TMEM173/STING gene have been identified in patients with a spectrum of inflammatory lung disease [44-49]. Targeted therapies are available for some of these disorders [41]. (See "Pulmonary complications of primary immunodeficiencies" and "Autoimmunity in patients with inborn errors of immunity/primary immunodeficiency".)

An approach to genetic testing is described in a review [31], and a list of laboratories that perform such tests is available at the Genetic Testing Registry website.

Assessment of severity — The severity of DLD is assessed with pulmonary function tests (PFTs), pulse oximetry (with or without arterial blood gas measurement), and a six-minute walk test (if age appropriate). Patients are evaluated for pulmonary hypertension using echocardiography and/or cardiac catheterization. The extent of hypoxemia and pulmonary hypertension form the basis of the Severity of Illness Score, which may be of value in predicting survival [27]. (See 'Clinical course and outcome' below.)

Nutritional status and growth trajectory also play a role in assessing disease severity, particularly in infants and young children.

Pulmonary function tests — Complete lung function testing (spirometry, lung volumes, diffusing capacity) should be obtained if possible, depending on the age and cooperation of the child.

DLD is usually characterized by restrictive rather than obstructive lung disease. However, it should be noted that some forms of childhood DLD may include obstructive lung physiology, including bronchiolitis obliterans, follicular bronchiolitis, and, sometimes, hypersensitivity pneumonitis. PFTs are very helpful in characterizing disease physiology and in assessing severity of illness. (See "Overview of pulmonary function testing in children".)

●Spirometry, which includes measurement of forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC), usually will be consistent with restrictive disease [11,25]. Affected children typically have a decrease in FVC and FEV₁ with normal or increased FEV₁:FVC ratio [25].

●Lung volume measurements reveal a normal to decreased total lung capacity (TLC) and an increase in residual volume (RV)/TLC. This increased RV/TLC ratio may reflect the relative decrease in TLC or a real increase in RV (true hyperinflation) [50-52].

●The single-breath diffusing capacity for carbon monoxide (DLCO) is below normal in absolute terms but usually corrects when adjusted for lung volume [11,50-52]. (See "Overview of pulmonary function testing in children" and "Diffusing capacity for carbon monoxide".)

●Infant PFTs (iPFTs) have been used to characterize the physiologic alterations in children with DLD [53]. Two studies suggest patterns that may be useful in the evaluation of infants with neuroendocrine cell hyperplasia of infancy (NEHI) [54,55]. Because of need for sedation but spontaneous respiration, some infants with DLD may be too ill to undergo this testing. iPFTs are rarely utilized for evaluation and monitoring of ILD.

A six-minute walk test is a clinically practical measure of exercise capacity and is useful in assessing disease severity and disease progression over time. (See "Overview of pulmonary function testing in adults", section on 'Six-minute walk test'.)

Pulse oximetry can be used to assess oxygenation in children with mild to moderate disease. Oximetry correlates well with arterial blood gas measurements and is noninvasive. Oxygen saturation is normal with mild disease, but progressive illness leads to desaturation during sleep and exercise and, eventually to hypoxemia at rest [6]. In infants, assessment of oxygen saturation during feeding may also be informative. Use of arterial blood gas to assess oxygenation is usually reserved for those patients with particularly severe disease. Hypercarbia typically is absent except in advanced disease, and venous or capillary blood gases are often used for ease of sampling in younger children.

Evaluation for pulmonary hypertension — Hypoxemia and structural changes in the lung contribute to increased pulmonary artery pressure. More than 25 percent of children with DLD have pulmonary hypertension at presentation [26]. Because of the impact on prognosis, early evaluation for pulmonary hypertension is recommended in children with DLD [7]. Echocardiography is often the preferred initial approach because it is noninvasive. However, echocardiography has important limitations for the evaluation of pulmonary hypertension, and cardiac catheterization may be needed to accurately assess pulmonary artery pressures.

Diagnostic imaging

Chest radiograph — The chest radiograph, an important modality in diagnosis, is typically abnormal but rarely specific (image 1A-B). In a retrospective series of 48 children with DLD, chest radiographs were abnormal in every case. Infiltrates were predominantly interstitial, alveolar, and mixed in 75, 8, and 13 percent, respectively [25]. An exception is NEHI, in which chest radiographs are often normal or show hyperinflation or peribronchial cuffing consistent with peripheral airways disease [24].

Computed tomography — Computed tomography (CT), performed at end inspiration and with thin slices, or "high-resolution," is the gold standard for confirming and characterizing DLD [56] and correlates better with the extent, distribution, and severity of disease than does a chest radiograph. Chest CT findings are specific or strongly suggestive for some types of DLD (eg, NEHI, bronchiolitis obliterans [57-59]). Expiratory images are not needed for all diagnoses or clinical contexts. However, including expiratory images may be useful for disorders in which demonstration of air trapping physiology aids in diagnosis, such as bronchiolitis obliterans and FLNA deficiency.

Other CT results are nonspecific but may inform next steps, such as genetic testing or bronchoscopy for some other types of DLD (eg, pulmonary alveolar proteinosis, genetic disorders of surfactant dysfunction, FLNA deficiency) [60], and thus may reduce need for lung biopsy. If biopsy is needed, imaging information is useful to direct the choice of surgical biopsy sites [56,61].

In infants, use of a modern CT scanner capable of very rapid imaging often permits high-quality imaging during free breathing; this technique avoids the need for sedation and minimizes related atelectasis [56]. If such a scanner is not available, or for noncooperative patients (eg, young children) or those with prominent tachypnea, anesthesia or controlled ventilation CT (CV-CT) techniques may be needed to reduce motion artifact and enable inspiratory imaging. The controlled ventilation technique uses noninvasive positive pressure ventilation in the sedated child to allow a brief respiratory pause at full inflation or end expiration, during which CT images can be obtained with minimal artifact [53,62]. Newer fast pitch scanning techniques reduce the scanning time, improve the resolution of studies, and may reduce need for controlled ventilation. (See "Principles of computed tomography of the chest".)

CT features that may be present in different forms of pediatric DLD include septal thickening, ground glass opacification (image 1B), geographic hyperlucency (image 2) or mosaic attenuation, lung cysts or nodules, and consolidation.

Studies have confirmed the diagnostic accuracy of CT in certain forms of pediatric DLD [63,64]. In one study of 20 children with biopsy-proven DLD, two experienced radiologists made a diagnosis with a high degree of confidence more often with CT than chest radiographs (63 versus 13 percent) [63].

CT patterns are also particularly helpful in diagnosing certain forms of DLD in infants, including surfactant dysfunction disorders and NEHI (image 3) [7,28,65]. In one study of 23 cases of NEHI and 6 cases of other forms of childhood DLD, the CT pattern, as judged by radiologists experienced with NEHI, was found to be 100 percent specific for diagnosis of NEHI when compared with lung biopsy. However, not all NEHI cases had consistent imaging findings, as CT sensitivity was 78 to 83 percent compared with lung biopsy [65]. Based on this data and on clinical experience, it has been proposed that the diagnosis of NEHI can be made based on CT findings in a compatible clinical context [7,54]. (See "Neuroendocrine cell hyperplasia of infancy (NEHI)", section on 'Chest computed tomography'.)

Bronchoscopy and bronchoalveolar lavage — Flexible bronchoscopy has many uses in pediatric patients including evaluation of infection, airway anatomy and physiology, and sampling of alveolar constituents for additional diagnostic purposes. In children with suspected DLD, bronchoscopy often plays a key role in ruling out alternative diagnoses or comorbid conditions that may contribute to pulmonary symptoms. In particular, bronchoalveolar lavage (BAL) is used in patients with DLD mainly to diagnose infection and detect aspiration and hemorrhage. In addition, BAL may help diagnose certain specific conditions (eg, Langerhans cell histiocytosis [66], pulmonary alveolar proteinosis [67] or lysosomal diseases [68,69]), or disease mechanisms (eg, sarcoidosis [70,71] or hypersensitivity pneumonitis [72,73]). The utility of serial BAL in the reassessment and management of pediatric patients with most forms of DLD remains to be established.

Lung biopsy — Prior to the availability of clinical genetic testing, lung biopsy was considered the gold standard for diagnosis of DLD because the diagnostic categories of DLD were based on histopathologic description. Many forms of DLD are diagnosed and categorized based on the mechanism of disease or CT appearance. However, lung biopsy remains the means of definitive diagnosis for forms of DLD for which the cause is unknown and the CT patterns have not been determined or validated, such as pulmonary interstitial glycogenosis. To maximize diagnostic yield of lung biopsies, standardized published protocols for tissue processing should be utilized, including fixation for electron microscopy (EM) [74]. Because of the relative rarity of pediatric lung biopsies, cases should be interpreted by a pathologist experienced with pediatric lung disease [6]. (See "Classification of diffuse lung disease (interstitial lung disease) in infants and children".)

Video-assisted thoracoscopy (VATS) is the procedure of choice in children requiring lung biopsy because morbidity is less than with open lung biopsy [75]. In a prospective study of 30 children with DLD, VATS and open lung biopsy had similar diagnostic yield (60 and 53 percent), but VATS resulted in shorter durations of surgery, hospitalization, and chest tube drainage [76].

Transbronchial biopsy is not recommended for evaluation of DLD in children. Although transbronchial biopsy is used routinely to detect infection or rejection in children with heart-lung and lung transplantation, it has limited diagnostic value in young children with diffuse infiltrates. This is due to the small size of these biopsy specimens, which are rarely able to provide sufficient architectural detail to allow definitive histologic diagnosis.

TREATMENT — Treatment consists of supportive therapy and pharmacologic interventions that are tailored to the type of DLD. In most cases, treatment is based on anecdotal evidence. There have been no controlled treatment trials in children with most types of DLD [7].

Supportive therapy — Supportive therapy should focus on:

●Limiting exposure to cigarette smoke and other inhaled irritants

●Nutritional support as needed

●Oxygen therapy for hypoxemia

●Supervised exercise (for older children)

●Bronchodilators for reversible airway obstruction

●Aggressive treatment of intercurrent infections

●Standard childhood vaccinations

●Annual influenza vaccinations

●Respiratory syncytial virus immunoprophylaxis

(See "Seasonal influenza in children: Prevention with vaccines", section on 'Target groups' and "Standard immunizations for children and adolescents: Overview", section on 'Infants and children' and "Respiratory syncytial virus infection: Prevention in infants and children".)

Specific treatment — Specific treatment is available for some DLD disorders. Examples include antimicrobials for certain infections, management of swallowing dysfunction and/or reflux in patients with chronic aspiration, avoidance of the offending antigen in hypersensitivity pneumonitis, and whole lung lavage for older children with pulmonary alveolar proteinosis [77]. Granulocyte-macrophage colony-stimulating factor (GM-CSF), which is required for normal surfactant homeostasis, may have a role in acquired pulmonary alveolar proteinosis. (See "Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults" and "Pulmonary alveolar proteinosis in children".)

Glucocorticoids — Glucocorticoids have a role in the treatment of children with some subtypes of DLD in which inflammation and inappropriate cellular proliferation are thought to play an important role in pathogenesis. Treatment decisions in children with DLD should be individualized based on the relative risks of disease and treatment, and monitoring and management of adverse effects is required.

Patient selection — Glucocorticoids are effective in some cases (probably less than one-half), and the likelihood of response depends in part on the type of DLD [25,78]. Defining the specific type of DLD is thus essential to assess the potential role for treatment with glucocorticoids.

●Conditions that appear to respond to glucocorticoid therapy, to a variable degree, include:

•DLD associated with connective tissue disease (see "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on 'Pulmonary')

•Hypersensitivity pneumonitis (see "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Treatment, prognosis, and prevention", section on 'Treatment')

•Lymphocytic interstitial pneumonia (see "Classification of diffuse lung disease (interstitial lung disease) in infants and children", section on 'Lymphoid interstitial pneumonia')

•Cryptogenic organizing pneumonia (previously known as bronchiolitis obliterans organizing pneumonia)

•Eosinophilic pneumonia

•Sarcoidosis

•Capillaritis (which often is associated with underlying connective tissue disease such or other autoimmune diseases but may occur as an isolated apparently idiopathic entity)

It should be noted that additional immunomodulatory therapies and steroid-sparing agents are often indicated in management of many of the disorders listed above.

●Conditions for which there is insufficient evidence to determine whether or not glucocorticoids are beneficial, or whether the potential benefits outweigh the known toxicities, include:

•Surfactant dysfunction disorders – Overall there are very limited data from case reports and no established efficacy of glucocorticoids for these rare disorders. Because of NF-kB driven alveolar inflammation, glucocorticoids are often trialed in children with severe lung disease due to SFTPC gene mutations. (See "Genetic disorders of surfactant dysfunction", section on 'Pharmacologic therapies'.)

•Pulmonary interstitial glycogenosis (P.I.G.) – Glucocorticoids may be effective for the diffuse form of P.I.G The diffuse form is less common than the patchy form of P.I.G., which is associated with pulmonary growth abnormality. The rationale for performing a trial of glucocorticoids in P.I.G. is not their antiinflammatory properties, because this disorder is not characterized by cellular inflammation. Instead, they are used for their antiproliferative properties, based on evidence of prominent proliferative activity in the P.I.G. mesenchymal lesions. There are no controlled trials of glucocorticoids in P.I.G., but it has been recommended that use of glucocorticoids for P.I.G. be restricted to a focused early neonatal time period since P.I.G. is not present in lung biopsies of children beyond approximately six to eight months of age. Use of glucocorticoids in this neonatal population must be carefully considered in the context of potential negative impact on postnatal alveolarization and neurodevelopmental outcomes. (See "Classification of diffuse lung disease (interstitial lung disease) in infants and children", section on 'Pulmonary interstitial glycogenosis'.)

•Postinfectious bronchiolitis obliterans – Glucocorticoids and other immunomodulatory therapies are frequently utilized in the early phases of this disease if active inflammation is present. Once airway remodeling is established there is likely little benefit to use of glucocorticoids in this population.

●Conditions for which glucocorticoids are likely not beneficial based on lack of scientific rationale for their use include:

•Neuroendocrine cell hyperplasia of infancy (NEHI) – Glucocorticoids are considered not to have been helpful in most cases and are generally not recommended. (See "Neuroendocrine cell hyperplasia of infancy (NEHI)", section on 'Treatment'.)

•Disorders of lung development including alveolar capillary dysplasia (ACD) with or without misalignment of the pulmonary veins (ACD-MPV).

•Alveolar growth abnormalities including pulmonary hypoplasia.

Dosing — If the decision is made to proceed with glucocorticoids, we suggest a time-limited trial for three months, up to potentially six months depending on the disease process and the balance of benefit versus adverse effects in the first several months of therapy. In children with DLD, there are no studies to inform dosing or duration of treatment. Pulse therapy with intravenous methylprednisolone (10 to 30 mg/kg per day [maximum 1000 mg], administered over one hour, for three consecutive days each month or a single dose weekly) is often preferred compared with daily oral therapy, and may be equally or more effective with fewer side effects [6,79]. If oral dosing is utilized, oral prednisone (1 to 2 mg/kg per day) or an equivalent glucocorticoid is a standard initial approach. Patients with connective tissue disease or capillaritis may require daily oral glucocorticoids at least until disease control is achieved with other immunomodulator agents, and consultation with a rheumatologist is recommended for management of these patients.

Monitoring — The patient should be carefully reevaluated and the treatment continued only if there is good evidence for benefit. A favorable response to treatment is suggested by decreased severity of symptoms, better oxygenation, increased exercise capacity, and improved pulmonary function tests (PFTs). A six-minute walk test is a useful measure of exercise capacity for children four years and older. Improvements also may be seen on chest radiograph or CT scan, but these changes tend to occur over a much longer period of time [11]. If the trial is successful and the glucocorticoid treatment is continued, the minimal glucocorticoid dose needed for acceptable response should be utilized whenever possible.

The long-term use of glucocorticoids, particularly in the developing infant, must be considered with caution because of the potential adverse effects on neuromotor and cognitive function [80] (see "Bronchopulmonary dysplasia (BPD): Prevention"). Monitoring for treatment-associated side effects and toxicities is needed, including attention to growth, nutrition, bone density, hypertension, hyperglycemia, and others [7].

Other drugs — If glucocorticoids fail or result in significant side effects, alternative immunosuppressive agents may be considered, although their efficacy is uncertain. In these circumstances, a second drug is started and the glucocorticoids are weaned.

Hydroxychloroquine (up to 6 mg/kg per day) is used most frequently for attempted empiric therapy and/or steroid-sparing effect. In case reports, chloroquine or hydroxychloroquine have been associated with improvement in cases reported as desquamative interstitial pneumonitis [81,82], lymphocytic interstitial pneumonitis [83,84], nonspecific interstitial pneumonitis, pulmonary hemorrhage syndromes/capillaritis [85], and in surfactant dysfunction disorders [86-88]. The variable natural history of some of these disorders makes outcome assessments challenging. Retinal toxicity is a rare but serious complication of chloroquine and hydroxychloroquine therapy. More recent clinical practice is to use hydroxychloroquine instead of chloroquine. Neither of these drugs has been systematically evaluated in children with DLD outside of rheumatologic disease.

Nintedanib is an antifibrotic agent that slows progression of fibrosing ILD in adults (see "Treatment of idiopathic pulmonary fibrosis", section on 'Medical therapies'). In an early phase 3 randomized trial that evaluated dose exposure and safety, 39 children and adolescents (ages 6 to 17 years, various causes) were randomized to treatment with nintedanib or placebo. Eligibility criteria included clinically significant fibrotic DLD based on disease severity scores and evidence of clinical progression by chest CT, forced vital capacity (FVC) decline ≥10 percent predicted, or a relative decline in FVC of 5 to 10 percent predicted with worsening symptoms. Patients with FVC <25 percent predicted, underlying chronic liver disease, significant pulmonary arterial hypertension, cardiovascular disease, or increased bleeding risk were ineligible for this trial. Nintedanib treatment was reasonably well tolerated; diarrhea was the most common adverse event. Compared with placebo, nintedanib treatment for 24 weeks was associated with a nonsignificant trend toward improvement in mean FVC (NCT04093024) [89]. This trial continues in an open-label treatment phase. Nintedanib has not been approved by the US Food and Drug Administration for treatment of fibrosing ILD in children. Further trial data are needed to determine whether nintedanib is effective in childhood DLD, guide patient selection, and continue to evaluate the benefit:risk profile.

Some clinicians use cyclophosphamide, mycophenolate mofetil, or azathioprine instead of hydroxychloroquine. Methotrexate, cyclosporine, rituximab, and high-dose intravenous immune globulin also have been used. Such therapies are typically reserved for DLD associated with connective tissue disease, capillaritis, or other unusually severe and progressive disease where a high degree of ongoing inflammation has been documented. Other targeted therapies may be considered when specific pathways of immune dysfunction are identified (eg, JAK inhibitors are sometimes useful for STING-associated DLD [MIM #615934] [41,47,49]).

Lung transplantation — Lung transplantation is an option for children who have severe and progressive disease and no response to therapy. Timely referral may improve outcome [90]. (See "Lung transplantation: General guidelines for recipient selection".)

The survival rate after transplantation for children with DLD is similar to that of pediatric lung transplantation for all indications, ie, approximately 50 percent at five years. However, mortality from obliterative bronchiolitis after heart-lung transplantation is higher in children than in adults (38 versus 17 percent) [91]. (See "Lung transplantation: An overview" and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome".)

Lung transplantation is the only effective treatment for some highly lethal diseases such as surfactant protein B (SFTPB) deficiency, certain ABCA3 null mutations, and ACD (or ACD-MPV), and for patients with progressive lung disease due to mutations in the FLNA gene [6,60,92]. These disorders must be diagnosed as soon as possible after birth to give these patients a chance to undergo transplant. Recurrence of the primary DLD in transplanted lungs of children has not been reported.

CLINICAL COURSE AND OUTCOME

●Acute exacerbations – The clinical course of DLD may include acute exacerbations (similar to some other chronic lung diseases), although limited data are available to define the criteria and frequency of these events. In a registry study of 719 infants and children with DLD, most patients experienced one or more acute exacerbations, with symptoms characterized by increased dyspnea and respiratory rate. Events were usually triggered by an infectious respiratory illness, and these episodes were accompanied by deterioration in pulmonary function [93]. During the 2.5-year observational period, 81 patients died and more than one-half of the deaths were associated with an acute exacerbation.

The optimal approach to managing acute exacerbations has not been established and likely depends on the underlying disease and cause of the exacerbation. In the registry study above, most patients were treated with antibiotics; other treatments included systemic glucocorticoids or bronchodilators and, occasionally, antiviral medication [93].

●Survival – The prognosis in DLD depends on the underlying disorder. As an example, most infants with neuroendocrine hyperplasia of infancy (NEHI) and many with pulmonary interstitial glycogenosis (P.I.G.) improve over time, although they are typically symptomatic and may require supplemental oxygen for years. In contrast, the prognosis is poor for patients with alveolar capillary dysplasia (ACD) with or without misalignment of the pulmonary veins (ACD-MPV), congenital alveolar dysplasia, SFTPB gene mutations, or DLD complicated by pulmonary hypertension [13]. Details about each of these disorders are described separately. (See "Classification of diffuse lung disease (interstitial lung disease) in infants and children".)

Some studies report overall prognosis among cohorts of children with various types of DLD. As an example, in a multicenter case series of 191 children with DLD who underwent lung biopsy, immunocompromised patients (41 percent of the cohort) had the highest mortality (>50 percent) [94]. By contrast, mortality was 7 percent among immunocompetent children with a primary lung disorder (typically infectious or postinfectious, environmental or eosinophilic). Another study reported outcomes of 99 children with chronic DLD seen in Denver, Colorado, over a 15-year period [26]. A variety of disorders, including infection, bronchiolitis obliterans, hypersensitivity pneumonitis, and pulmonary vascular disease, were encountered; 15 patients died. After the onset of symptoms, the probability of survival was 83, 72, and 64 percent at 24, 48, and 60 months, respectively. Clinical features present at the time of initial evaluation, including duration of symptoms, weight below 5th percentile, crackles, clubbing, and family history of DLD, were not associated with decreased survival. However, a higher severity of illness score, based on hypoxemia and pulmonary hypertension, was significantly associated with lower probability of survival (table 7).

SUMMARY AND RECOMMENDATIONS

●Terminology – Diffuse lung disease (DLD), traditionally known as interstitial lung disease (ILD), consists of a diverse group of disorders that involve the pulmonary parenchyma and interfere with gas exchange. Because many of these disorders are associated with extensive alteration of alveolar and airway architecture, in addition to changes in the interstitial compartment, we prefer the term DLD rather than ILD. (See 'Terminology' above.)

●Types – The causes of DLD in children can be classified by age group and other clinical context, especially the presence or absence of an immunodeficiency or related systemic disease (table 1). In some cases, it is classified by histopathologic pattern (table 3). (See 'Classification' above and "Classification of diffuse lung disease (interstitial lung disease) in infants and children".)

●Clinical presentation – In neonates, DLD often presents with unexplained respiratory failure. In infants and children with a normal birth history, DLD may present with persistent tachypnea, dyspnea, dry chronic cough, hypoxemia, exercise intolerance, and/or clubbing of the digits. Associated symptoms may include failure to thrive. (See 'Clinical presentation' above.)

●Diagnostic approach – The first step is to exclude more common causes for this presentation, including infection, immunodeficiency, structural airway abnormalities, congenital heart disease, and cystic fibrosis. Once more common explanations are excluded, a child with unexplained pulmonary symptoms and diffuse pulmonary infiltrates may be considered to have a childhood DLD syndrome and further investigations to determine a specific cause are warranted. (See 'Diagnostic approach' above.)

●Diagnostic testing – Patients with suspected childhood DLD should be evaluated by a pediatric pulmonologist. Following a thorough history and physical examination, a chest radiograph should be obtained. Patients with diffuse pulmonary infiltrates consistent with DLD should have additional step-wise testing to evaluate for predisposing disorders, assess the extent and severity of disease, and identify the primary DLD disease, if possible. Selection of tests is guided by the patient's age and other clinical characteristics that suggest certain categories of DLD and typically includes (table 4):

•Laboratory studies – Immune workup, consideration of rheumatologic testing, cultures, or hypersensitivity pneumonitis screen if indicated. (See 'Laboratory studies' above.)

•Pulmonary function tests (PFTs) – Measurements include standard spirometry, lung volume measurements, diffusing capacity for carbon monoxide (DLCO), and pulse oximetry. A six-minute walk test is most useful in assessing disease severity and disease progression over time. (See 'Pulmonary function tests' above.)

•Bronchoscopy – With bronchoalveolar lavage (BAL). (See 'Bronchoscopy and bronchoalveolar lavage' above.)

•CT. (See 'Diagnostic imaging' above.)

•Genetic testing – For selected patients (eg, neonates presenting with respiratory failure, children with symptoms of DLD and a family history of a similarly affected sibling, or as indicated based on radiographic patterns or bronchoscopic findings). (See 'Genetic testing' above.)

•Lung biopsy – This is typically considered if the above studies are nondiagnostic and if there is sufficient clinical urgency (eg, severe or progressive disease and/or consideration for lung transplantation). (See 'Lung biopsy' above.)

●Management

•Supportive therapy – General supportive measures are recommended in all patients. These include avoiding exposure to cigarette smoke, nutritional support as needed, oxygen therapy for hypoxemia, bronchodilators for reversible airway obstruction, treatment of intercurrent infections, and close attention to childhood vaccinations including annual influenza vaccinations and respiratory syncytial virus prophylaxis. (See 'Supportive therapy' above.)

•Specific treatments – Certain DLDs are amenable to specific treatments. Examples include antimicrobials for certain infections, management of swallowing dysfunction and/or reflux in patients with chronic aspiration, avoidance of the offending antigen in hypersensitivity pneumonitis, and whole lung lavage for older children with pulmonary alveolar proteinosis. (See 'Specific treatment' above and 'Glucocorticoids' above and 'Other drugs' above.)

•Lung transplantation – Lung transplantation is an option for children who have severe and progressive disease and no response to therapy. It is the only effective treatment for some highly lethal diseases such as surfactant protein B (SFTPB) deficiency, certain ABCA3 null mutations, and alveolar capillary dysplasia (ACD) with or without misalignment of the pulmonary veins (ACD-MPV). Timely referral may improve outcome. (See 'Lung transplantation' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Leland Fan, MD, who contributed to earlier versions of this topic review.