Chapter 515. Interstitial Lung Disease

Childhood interstitial lung disease (ChILD) comprises a heterogeneous group of chronic pulmonary disorders, characterized by diffuse parenchymal infiltrates and impaired gas exchange, often leading to hypoxemia. Delineation of a ChILD classification scheme is complicated, because many disorders that could be included in the schema also involve the airways and air spaces, more than the interstitium. The term ChILD syndrome may be more appropriate, since patients with these disorders share common symptoms, physical findings, and radiologic abnormalities (see Table 515-1).1,2 In the past few years, specific entities presenting in this manner that are unique to children, including inborn errors of surfactant metabolism, have been recognized.1 This chapter provides an overview of ChILD with a focus on these recent developments.2 Although no classification scheme is ideal, a list of ChILD disorders is given in Table 515-1. It is not possible to discuss each entity in detail, but some of these disorders deserve emphasis.

Disorders of known etiology include aspiration syndromes (see Chapter 511), infectious etiologies, bronchopulmonary dysplasia (see Chapters 59 and 513), and certain metabolic disorders (Section 11).

Hypersensitivity Pneumonitis

Also known as extrinsic allergic alveolitis, hypersensitivity pneumonitis (HP) includes a variety of disorders resulting from an immune response to inhaled organic antigens (Farmer’s lung, bird fancier’s disease). HP is uncommon but under-recognized in children. The specific nature of the immune response is uncertain but is of type III or IV. In contrast to adults, whose exposure is often in the workplace, the most common cause in children is exposure to avian antigens.3 The entity should be suspected if onset of recurrent pneumonias can be linked to environmental exposures, especially to birds, or changes in the environment. HP from hay or mold (especially in aerosolized water) exposure occurs less commonly in children. An acute form results in symptoms of fever, chills, malaise, cough, chest tightness, dyspnea, and/or headache within hours of antigen exposure. Chest radiographs are either normal or show a “ground-glass” appearance with micronodular interstitial pattern. Symptoms resolve within 12 hours to several days upon cessation of exposure. An intermittent or subacute form has also been described in which patients have symptoms of chronic cough, dyspnea, fatigue, and often pleurisy.

This intermediary form has variable chest radiographs, but pneumonia may be seen. The chronic form presents with persistent dyspnea, tachypnea, and often clubbing. Pathology shows poorly formed noncaseating granulomas in all forms, but bronchiolitis with or without organizing pneumonia, interstitial fibrosis, alveolar destruction, dense fibrosis, and cholesterol clefts are present, along with the granuloma with more severe disease. Diagnosis depends upon a careful history that identifies a potential offending antigen. Characteristic findings on chest radiograph or computerized tomography (CT), lymphocytosis on bronchoalveolar lavage, and specific antibody help confirm the diagnosis. Lung biopsy can reveal typical changes consistent with hypersensitivity pneumonitis. Other diagnoses that must be considered include infections (eg, histoplasmosis, coccidiomycosis, psittacosis, tuberculosis) and noninfectious granulomatous disease (eg, sarcoidosis). Avoiding the allergen is the best therapy, but corticosteroids are useful to control symptoms.

Idiopathic Interstitial Pneumonias

The American Thoracic Society/European Respiratory Society international consensus classification of idiopathic interstitial pneumonias in adults recognizes seven disorders, each of which has a specific histological description and a corresponding clinical-radiological-pathological diagnosis (Table 515-2).4 Five of these disorders are seen in children, including nonspecific interstitial pneumonitis (NSIP), cryptogenic organizing pneumonia, acute interstitial pneumonia, desquamative interstitial pneumonitis (DIP), and lymphocytic interstitial pneumonia (LIP). The remaining two, usual interstitial pneumonia (UIP) and respiratory bronchiolitis, probably do not exist in children, even though there are many cases of UIP, idiopathic pulmonary fibrosis (IPF), and cryptogenic fibrosing alveolitis (CFA) reported in children.

Applying adult classification schemes for ChILD has been problematic, because significant differences exist between pediatric and adult reported cases. For example, biopsies from previously reported cases of UIP, IPF, and CFA in children have not identified fibroblastic foci, a pathological feature essential for the diagnosis of UIP.5 Furthermore, the reported mortality for these disorders is very low in children,5 in stark contrast to a mortality of 50% to 80% in adults6; this suggests that children have a completely different disease process. It is therefore likely that the terms UIP, IPF, and CFA have been applied indiscriminately to children with a variety of diffuse lung disorders.

Another example of differences between children and adults is the changing perspective of pediatric desquamative interstitial pneumonitis (DIP). Whereas DIP in adults carries a good prognosis, children reported in the older literature with this histological diagnosis had a high mortality rate,7 and lethal familial cases were reported.8 It is now recognized that most cases of pediatric DIP are due to inborn errors of surfactant metabolism. Although NSIP can be a feature of autoimmune disease or hypersensitivity pneumonitis, it can also be a manifestation of inborn errors of surfactant metabolism.9

Lymphocytic interstitial pneumonia is actually not a true interstitial lung disease (ILD) but rather is a lymphoproliferative process involving the lung. Although it can be an idiopathic condition, it more commonly is found in children with immunodeficiencies and autoimmune diseases. In the past, the most common condition associated with LIP was AIDS. With the advances in treatment for AIDS, the incidence of LIP has fallen dramatically.

Alveolar Hemorrhage Syndromes

Bleeding in the lung can originate from the high-pressure bronchial circulation or the low-pressure pulmonary circulation. Generally, bleeding from the pulmonary circulation leads to diffuse alveolar hemorrhage (DAH) but rarely causes massive hemoptysis. Historically, the classic example of DAH has been idiopathic pulmonary hemosiderosis (IPH), characterized by diffuse infiltrates; anemia; the hemosiderin-laden macrophages (HLMs) in gastric aspirate, bronchoalveolar lavage (BAL), or lung biopsy; and the absence of serological markers of immune-mediated lung disease. By definition, IPH is a diagnosis of exclusion with the histology of bland, noninflammatory hemorrhage. Many experts still believe that if a patient has the clinical features of IPH, hemosiderin-laden macrophages, negative serology for immune-mediated disorders, and absence of systemic disease or cardiac disease, a diagnosis can be made without lung biopsy.

However, more recent studies have shown that patients with all of the clinical features of IPH can have histological evidence of pulmonary capillaritis, a capillary form of vasculitis, even in the absence of positive serology.10 Pulmonary capillaritis can occur as an isolated, idiopathic condition or as a manifestation of microscopic polyangiitis, Wegener’s granulomatosis, systemic lupus erythematosus, or other immune-mediated disorders. Therefore, the new classification of DAH syndromes can be divided into those with and without capillaritis. Those without capillaritis would have noncardiac causes such as IPH and bleeding disorders and would have cardiac causes such as veno-occlusive disease and mitral stenosis.11

The diagnostic approach to a patient with suspected DAH would include complete blood count, erythrocyte sedimentation rate, C-reactive protein coagulation studies, blood urea nitrogen (BUN), creatinine, and urinalysis. Serological markers for immune-mediated lung disease would include antineutrophil cytoplasmic antibody (ANCA), antinuclear antibody (ANA), and antiglomerular basement membrane antibody (Anti-GBMA). Electrocardiogram and echocardiogram are essential to rule out cardiac causes of DAH. The identification of HLMs by BAL or gastric aspirate can be helpful to confirm pulmonary hemorrhage. However, because children with capillaritis can have negative serology, it is recommended that all children with DAH without cardiac cause undergo lung biopsy.

Patients with IPH generally respond to corticosteroids. However, patients with capillaritis often require more aggressive intervention, and consideration should be given to corticosteroids and additional steroid-sparing therapy. Patients with life-threatening DAH should be given corticosteroids, cyclophosphamide, and IVIG, as this aggressive approach can be lifesaving.

Pulmonary Infiltrates with Eosinophilia (PIE)

The eosinophilic lung diseases include a heterogeneous group of rare disorders that share the common feature of eosinophils in the peripheral blood, BAL, or lung parenchyma.12 Known causes of pulmonary infiltrates with eosinophilia (PIE) include parasitic infections and drugs. Loeffler’s syndrome, associated with minimal respiratory symptoms, migratory infiltrates, and often pronounced eosinophilia, is now recognized to be caused by parasite larvae passing through the lungs, especially Ascaris lumbricoides, but also Ancyclostoma,Echinococcus,Shistosoma, Strongyloides stercoralis,Necator americanus, and Toxocara species. Generally, patients respond favorably to thiabendazole or albendazole, although alternative treatments would include piperazine, levamisole, and pirantel. Other similar clinical disorders include visceral larva migrans caused by Toxocara canis and tropical pulmonary eosinophilic syndrome caused by Wuchereria bancrofti and Brugia malayi. A large variety of drugs, including penicillin, cocaine, phenytoin, chlorpromazine, and many others are known to cause PIE. Patients typically respond favorably to drug elimination and corticosteroids.

The differential of eosinophilic lung diseases also includes allergic asthma, allergic bronchopulmonary aspergillosis, acute eosinophilic pneumonia, chronic eosinophilic pneumonia, Churg-Strauss syndrome, and idiopathic hypereosinophilic syndrome. The diagnosis of these disorders is made by identifying eosinophils in peripheral blood, BAL, or lung biopsy.13 Patients with acute eosinophilic pneumonia classically present with acute respiratory failure and the notable absence of peripheral eosinophilia. Therefore, a strong index of suspicion is necessary, as BAL is required to demonstrate marked eosinophils in the lung. In these cases, the early institution of corticosteroids can be lifesaving.

Bronchiolitis Obliterans

Bronchiolitis obliterans (BO) is an uncommon form of obstructive lung disease that occurs as a result of a severe insult to the small airways and ultimately leads to fibrosis and obliteration of the bronchioles.14 Epidemiology studies suggest that BO is common in children of Asian descent. In children, the leading cause of BO is infectious, with adenovirus being the most common offending agent. BO also occurs in patients with lung or bone marrow transplantation (BMT) and in those with autoimmune disorders. Other causes include toxic inhalation injury or aspiration, hypersensitivity pneumonitis, drug toxicity, and Stevens-Johnson syndrome (SJS).

The clinical presentation can vary, from an acute onset with symptoms of severe pneumonia or bronchiolitis to a more insidious onset with progressive symptoms of cough, wheezing, and exercise intolerance. Pulmonary function testing usually reveals fixed small airways obstruction with marked air trapping and hyperinflation. High-resolution computed tomography of the chest classically shows mosaic perfusion, vascular attenuation in the hyperinflated regions, and central bronchiectasis. Studies have shown that these classic features have high sensitivity and specificity for BO; thus, CT has largely supplanted lung biopsy for confirmation of diagnosis. Therapy is largely empiric and unproven. Corticosteroids, both inhaled and systemic, are often given, especially in the early stages, based on the premise that controlling inflammation may mitigate against the development of airway fibrosis. According to studies demonstrating benefit in diffuse panbronchiolitis and cystic fibrosis, long-term macrolide therapy may have some benefit in controlling the disease. There are case reports of successful use of anti-TNF alpha therapy in BO related to BMT. However, it remains to be seen if this therapy is useful for postinfectious BO. Lung transplantation remains the ultimate option for end-stage BO. Generally, children with postinfectious BO tend to follow a nonprogressive course. In contrast, BO related to SJS and to lung transplant or BMT often follows a progressive course.

Neuroendocrine Cell Hyperplasia of Infancy

Neuroendocrine cell hyperplasia of infancy (NEHI) is an idiopathic disorder that presents in infants less than 1 year of age. It is characterized by the presence of persistent tachypnea, hypoxemia, and crackles and by distinctive features of ground-glass opacities in the right middle lobe, lingula, and perihilar areas on high-resolution computed tomography (HRCT).15 Although controversial, classic high-resolution computerized tomography (CT) findings in a child with typical clinical presentation may be sufficient for diagnosis. Characteristic histopathologic features found in lung biopsy specimens include almost normal lung parenchyma with hyperplasia of neuroendocrine cells, demonstrated by bombesin immunostaining, in the distal airways.16Children with NEHI typically have a prolonged supplemental oxygen requirement with gradual improvement over years, and they do not respond consistently to corticosteroid therapy. The prognosis is excellent with no deaths reported.

Pulmonary Interstitial Glycogenosis

Previously known as cellular interstitial pneumonitis, pulmonary interstitial glycogenosis (PIG) typically occurs in infants with hypoxemia, respiratory distress, and diffuse reticulonodular lung infiltrates evident on chest film or HRCT.15 As these findings are nonspecific, lung biopsy is necessary for diagnosis. Periodic Acid-Schiff staining of light microscopy sections and electron microscopy demonstrate the proliferation of primitive mesenchymal cells containing glycogen within the alveolar interstitium and the absence of significant inflammation or abnormalities of epithelial or endothelial cells.15Although the etiology is unknown, it is hypothesized that a developmental abnormality is the primary disturbance. As in NEHI, prognosis is favorable, but in contrast to NEHI, patients with PIG may respond to corticosteroids, presumably by hastening the cellular maturation process.17,18

Genetic Surfactant Defects

The most important advance in the field of ChILD has been the discovery of genetic defects that result in surfactant dysfunction, including mutations in the surfactant protein B (SP-B), the surfactant protein C (SP-C), and the ATP binding cassette 3 (ABCA3) genes. Many children with ChILD of previously unknown etiology have one of these surfactant defects. These are discussed in detail in Chapter 518.

Because the differential diagnosis of ChILD is extensive, evaluation requires a systematic approach that begins with a complete history and physical exam, followed by selected noninvasive and invasive studies.19,20 A thorough history to identify specific causes of ChILD should include a careful feeding history to exclude aspiration; a detailed environmental history to uncover potential organic antigen exposure; a history of past infectious illnesses that could cause bronchiolitis obliterans; and a search for other organ involvement, such as joint pain, rash, or hematuria that may indicate a connective tissue disorder or other systemic process.

The onset of symptoms for ChILD is usually insidious, with many patients having symptoms for years before their diagnosis. Typical symptoms of ChILD include tachypnea, cough, dyspnea, and exercise intolerance. On physical exam, the most common findings include retractions, tachypnea, and basilar crackles. Failure to thrive, cyanosis, hypoxemia, and digital clubbing are also often present. Diagnostic studies can be divided into those that assess extent and severity of disease, identify primary disorders that predispose one to lung disease, and identify the primary lung disease (Table 515-2).21 The table provides an overview of possible tests to consider, but every patient does not need every study listed, and clinical judgment is required to determine which tests are appropriate for each individual. In addition to assessing extent and severity of disease, high resolution CT can be used to diagnose some specific conditions with confidence, such as bronchiolitis obliterans and NEHI, and to determine optimal sites for lung biopsy.

The main usefulness of bronchoscopy with bronchoalveolar lavage is for the diagnosis of infection in both immunocompromised and immunocompetent hosts. Lung biopsy is required for most cases in which the diagnosis remains uncertain after a thorough investigation. Video-assisted thoracoscopy is now the preferred method compared to open lung biopsy, as it has a comparable diagnostic yield but is associated with less morbidity.22,23

Supportive care includes adequate nutritional support; proper immunizations, including the flu vaccine; a supervised fitness program; and supplemental oxygen when hypoxemia is demonstrated.

Because of the rarity of these conditions, there are no controlled clinical trials supporting the effectiveness of any pharmacological therapy, although numerous anecdotal reports and individual experiences suggest benefit with corticosteroids and other anti-inflammatory agents and immune modulators. Oral prednisolone or prednisone (1 to 2 mg/kg/day) or IV methylprednisolone in pulse dosages (30 mg/kg/day with a maximum of 1 g × 3 days), continued at monthly intervals for 3 to 6 months, are the most commonly used monotherapies. Intermittent pulse dosages are generally better tolerated than continuous oral daily or every-other-day corticosteroids.24

The prognosis for children with ILD remains variable and is dependent upon the underlying disease process. For example, there are no recorded deaths from NEHI in contrast to a high mortality rate for inborn errors of surfactant metabolism. A severity-of-illness score based on symptoms, hypoxemia, and pulmonary hypertension may be a useful outcome measure in that a higher score is associated with a lower probability of survival.25 In a study of infants less than 2 years of age who required lung biopsy for diffuse lung disease, the presence of pulmonary hypertension, a primary developmental abnormality, or an ABCA3 mutation was associated with high mortality.9