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

Author:

Lisa R Young, MD

Section Editor:

George B Mallory, MD

Deputy Editor:

Alison G Hoppin, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Nov 2016. | This topic last updated: Nov 18, 2016.

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, hypoxemia, retractions, cough, exercise intolerance, failure to thrive, gastroesophageal reflux, 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 interstitial lung diseases) 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 syndrome (chILD) 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 current definition of DLD.

It is likely that prevalence estimates will increase as current and broader definitions of DLD are used (table 1A-C), 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].  

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 [16-18] (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 [19].

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 [7,13,20]. One strategy is to consider whether the DLD is primarily a pulmonary process or whether it occurs in association with a systemic disorder (table 1B). Another approach that is particularly useful is to specifically consider the forms of DLD most commonly presenting in infancy because this substantially narrows the diagnostic possibilities (table 1A) [7,13]. An overview 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".)  

However, some cases of DLD have no recognized cause and are not associated with a systemic disease. These cases may be classified histopathologically (table 1C). Because each histopathologic pattern has been associated with certain causes of DLD or with underlying systemic disorders, identification of these patterns should guide a focused evaluation for the underlying disorder.

CLINICAL PRESENTATION — DLD should be considered in any neonate who presents with unexplained respiratory failure, or in infants and children with a normal birth history who present with persistent tachypnea, crackles, hypoxemia, chronic cough, or clubbing of the digits. DLD should also be considered in late preterm or preterm infants who present with chronic lung disease out of proportion to the degree of prematurity or other known comorbidities [21,22]. Another common presentation is 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') [10,21]. Feeding difficulties, poor weight gain, and gastroesophageal reflux are also common presenting features in infants and young children [13,23]. Imaging findings are also an important trigger for a full evaluation for DLD, as many children with DLD present with persistent diffuse infiltrates of otherwise unknown etiology.

For older children, exercise intolerance and clubbing may be prominent. The onset of these 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 [24]. 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 [25], and 35 percent have been treated for asthma before undergoing a definitive evaluation [24].

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 2). 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 [26]. Among the 51 patients, the diagnosis was based upon history and physical examination alone in 1 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 multi-center 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 multi-center 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 — 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.  

The European Respiratory Society Task Force (ERSTF) retrospectively reviewed 185 cases of DLD in immunocompetent children, including 58 cases in children younger than two years of age [11]. The most common symptoms of chronic DLD included:

●Cough (78 percent, overall; 73 percent of those ................
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