Children’s interstitial lung disease (ILD) encompasses a heterogeneous group of uncommon lung disorders with varying clinical presentations and morbidity. Because these conditions often involve the alveoli and distal airways, and not just the interstitial compartment, they are also referred to as diffuse lung diseases . In many of these disorders, injury to the alveolar wall gives rise to an inflammatory response with subsequent repair that potentially can lead to pulmonary fibrosis. Infections of the lung, either chronic or acute with postinfectious sequelae, form the largest category of children’s ILD in both the immunocompetent and immunocompromised hosts. Diffuse lung disease can also be the presenting manifestation of certain systemic disease processes, sometimes with acute onset accompanied by fever. Therefore some of these entities may present first to the pediatric infectious disease specialist rather than the pediatric pulmonologist.
Classification
A recently modified classification of the conditions that encompass children’s ILD, based on reviews of a large number of diagnostic lung biopsies in children younger than 2 years and in children between 2 and 18 years of age, is presented in Box 24.1 . Although a description of each disorder is beyond the scope of this chapter, certain conditions under the categories of primary lung disorders of the immunocompetent host, disorders related to systemic disease processes, and disorders of the immunocompromised host warrant brief mention because they are either caused by or associated with infection or its treatment, or they mimic community-acquired pneumonia in their presentation.
Disorders of Infancy
Diffuse developmental disorders:
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Acinar/Alveolar dysgenesis/Primary pulmonary hypoplasia
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Congenital alveolar dysplasia
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Alveolocapillary dysplasia with misalignment of pulmonary veins ( FOXF1 mutations)
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Growth abnormalities:
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Prenatal conditions: secondary pulmonary hypoplasia
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Postnatal conditions: chronic neonatal lung disease (in premature and term infants)
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Structural changes in chromosomal abnormalities (i.e., trisomy 21)
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Associated with congenital heart disease in chromosomally normal children
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Specific conditions of unknown/poorly understood etiology
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Pulmonary interstitial glycogenosis (primary and associated)
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Neuroendocrine cell hyperplasia of infancy/persistent tachypnea of infancy
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Surfactant dysfunction disorders and related abnormalities:
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Surfactant protein B genetic mutations
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Surfactant protein C genetic mutations
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ABCA3 genetic mutations
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NKX2-1 genetic mutations
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Congenital GM-CSF receptor deficiency
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Others with histology consistent with surfactant dysfunction disorder without a recognized genetic disorder
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Lysinuric protein intolerance
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Primary Lung Disorders of the Immunocompetent Host
Infections and postinfectious processes
Chronic airway changes with and without preceding history of viral respiratory infection
Organizing pneumonia
Specific infections identified (bacterial, fungal, mycobacterial, viral)
Disorders related to environmental agents:
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Hypersensitivity pneumonitis
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Toxic inhalation
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Aspiration syndromes
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Eosinophilic pneumonias
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Acute interstitial pneumonia/Hamman-Rich syndrome/Idiopathic diffuse alveolar damage
Nonspecific interstitial pneumonia
Idiopathic pulmonary hemosiderosis
Others
Disorders Related to Systemic Disease Processes
Immune-mediated disorders
Goodpasture syndrome
Acquired pulmonary alveolar proteinosis/autoantibody to GMCSF
Pulmonary vasculitis syndromes
Nonspecific interstitial pneumonia
Pulmonary hemorrhage syndromes
Lymphoproliferative disease
Organizing pneumonia
Nonspecific airway changes
Other manifestations of collagen-vascular disease
Storage disease
Sarcoidosis
Langerhans cell histiocytosis
Malignant infiltrates
Others
Disorders of the Immunocompromised Host
Opportunistic infections ( Pneumocystis jiroveci , fungal/yeast, bacterial, mycobacterial, viral, suspected infection)
Disorders related to therapeutic intervention (chemotherapeutic drug, radiation, drug hypersensitivity)
Disorders related to solid organ, lung, and bone marrow transplantation and rejection syndromes (rejection, graft-versus-host disease, posttransplant lymphoproliferative disorder)
Diffuse alveolar damage of undetermined etiology
Lymphoid infiltrates related to immune compromise (nontransplanted patients)
Vascular Disorders Masquerading as Interstitial Lung Disease
Arterial hypertensive vasculopathy
Congestive vasculopathy and veno-occlusive disease
Lymphatic disorders (lymphangiectasis, lymphangiomatosis)
Pulmonary edema
Thromboembolic disease
Unclassified
Postinfectious Bronchiolitis Obliterans
Probably the best example of postinfectious chronic lung disease is found in children who develop bronchiolitis obliterans after having severe adenoviral pneumonia. Bronchiolitis obliterans is characterized by a fibrosing process of the small airways that results in severe, irreversible obstruction of the airways. Clinically patients present with tachypnea, crackles, wheezing, and a productive cough that persists for more than 8 weeks after the initial illness. Chest radiographs commonly show a mixed pattern of hyperinflation, persistent atelectasis, and peribronchial thickening; on high-resolution computed tomography (HRCT) in which both inspiratory and expiratory images are obtained, a combination of mosaic perfusion due to air trapping, central bronchiectasis, and vascular attenuation is highly specific for bronchiolitis obliterans, although not entirely sensitive. Occasionally severe involvement of one lung leads to the development of a unilateral, small, hyperlucent lung, known as Swyer-James syndrome. Pulmonary function testing demonstrates an obstructive pattern characterized by a disproportionate reduction in the midexpiratory flow (FEF 25–75 ) that is usually fixed, although a small response to bronchodilator is sometimes seen.
Patients with severe adenovirus pneumonia have been shown to have immune complexes containing adenovirus antigen in the lung and increased serum levels of interleukin-6 (IL-6), IL-8, and tumor necrosis factor-α (TNF-α). These studies suggest that abnormal or excessive host immunologic and inflammatory responses may be important in the development of chronic lung disease from adenovirus in infants and young children. Although lower respiratory tract infection with Mycoplasma, respiratory syncytial virus, parainfluenza, influenza, measles, varicella, and pertussis also can result in bronchiolitis obliterans, adenovirus is the most common etiologic agent. The need for mechanical ventilation during the initial illness is a strong independent risk factor for the subsequent development of this disease.
Organizing Pneumonia
Organizing pneumonia (OP), defined pathologically by the presence of buds of granulation tissue in the alveolar spaces that may extend into the bronchiolar lumen, is another type of inflammatory process that can result from lung injury. It can be associated with various infections, medications, malignancy, radiation therapy, and autoimmune diseases (secondary OP) or occur in isolation without a defined cause, when it is known as cryptogenic organizing pneumonia (formerly named bronchiolitis obliterans/organizing pneumonia [BOOP], although it is a distinct process from bronchiolitis obliterans). Clinical descriptions of organizing pneumonia in children in the literature are rare, but adults can present with fever, cough, malaise, and dyspnea, with findings of bilateral, peripheral ground-glass opacities and consolidation on high-resolution CT chest scan.
Infections
Chronic infections or long-term sequelae from acute infections account for many cases of ILD in children. In a prospective study of immunocompetent children with chronic diffuse infiltrates, Fan and coworkers found an infectious agent as the underlying cause in 10 (20%) of 51 children with ILD. Identified agents included adenovirus alone in four children, adenovirus and cytomegalovirus in two, varicella in one, Epstein-Barr virus (EBV) in one, Chlamydia in one, and Toxocara in one. These early findings have been supported by large retrospective reviews of lung biopsies conducted by the Children’s Interstitial Lung Disease Research Network. In 187 biopsies from children younger than 2 years of age, infection or postinfectious chronic lung disease was identified in 9% and infection in the immunocompromised host in 11%, whereas 191 lung biopsies in children 2 to 18 years of age yielded infection or postinfectious chronic lung disease in 8% and infection in the immunocompromised host in 20%.
Hypersensitivity Pneumonitis
Acute episodes of hypersensitivity pneumonitis may present as fever, cough, dyspnea, and pulmonary infiltrates (see later section for a more detailed discussion).
Toxic Inhalation
While not specific to children, inhalational exposure to metal-containing fumes generated by welding or to certain fluorinated polymer products (such as from overheating of Teflon-coated cookware) can result in metal fume fever or polymer fume fever, respectively, which are typically self-limited syndromes of acute toxic alveolitis. On the other hand, outbreaks of humidifier disinfectant-associated interstitial lung disease in young Korean children, about 25% of whom presented with fevers, led to a mortality rate of 58%. An acute respiratory syndrome manifesting with fever, hemoptysis, dyspnea, and pulmonary infiltrates occurring up to 48 hours after inhalation of free-base cocaine (“crack lung”) has also been described.
Eosinophilic Pneumonias
Acute eosinophilic pneumonia is the most severe form of the eosinophilic pneumonias. It is characterized histologically by very large numbers of eosinophils infiltrating the alveoli and interstitium, with resultant acute respiratory failure. Acute eosinophilic pneumonia can be idiopathic or result from inciting triggers such as drugs (penicillins, trimethoprim-sulfamethoxazole, minocycline, ethambutol) and inhalational exposures (recent-onset cigarette smoking, cannabis). Patients present with acute onset of fever, dyspnea, and cough; pleuritic chest pain; and myalgias. On examination, crackles are present in 80% of patients; wheezing is a rare manifestation. Hypoxemia is uniformly present, and patients can progress rapidly to severe respiratory failure with a clinical picture of acute respiratory distress syndrome. In contrast to patients with other eosinophilic lung diseases, patients with acute eosinophilic pneumonia generally do not have significant peripheral eosinophilia (>350 cells/mm 3 ) on presentation as a diagnostic clue. Chest radiographs and CT scans show bilateral infiltrates with a variable mix of interstitial and alveolar patterns; pleural effusions are present in 50% of cases. Flexible bronchoscopy to obtain a true bronchoalveolar lavage (BAL) is necessary for the diagnosis, and fluid analysis shows marked eosinophilia (>20%) in most patients. Although pleural fluid also has increased eosinophils, this finding in isolation is not specific for acute eosinophilic pneumonia. Treatment with corticosteroids (i.e., methylprednisolone 2 to 4 mg/kg per day) usually results in a rapid and complete resolution, and recurrences have not been reported.
Pulmonary Vasculitis Syndromes
In children, the spectrum of pulmonary vasculitides includes granulomatosis with polyangiitis (GPA, formerly Wegener granuloma), eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome), microscopic polyangiitis, and pulmonary capillaritis. These disorders can present as diffuse alveolar hemorrhage, with fever, dyspnea, hemoptysis (may not present in a third of patients), anemia, and patchy alveolar infiltrates on chest radiographs. Other patients may have fever and cavitary or nodular lesions on imaging. Diffuse alveolar hemorrhage can be diagnosed with BAL when sequentially recovered aliquots of fluid show persistently bloody return. If hemosiderin-laden macrophages are seen on BAL cytology, then this suggests that the blood has been present in the alveolar spaces for at least 3 days and is not the result of the bronchoscopy itself. Renal involvement may sometimes be present, with microscopic hematuria and red blood cell casts seen on urinalysis. A positive serum antineutrophil cytoplasmic antibody (ANCA) may be seen, with antiproteinase-3 antibody resulting in a cytoplasmic (c-ANCA) staining pattern being associated with GPA and with antimyeloperoxidase antibody giving a perinuclear (p-ANCA) pattern seen in EGPA and microscopic polyangiitis. The presence of significant peripheral and pulmonary eosinophilia would support the diagnosis of EGPA. Pulmonary capillaritis is associated with a variety of conditions and requires a surgical lung biopsy for diagnosis because it may present as an ANCA-negative, hematuria-negative diffuse alveolar hemorrhage syndrome. Therapeutic options for pulmonary vasculitis include systemic corticosteroids, cyclophosphamide, intravenous immunoglobulin, and rituximab ; aggressive treatment is required in severe cases.
Collagen-Vascular Diseases
Pulmonary involvement can be seen at the initial presentation of systemic lupus erythematosus, juvenile idiopathic arthritis, and juvenile dermatomyositis, and these patients may present with acute respiratory symptoms associated with fever. In acute lupus pneumonitis, signs and symptoms include high fevers, dyspnea, tachypnea, crackles, and cyanosis. Chest radiographs may show areas of consolidation and pleural effusions or a pattern of interstitial infiltrates with elevation of the hemidiaphragms. Other pulmonary manifestations of systemic lupus erythematosus include pulmonary hemorrhage, pulmonary hypertension, ILD, pneumothorax, and shrinking lung syndrome. Multisystem involvement, including renal and skin, may provide clues to the underlying diagnosis. Treatment usually requires corticosteroids and other immunosuppressive agents.
Sarcoidosis
Sarcoidosis is a chronic inflammatory disease of unknown cause, characterized by the formation of noncaseating granulomas in many organs, but predominantly affecting the lung. Although uncommon, sarcoidosis can even occur in young children, with the median age at diagnosis of about 12 years in a recently reported cohort of 41 affected children; the youngest patient was diagnosed at age 1 year. Fever was present at diagnosis in more than 70% of the patients under age 10 years, whereas respiratory symptoms were noted in about half of the entire cohort. Chest radiographs were reported to be normal in 44%, but high-resolution CT chest scan demonstrated abnormalities in 95% of all patients, with the predominant findings being nodules, ground-glass opacities, and hilar and mediastinal adenopathy.
Drug Hypersensitivity
Several antimicrobials are known to be associated with the development of ILD, including amphotericin B, isoniazid, and nitrofurantoin. In addition, certain biologics and chemotherapeutic agents may rarely induce acute pneumonitis, with associated fever. Thus, in immunocompromised patients being treated with such medications, drug toxicity must also be considered in the setting of febrile respiratory illnesses. The website pneumotox.com can be a useful resource in this regard.
Nonspecific Lymphoproliferation
Well recognized because it is an acquired immunodeficiency syndrome (AIDS)-defining condition in children infected with human immunodeficiency virus (HIV), lymphocytic interstitial pneumonitis (LIP) is actually a form of pulmonary lymphoproliferative disease characterized histologically by a dense interstitial infiltrate composed of T lymphocytes, plasma cells, and macrophages that diffusely expands the alveolar septa. The etiology of LIP remains unknown, but EBV is thought to be important in the pathogenesis. LIP also occurs in association with common variable immunodeficiency, juvenile idiopathic arthritis, and Sjögren syndrome, as well as in idiopathic and familial forms.
LIP occurs in 30% of children infected perinatally with HIV and typically presents between the second and third years of life as an insidious onset of cough, tachypnea, dyspnea, and hypoxemia. Bilateral nontender parotid enlargement is frequently present and may help to differentiate LIP from other pulmonary complications of HIV infection. Chest radiographs characteristically reveal a diffuse, symmetric reticulonodular or nodular pattern, occasionally with mediastinal or hilar adenopathy, although HRCT is more sensitive and allows for the identification of the subpleural and perilymphatic distribution of the micronodules. Among HIV-infected children, the incidence of acute lower respiratory tract infection is higher in children with LIP, and these patients ultimately may develop bronchiectasis.
Clinical Presentation
Although some patients may present acutely, most children with ILD have insidious symptoms that may go unrecognized for years. Many have been misdiagnosed as having asthma and have been treated with bronchodilators and inhaled corticosteroids. Although a history of wheezing can be elicited in half of patients, it can be documented by physical examination in only approximately 20% of cases. Clinical suspicion for children’s ILD should arise when patients meet at least three of the four following criteria: (1) presenting symptoms of dyspnea, tachypnea, retractions, cough, exercise intolerance, or respiratory failure; (2) presenting signs of crackles, failure to thrive, clubbing, or respiratory failure; (3) hypoxemia; and (4) diffuse abnormality on chest radiographs or CT not attributable to other known processes.
A careful history should be taken to assess the severity of the disease and to obtain information that may contribute to establishing a diagnosis. A search for precipitating factors should include a history of feeding difficulties that may suggest aspiration; any prior acute or severe respiratory tract infections; and environmental exposures, especially to birds or molds. Hemoptysis may indicate a pulmonary vascular disorder or hemosiderosis. Joint disease or rash may indicate a systemic process, such as a connective tissue disease. A family history of relatives or siblings with similar respiratory conditions may provide clues to genetic or familial lung diseases, such as inborn errors of surfactant metabolism.
On physical examination, tachypnea and retractions often are observed, and crackles commonly are heard, particularly at the bases. Chest wall deformity, in particular pectus excavatum, may be noted. In severe cases, cyanosis, clubbing, an accentuated pulmonic component of the second heart sound, and evidence of growth failure are seen. Oxygen saturation usually is normal under all conditions in most patients with mild disease, but desaturation may occur with exercise or during sleep as the disease progresses and ventilation-perfusion mismatch ensues. Patients with more advanced disease are hypoxemic at rest.
Diagnostic Evaluation
A systematic approach to children’s ILD is essential when physicians are confronted with such a large differential of rare conditions, as listed in Box 24.1 . In general, diagnostic studies can be divided into studies used to assess the extent and severity of disease, to identify disorders that predispose to ILD, and to identify the primary ILD ( Box 24.2 ). However, from the perspective of the pediatric infectious disease specialist, the emphasis should be on the inclusion of specific children’s ILD, such as those mentioned earlier, in the differential diagnosis when faced with difficult or atypical cases of respiratory illnesses in which infection is initially suspected. Labs to assess for immune function, autoantibodies, hypersensitivity pneumonitis, and angiotensin-converting enzyme level may have a role in selected cases; pulmonary function tests in older children may also provide clues, such as an elevated diffusion capacity for carbon monoxide as a potential indicator of pulmonary hemorrhage. Most important, if a CT scan of the chest is planned as part of the evaluation, it is critical that the study be ordered in such a fashion as to also enable the evaluation for ILD—namely, with thin-section or high-resolution technique.
To Assess Extent and Severity of Disease
Chest radiography, high-resolution computed tomography
Pulmonary function studies: spirometry, pulse oximetry and arterial blood gases (resting, sleeping, and with exercise), diffusion, pressure-volume curve, infant studies
Electrocardiography, echocardiography
To Identify Primary Disorders That Predispose to Interstitial Lung Disease
HIV test
Immune studies: immunoglobulins including IgE, skin tests for delayed hypersensitivity, response to immunizations, T- and B-cell subsets, complement, others as indicated
Barium swallow, pH/impedance probe
DNA analyses for mutations in the surfactant protein B, surfactant protein C, and ABCA3 and TTF-1 genes
To Identify Primary Interstitial Lung Disease
Antinuclear antibody
Angiotensin-converting enzyme
Antineutrophil cytoplasmic antibody
Antiglomerular basement membrane antibody
Hypersensitivity screen
Infectious disease evaluation—cultures, titers, skin tests
Cardiac catheterization (in selected cases)
Bronchoalveolar lavage and transbronchial biopsy
Transthoracic biopsy
HIV, Human immunodeficiency virus.
High-Resolution Computed Tomography
An HRCT of the chest is one of the initial recommended studies in proposed diagnostic approaches for the evaluation of possible children’s ILD. It is used to evaluate the presence, extent, and distribution of the diffuse lung disease; to select favorable sites for surgical lung biopsy; and, when classic patterns of abnormalities are seen, to either make a confident diagnosis for some conditions or to guide specific but less-invasive testing (genetic testing, autoantibody levels, bronchoscopy) for other conditions. The optimal technique is a volumetric scan acquired during inspiration, from which thin (usually 0.625 to 1.25 mm in thickness) reformats can be constructed (on certain models of CT scanners, the bone reconstruction algorithm actually gives better lung image resolution than does the lung reconstruction algorithm, so collaboration with the radiology department may be helpful). The thin sections avoid the volume averaging that occurs with 2.5- to 5-mm sections, which obscures the fine parenchymal details and airway abnormalities, including mild bronchiectasis. At the same time, the volumetric scan allows for a complete evaluation of the central airways and mediastinum. Images obtained at end-exhalation can provide additional helpful information, especially in terms of air trapping and pulmonary vascular disease, but does entail either a second volumetric scan, or preferably, just a few spaced, successive thin-slice acquisitions to reduce the total radiation dose. If appropriate pediatric protocols are used, a volumetric pediatric chest CT scan with high-resolution reformatted images can be performed with radiation doses of less than 1.5 mSv (equivalent to 6 months of natural background radiation exposure).
Obtaining high-quality CT images of the lungs also requires the avoidance of respiratory motion artifact. In younger children and infants in whom cooperation for breath-holding is impossible and in whom rapid respiratory rates especially predispose to motion artifact, a sedated controlled-ventilation CT technique can be used. Giving several assisted deep breaths using mask ventilation to these sedated young children results in a short period of apnea during which the lungs can be fully inflated to obtain the routine inspiratory images. Expiratory images can be acquired after allowing for passive deflation of the lungs or with voluntary end-expiratory breath-holding. General anesthesia produces similar results, although frequent large sigh breaths are necessary to prevent dependent atelectasis, which occurs within minutes of intubation.
Finally the use of intravenous contrast when evaluating for infections may be helpful in delineating hilar adenopathy but will make the assessment of ground-glass opacification seen with many interstitial lung diseases more difficult. Overall, in studies that have investigated the diagnostic accuracy of HRCT in pediatric diffuse lung disease, the first-choice diagnosis was proved correct in 38% to 61% of cases by subsequent surgical lung biopsy.
Bronchoalveolar Lavage
BAL via flexible bronchoscopy allows for sampling of the alveolar lining fluid to assess its gross appearance and to send for measurement of cell count and differential, cytologic examination, and microbial cultures, as well as for molecular and biochemical analyses, all of which may be helpful in the evaluation of certain cases of children’s ILD. A milky appearance of the BAL fluid with a layering of sediment strongly suggests pulmonary alveolar proteinosis, whereas the progressively bloody appearance of the fluid in sequential aliquots indicates the presence of an alveolar hemorrhage syndrome. Normal indices for pediatric BAL fluid have been described against which abnormal results can be compared. Finding significant eosinophilia or lymphocytosis in the BAL would substantially narrow the differential diagnoses, and detection of lipid- or hemosiderin-laden macrophages can serve as sensitive, albeit not specific, markers for aspiration or alveolar hemorrhage syndromes. Cytologic examination can also be used to diagnose pulmonary alveolar proteinosis, lysosomal storage disorders, and histiocytosis.
The most common indication for pediatric BAL has been to detect infection in the immunocompromised host. The use of quantitative bacterial cultures may help to differentiate whether recovered organisms represent true infection, colonization, or contamination, whereas polymerase chain reaction (PCR) techniques allow for increased sensitivity in detecting Pneumocystis jiroveci pneumonia in non–HIV-immunocompromised patients and for the rapid detection of Mycobacterium tuberculosis. Cytologic examination may identify cases of aspergillosis not otherwise detected by culture alone, and measurement of galactomannan levels in BAL has also been used for early diagnosis of invasive aspergillosis.
When BAL should be performed may be important because investigators have shown in a murine model that hemosiderin-laden macrophages first appear at 3 days, peak at 1 week, and persist in small numbers for 2 months after a single episode of hemorrhage. In adult hematopoietic stem cell transplantation recipients with new pulmonary infiltrates, the diagnostic yield of BAL was highest when performed within 24 hours of presentation.
Finally, while bronchial washings obtained via a suction catheter introduced through an endotracheal tube have proved useful in the evaluation of ventilator-associated pneumonia, they do not adequately sample the alveolar lining fluid and therefore give a different cellular profile from that obtained by bronchoscopic BAL. This discrepancy may result in missed detection of conditions such as acute eosinophilic pneumonia if only the former is performed.
Lung Biopsy
Lung biopsy is the gold standard for establishing the diagnosis of children’s ILD because most diseases are classified in terms of previously defined histopathologic patterns. Although transbronchial or percutaneous needle biopsy may be helpful in certain conditions, a transthoracic approach, usually by video-assisted thoracoscopic surgery (VATS), remains the gold standard for obtaining tissue adequate for diagnosis. Technical advances and now widespread experience with VATS, including in infants, make it the method of choice, especially in light of research demonstrating comparable diagnostic yield in the evaluation of children with ILD (54% with VATS, 57% with open-lung biopsy). Selection of biopsy sites should be determined by findings on HRCT, although the tip of the right middle lobe and lingula should be avoided. Ideally biopsies should be taken from two sites and sample areas of varying disease severity.
Lung biopsy material must be processed in a consistent manner to ensure optimal interpretation, and a protocol for such handling was published based on the recommendations of the Children’s Interstitial Lung Disease (chILD) Pathology Group. A general scheme for division of the biopsy specimen is as follows: (1) microbiology cultures, 35%; (2) snap-frozen for PCR or other molecular studies, 10%; (3) snap-frozen in cryomatrix for immunofluorescent, laser capture, or other studies requiring frozen sections, 10%; (4) fixed in glutaraldehyde for electron microscopy, less than 5%; (5) imprints for cytologic examination or rapid identification of organisms, 0%; and (6) expanded and fixed in formalin (methods previously described ) for light microscopy, 40%. It is crucial that the biopsy material be interpreted by a pathologist with considerable expertise in pediatric lung disease because the normal lung of an infant differs greatly from that of an older child or adolescent and any pathologic finding needs to be interpreted in light of the normal age-dependent variations of lung architecture.
Treatment
Supportive care is important in the management of children’s ILD. Good nutrition is paramount, to the extent that gastrostomy feedings should be considered in selected patients who have poor weight gain despite maximal conventional treatment. Nocturnal or continuous oxygen therapy should be provided in children who are hypoxemic to decrease the risk for the development of pulmonary hypertension. Annual influenza vaccination through the injectable route should be given. Avoiding inhalant hazards such as tobacco smoke should be stressed. Patients with underlying systemic disorders need primary treatment for that disorder, such as intravenous γ-globulin (IVIG) for hypogammaglobulinemia. Specific therapy for primary ILD should be used when possible, such as aggressive management of identified causes of aspiration syndromes, lung lavage and inhalational granulocyte-macrophage colony-stimulating factor for certain types of pulmonary alveolar proteinoses, and interferon-α for pulmonary hemangiomatosis. When environmental agents such as bird antigens are causative, avoiding contact with them is crucial (see later section on hypersensitivity pneumonia [HP]).
Generally, corticosteroids remain the treatment of choice for most patients with ILD on the presumption that suppression of inflammation may reduce the risk for developing fibrosis. Although controlled clinical studies are lacking, corticosteroids have been used to treat such diverse types of diffuse lung diseases as desquamative interstitial pneumonitis, nonspecific interstitial pneumonitis, acute interstitial pneumonia, cryptogenic organizing pneumonia, lymphocytic interstitial pneumonia, HP, eosinophilic pneumonia, diffuse alveolar hemorrhage, ILD associated with connective tissue diseases, and surfactant protein C mutations. In a retrospective study of pediatric ILD by Fan and coworkers, corticosteroids were judged to be effective in 40% (12 of 30) of treated children in terms of improved clinical status, decreased oxygen requirements, and improved pulmonary function. A trial of prednisone or equivalent corticosteroid in a dose of 1 to 2 mg/kg per day for at least 6 to 8 weeks probably is warranted, although it may be preferable to instead use intravenous pulses of methylprednisolone 30 mg/kg, with a maximum dose of 1 g, given for either 3 consecutive days every month or 1 day every week, based on experience that pulse intravenous therapy is at least as effective as oral therapy and has fewer side effects.
Alternative immunomodulatory agents that have also been used include hydroxychloroquine, azathioprine, cyclophosphamide, methotrexate, cyclosporine, IVIG, and mycophenolate mofetil. Of these, hydroxychloroquine probably has been used most frequently. The precise mechanism of action is unknown, but chloroquine and hydroxychloroquine have shown immunosuppressive effects with the ability to inhibit the functional capabilities of monocytes and the generation of antibody-forming cells. Hydroxychloroquine is preferred over chloroquine because the former has less retinal toxicity. The recommended dose in children for the treatment of ILD is 10 mg/kg per day. Additionally there has been a case report describing the successful use of infliximab, an anti–TNF-α monoclonal antibody, in reversing bronchiolitis obliterans in a hematopoietic stem cell transplant recipient. Finally treatment regimens for ILD associated with systemic sclerosis, Langerhans cell histiocytosis, and Wegener granulomatosis have been reviewed. The fact that many alternative pharmacologic approaches are considered for children and adults with ILD implies that conventional therapy often is ineffective. New strategies are being developed based on animal models of pulmonary fibrosis and more recent advances in the cellular and molecular biology of inflammatory reactions. Such therapies would be directed against the action of certain cytokines, oxidants, and growth factors that may be involved in the fibrotic process. Two antifibrotic drugs, pirfenidone and nintedanib, have recently been shown to result in meaningful reductions in disease progression in adults with IPF. Whether these drugs will be useful in children with fibrotic lung disease remains to be determined. The potential to deliver specific inflammatory inhibitors or inhibitors of collagen biosynthesis directly to the lung via aerosolization suggests that disease processes in the lung may be more amenable to novel therapies than are disease processes in other internal organs.
Lung transplantation can be used as a final therapeutic modality for some forms of children’s ILD that progress to irreversible respiratory failure secondary to pulmonary fibrosis. Although the overall 5-year survival after lung transplantation is still disappointing at approximately 50%, it appears that outcomes for children with diffuse lung disease are comparable to those undergoing transplantation for cystic fibrosis or pulmonary hypertension. In certain systemic conditions, such as hereditary pulmonary alveolar proteinosis, however, transplantation may not be appropriate because the primary disease may recur in the transplanted lungs.
Outcome
The prognosis of children with ILD varies. Infants with neuroendocrine cell hyperplasia of infancy generally do well, although they may be symptomatic and require oxygen for years. At the other end of the spectrum, children with growth failure, pulmonary hypertension, and severe fibrosis do poorly. A survey that likely included many different types of pediatric interstitial lung diseases found an overall mortality rate of 15%.
Fan and Kozinetz reviewed the outcome of 99 children with chronic ILD seen in Denver, Colorado, over the course of 15 years (1980–94). As expected, a wide variety of disorders were encountered, and 15 recorded deaths occurred, with a probability that a patient would survive to 24 months, 48 months, and 60 months after onset of symptoms of 83%, 72%, and 64%, respectively. Of the clinical features present at the time of initial evaluation, weight less than the fifth percentile, crackles, clubbing, family history of ILD, and symptom duration were not associated with decreased survival rates. A severity of illness score, based on increasing levels of hypoxemia and the presence or absence of pulmonary hypertension, was related significantly to survival, with an increasing score associated with a higher probability of decreased survival rates. A simple scoring system seems to be a useful measure of outcome in children with ILD.
Hypersensitivity Pneumonitis
HP, also known as extrinsic allergic alveolitis, is a form of immune-mediated ILD that develops in response to repeated inhalation of finely dispersed organic antigens. HP should be considered in the differential diagnosis of a child who presents with acute or chronic respiratory symptoms associated with fever, and obtaining an environmental exposure history is essential to arrive at the proper diagnosis. A wide variety of organic particles, including mammalian and avian proteins, fungi, thermophilic bacteria, and certain low-molecular-weight volatile and nonvolatile chemical compounds, are known to induce HP in susceptible individuals. Certain systemic medications, such as ciprofloxacin, dapsone, and methotrexate, also have been reported as triggers.
In general, three forms of HP have been described: (1) acute (or episodic), with improvement between attacks; (2) insidious (gradual onset and progressive course) with superimposed acute episodes; and (3) insidious without acute attacks. Although exposure to antigens capable of provoking HP occurs commonly in the home and work environment, the overall incidence of the condition in the general population is low. It is estimated that only 5% to 15% of individuals exposed to high levels of a specific organic antigen develop clinical disease.
Pathology and Pathogenesis
Pathologically, HP is characterized by a diffuse, lymphoplasmacytic cell infiltration of the small airways and pulmonary parenchyma, often with associated multinucleated giant cells containing cholesterol clefts and poorly formed, nonnecrotizing granulomas. Foamy macrophages are seen commonly in the airspaces. With advanced disease, interstitial and intra-alveolar fibrosis develops that is indistinguishable from other causes of pulmonary fibrosis.
The mechanisms by which organic dusts induce these characteristic pathologic features of the disease are not completely understood, but it is thought that both type III (immune complex–mediated) and type IV (delayed) hypersensitivity mechanisms are involved. A type III reaction is suggested by the presence of precipitating antibody to the offending antigen, immune complex deposition, and activation of complement. A type IV reaction is suggested by an increased percentage of T lymphocytes in BAL fluid, with a strong predominance of CD8 + subsets and a low CD4:CD8 ratio, and the presence of granulomas on lung biopsy specimen. Considering the small proportion of exposed individuals who develop clinical symptoms, complex interactions among the nature of the antigen, the intensity and duration of the exposure, and the host response in affected individuals most likely are involved. Genetic predilection to the development of HP has been linked to polymorphisms in the genes encoding TNF-α and in those found within the major histocompatibility complex class II. Associated viral infections may also contribute to susceptibility, whereas cigarette smoking (nicotine) seems to confer a protective effect. Familial cases of HP have been identified.
Etiology
As shown in Table 24.1 , HP in adults is caused by a wide variety of occupational and environmental exposures. In contrast, in children, HP is caused mainly by exposure to an array of domestic birds (69%) and fungi (29%), based on a review of 191 reported pediatric cases. In HP due to bird exposure (bird fancier’s lung), bird droppings and feathers are the major sources of the offending antigens. Although exposure to pet birds is usually the cause, even low levels of environmental exposure to wild birds in the yard or birds raised by a neighbor may be enough to induce clinical HP, as may contact with feather-filled household items such as feather pillows, down comforters, and feather duvets. The onset of clinical disease typically follows months to years of continuous or intermittent exposure to the offending antigen, and it has been demonstrated that bird antigens can persist for months in the home environment even after removal of the birds. Possible sources of mold exposure are varied and can include contaminated air humidifiers, indoor hydroponics, organic compost in a play area, moist hay, and even wind instruments, in addition to overt mold contamination in areas of water damage or in poorly ventilated spaces exposed to moisture.
