Pediatric Annals

CME Article 

Diffuse Lung Disease in Children

Adrienne Prestridge, MD; Robin R. Deterding, MD

Abstract

A 3-month-old is brought in by her mother for evaluation because she said she believes the baby breathes faster than her older children. The infant was born at term, with no complications during the pregnancy and an uncomplicated delivery. The mother states that she always thought the baby was breathing fast, but she has recently noted some retractions. There is no cough or nasal congestion, nor spitting up or cough with feeds. She feeds well with no alterations in stool pattern. She is happy, smiling, and developmentally appropriate.

Abstract

A 3-month-old is brought in by her mother for evaluation because she said she believes the baby breathes faster than her older children. The infant was born at term, with no complications during the pregnancy and an uncomplicated delivery. The mother states that she always thought the baby was breathing fast, but she has recently noted some retractions. There is no cough or nasal congestion, nor spitting up or cough with feeds. She feeds well with no alterations in stool pattern. She is happy, smiling, and developmentally appropriate.

Adrienne Prestridge, MD, is Assistant Professor, Pulmonary Medicine, Children’s Memorial Hospital, Chicago, IL. Robin R. Deterding, MD, is Professor, Pulmonary Medicine, The Children’s Hospital of Denver, CO.

Dr. Prestridge and Dr. Deterding have disclosed no relevant financial relationships.

Address correspondence to: Adrienne Prestridge, MD, Children’s Memorial Hospital, 2300 Children’s Plaza #43, Chicago, IL 60614; fax: 773-880-6300; e-mail: aprestridge@childrensmemorial.org.

A 3-month-old is brought in by her mother for evaluation because she said she believes the baby breathes faster than her older children. The infant was born at term, with no complications during the pregnancy and an uncomplicated delivery. The mother states that she always thought the baby was breathing fast, but she has recently noted some retractions. There is no cough or nasal congestion, nor spitting up or cough with feeds. She feeds well with no alterations in stool pattern. She is happy, smiling, and developmentally appropriate.

Physical exam reveals an active infant whose weight and height are at the fifth percentile, respiratory rate of 85 breaths per minute. Pulmonary examination reveals mild retractions subcostally and suprasternally, clear lungs with normal aeration, and no crackles or wheezes. The remainder of examination was normal. Pulse oximeter reveals 95% oxyhemoglobin saturation. You provide counseling to the mother regarding normal respiratory rates and perform an evaluation to determine the etiology of the infant’s tachypnea.

Infants and children may present with interstitial lung disease acutely or with insidious, subtle symptoms, as in the case above. Older children may have symptoms associated with other systemic diseases, such as rheumatologic disorders. The most common signs and symptoms are chronic cough, tachypnea, dyspnea, hypoxemia, and retractions, all of which may vary depending upon the disorder and severity.

Because of the subtle nature of the presentation of interstitial lung disease (ILD), a comprehensive evaluation for more common etiologies of these symptoms should occur initially, including infections, aspiration, cystic fibrosis, and cardiac defects. Reflux is frequently associated with ILD and may be a secondary diagnosis.1 Known causes of pediatric ILD include infection, aspiration, hypersensitivity pneumonitis, collagen vascular disease, environmental exposures, immunodeficiency, bronchopulmonary, and lipid storage disease. However, the etiology of a large portion of pediatric ILD remains less common or idiopathic.

If suspicion is high for ILD, the general diagnosis of ChILD (children with interstitial lung disease) syndrome can be given if the patient has three of the following (in the absence of an identified etiology as the primary cause): symptoms of impaired respiratory function; hypoxemia; diffuse infiltrates; presence of adventitious breath sounds; and abnormal lung function.2

Once labeled as ChILD syndrome, a search for a more definitive diagnosis should be undertaken. In some instances, even in children with known etiologies (eg, RDS, aspiration, etc.), if respiratory signs and symptoms are out of proportion to the known disorder, a ChILD diagnosis may still need to be considered.

Background

ILD is a rare group of disorders characterized by derangement of the alveolar-capillary interface or interstitium, often characterized clinically with tachypnea, crackles, hypoxemia and/or abnormalities on radiographic evaluation.2 Although a strict definition implies an abnormality of the interstitium, there are some diseases that have minimal interstitial defect but have pathologic abnormalities in the air spaces and distal airway that are considered under the broad term of ILD.3 Thus, some authors prefer the term “diffuse lung disease.” Inflammation and abnormal growth, development, and repair are proposed mechanisms leading to defects of the alveolar-capillary units or abnormal airways. Mechanisms vary and are age-specific, with lung growth and development playing a critical role in progression.4,5

The frequency of ILD is not known because of a lack of systematic registries to collect data on these cases around the world. A survey in the United Kingdom and Ireland noted 46 cases, or a prevalence rate of 3.6 cases per million children from birth to 16 years.6 Additional research and recognition of these diseases will lead to a more accurate prevalence of cases of ILD.

It is important to understand that, in the past, much of the categorization of pediatric ILD was an extension of the adult ILD classification system. This created considerable confusion. Recently, a more coordinated effort of collecting pediatric cases has led to better understanding of the specific categories of pediatric ILD, as well as new nomenclature.7

An example of the problematic use of adult classifications of ILD in pediatrics can be illustrated with the case of usual interstitial pneumonia (UIP). UIP is a pathologic diagnosis, and more than 100 cases are reported in the pediatric literature. In a review of childhood cases, however, none had the characteristic pathologic findings seen in adults.8 In addition, the prognosis of UIP in adults is poor, with most dying within 5 years, while children reported to have UIP live much longer with a nonprogressive course.8 This demonstrates how pediatric ILD is not the same as adult ILD and why the new pediatric ILD classification scheme is a major advance.

Clinical Diagnosis

The first step in diagnosing a patient with ILD is to have a high degree of clinical suspicion. It is essential to distinguish between primary pediatric interstitial lung disease and that associated with other known causes of ILD. A patient’s age at presentation is important, because different diagnoses are more common in the neonate and those who are younger than 2 years.9–11 Specific tests are performed based on the patient’s age of presentation and the severity of the respiratory disorder.

A thorough medical history and physical exam may provide clues to the underlying diagnosis. Chronic dry cough, tachypnea, dyspnea, retractions, cyanosis, clubbing, failure to thrive, exercise intolerance, and frequent respiratory infections are all common presentations in children with ILD. Observed cyanosis is less common, but hypoxemia is common.

Before recent advances in diagnosis of children’s ILD, only 25% of the clinicians’ initial diagnosis, based on patient history, was correct, except in cases in which a history of a bird exposure led to a diagnosis of hypersensitivity pneumonitis.12 The recognition of genetic disorders has changed this paradigm.9,13 Up to 34%1 of patients have a family history of lung disease, and 10%4 of siblings were also affected by similar disease when evaluated retrospectively. A thorough review of systems, focusing on joints, skin, kidneys, sinuses, eyes, thyroid, and nervous system, may raise suspicion of known causes of ILD, such as autoimmune collagen vascular disease, sarcoidosis, and mutations in the NKX2-1 gene.13

Physical exam findings can also vary, with crackles frequently but not always present and wheezing occasionally present (∼20%).1,14 Other physical exam findings, such as joint disease and rashes, may provide clues to a systemic disease, such as collagen-vascular disease. With current knowledge of the genetic basis of many forms of ILD, the age of presentation and better clinical, radiographic, and pathologic correlation,1,4 some forms of ILD can be correctly identified by astute clinicians with historical information, although further genetic diagnostic evaluation is necessary for confirmation.

Laboratory, Radiographic and Pathologic Evaluation

Once a clinical suspicion is confirmed, appropriate laboratory, radiographic, and, if indicated, pathologic evaluation should occur. Depending on the patient’s age and history, tests to evaluate for known etiologies, such as immunodeficiencies, collagen-vascular disease, infections, and hypersensitivity panels (serum precipitins) to various bird agents should be performed. Electrocardiography and echocardiography should be undertaken, because cardiac disease can masquerade as ILD, and pulmonary hypertension is a risk factor for mortality in pediatric ILD.

Although they are not forms of ILD, cystic fibrosis and primary ciliary dyskinesia present with many similar symptoms, such as a productive cough and recurrent respiratory infections. Therefore, a review of cystic fibrosis newborn screening results, if available, followed by diagnostic testing with a sweat test or nasal ciliary biopsy, should be considered. Reflux and aspiration can be evaluated with a pH probe, barium swallow, and a videofluoroscopic swallow study.

It may also be important to send mutational analysis for surfactant protein B (SP-B), surfactant protein C (SP-C), ATP Binding Cassette A3 (ABCA3), and thyroid transcription factor-1 (TTF-1, also known as the NKX2-1 gene). These genes, encoding proteins involved in surfactant processing and production, have been recognized in recent years to account for many neonatal ILD cases. In children who present later than the neonatal period, testing for SP-C and ABCA3 are appropriate because patients with SP-B mutations rarely present outside the neonatal period, whereas clinical history of hypotonia or thyroid abnormalities should prompt testing for NKX2-1.

Besides laboratory evaluation, radiographic evaluation is critical to diagnose ILD. Chest radiographs can demonstrate diffuse pulmonary infiltrates, often in specific patterns described as reticular-nodular, ground glass, or honeycombing, as well as hyperinflation. Chest X-ray abnormalities suspicious for ILD should be pursued with a computed tomography (CT) scan of the chest as the next step. There are specific characteristics on CT scan for specific forms of ILD, such as bronchiolitis obliterans and neuroendocrine cell hyperplasia of infancy (NEHI).15,16

Because most CXRs demonstrate nonspecific findings in ILD, a high-resolution CT (HRCT) scan of the chest is useful to delineate parenchymal abnormalities further and, if necessary, to allow the surgeon to choose an optimal site for biopsy. The CT scan should be done under optimal settings; high-resolution scans with controlled ventilation help to eliminate false positive CT scan findings from motion artifact and effects of gravity. Controlled ventilation helps to induce an inspiratory pause, eliminating respiratory motion artifact.15,17 Quality CT scans in infants and young children frequently require sedation or general anesthesia.

Assessment of pulmonary function status is important, including spirometry, lung volumes by plethysmography, and diffusing capacity. Spirometry can reveal a pattern of restrictive lung disease, sometimes with an obstructive component of air trapping, and low diffusion capacity, normalized when corrected for alveolar volume.8

Infant pulmonary function testing has been found to have some characteristic patterns with various forms of ILD.18 Additional assessment of pulmonary function using pulse oximetry and arterial blood gases for severely ill children helps to determine the degree of hypoxia. Some patients who are normoxic while awake might desaturate with sleep or exercise, and this should be investigated. Polysomnography (PSG), a 6-minute walk test, or an exercise tolerance test, may be useful as indicated by results of history and other testing.

If noninvasive testing does not yield a diagnosis, pathologic evaluation may be necessary. Bronchoalveolar lavage (BAL) yielded a specific diagnosis in 17% of cases19 when evaluated prospectively, and 30% when evaluated retrospectively. A BAL can be evaluated for cell count, infectious agents (via microbiologic and PCR-based assays) and lipid and hemosiderin stains, which indicate processes such as infection, aspiration, and hemorrhage, as well as alveolar proteinosis, lysosomal storage disorders, and histiocytosis.8

Although currently of limited utility in idiopathic ILD, BAL is relatively noninvasive and can be done before more invasive procedures. Centers experienced in treating and testing for ChILD will frequently combine procedures (for example, CT and BAL) to limit anesthesic exposure. Active research is ongoing to determine potential biomarkers that may assist in diagnosis.

Lung biopsy is the gold standard to diagnose ChILD when less invasive testing has not proved diagnostic. Biopsy via video-assisted transthoracic surgery (VATS) has become the standard approach, even in small infants, dramatically reducing the morbidity associated with open thoractotomy,20 reducing operating time, decreasing incidence of chest tube placement and shortening hospitalizations.3

Once the specimen has been obtained, proper processing of the tissue is critical to provide a comprehensive diagnostic evaluation, including culture, light microscopy, immunohistochemistry, and electron microscopy (EM).21

An evaluation for children with ILD can be expensive, exhausting for the family, and fraught with potential risk for the patients. For all these reasons, referral and discussion with a major ChILD center before initiating the evaluation is advised. Support for the family can also be provided by the ChILD Foundation ( www.childfoundation.us)

Specific Forms of ILD

A classification system for pediatric ILD, based on clinical and pathologic characteristics, was recently developed and has provided more organizational structure and clarity.1 Diagnoses are separated into the following categories: 1) more prevalent in infancy (younger than 2 years); 2) related to systemic diseases in a normal host with presumed normal immune system; 3) associated with an immunocompromised host; and 4) masqueraders of ILD (see the Sidebar, page 781).

Sidebar.

  1. Disorders more prevalent in infancy

    1. Diffuse developmental disorders

    2. Growth abnormalities reflecting deficient alveolarization

    3. Specific conditions of undefined etiology

    4. Surfactant dysfunction

      1. Surfactant protein B

      2. Surfactant protein C

      3. ATP binding cassette A#

      4. Thyroid transcription factor-1 (NKX-2)

      5. Congenital GMCSF receptor deficiency

      6. Histology consistent with surfactant dysfunction disorder without a yet recognized genetic etiology

      7. Lysinuric protein intolerance

  2. Disorders related to systemic disease processes

    1. Immune mediated/collagen vascular disorders

    2. Storage disease

    3. Sarcoidosis

    4. Langerhans cell histiocytosis

    5. Malignant infiltrates

  3. Disorders of the normal host, presumed immune intact

    1. Infectious/post infectious process

    2. Related to environmental agents

      1. Hypersensitivity pneumonitis

      2. Toxic inhalation

    3. Aspiration syndromes

    4. Eosinophilic pneumonia

    5. Acute interstitial pneumonia/Hamman-Rich syndrome/Idiopathic diffuse alveolar damage

    6. Nonspecific interstitial pneumonia

    7. Idiopathic pulmonary hemosiderosis (bleeding in the lung)

  4. Disorders of the immunocompromised host

    1. Opportunistic infections

    2. Related to therapeutic intervention

    3. Related to transplantation and rejection

    4. Lymphoid infiltrates related to immune compromise (for non-transplanted patients)

    5. Diffuse alveolar damage, unknown etiology

  5. Disorders masquerading as ILD

    1. Arterial hypertensive vasculopathy

    2. Congestive changes related to cardiac dysfunction

    3. Veno-occlusive disease

    4. Lymphatic disorder

    5. Pulmonary edema

    6. Thromboembolic

This section focuses on the category of disorders more common in infancy, as newly defined entities have been recognized. Most ILD cases in children younger than 2 years are included in these areas. Among those conditions that are prevalent in infancy, there are four main categories: diffuse developmental disorder; growth abnormalities reflecting deficient alveolarization; specific conditions without a defined etiology; and disorders related to surfactant dysfunction.

Diffuse Developmental Disorders

Diffuse developmental disorders, such as acinar dysplasia and alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV), are rare and poorly understood. They are thought to be caused by an aberration in lung and/or vascular development, characterized by arrested lobular and alveolar density. Developmental disorders like these present in the newborn period and have high mortality. Genetic mutations have now been reported for ACDMPV.22

Distinct from these diffuse disorders, there are specific abnormalities that affect alveolar growth, such as pulmonary hypoplasia, bronchopulmonary dysplasia and those associated with chromosomal disorders or congenital heart disease. Growth disorders distort the interstitium and present in the newborn period with signs and symptoms of ChILD syndrome.

Two specific disorders of undefined etiology are NEHI and pulmonary interstitial glycogenosis (PIG). NEHI is a form of ChILD with a favorable outcome. Patients with NEHI present with persistent tachypnea, hypoxia, and crackles at variable ages, most commonly in the first year of life.1,23

Many of these patients may be initially misdiagnosed as having asthma, despite persistent fine crackles on examination. Chest radiographs show hyperinflation and typical CT scans show ground glass opacities in the right middle and lingual lobe and areas of hyper-expansion.24 Recently, familial cases have been described, suggesting a potential genetic etiology.25 Children are diagnosed by clinical history, imaging, infant pulmonary functions testing, and lung biopsy, which is still considered the gold standard. Most children show gradual improvement with no reported mortality. Chronic systemic steroids are not indicated and, thus, treatment is mainly supportive.23

PIG has been described in term and preterm infants. Presentation occurs most frequently in the immediate neonatal period, with hypoxemia and tachypnea out of proportion to the clinical circumstances. PIG has also been seen in association with, and can complicate, preterm growth abnormalities and congenital heart disease. The glycogen-rich cells that expand the interstitium in PIG produce a significant diffuse defect and can be recognized easily on lung biopsy, which is currently the only method of diagnosing PIG.

No patient older than 8 months has been histologically diagnosed with PIG. As with NEHI, long-term outcome is favorable in most patients with isolated PIG.26 However, mortality for PIG in association with growth abnormalities has been reported, so the prognosis is more guarded.1,26

Presentations of Deficiencies

Mutations in several components related to the processing and transport of surfactant can lead to ChILD. Surfactant is a mixture of proteins (SP-B and SP-C) and phospholipids that lowers the surface tension in the alveoli to prevent atelectasis.27 The ATP binding cassette A3 (ABCA3) has a role in surfactant processing and transport within the alveolar cell.20 Thyroid transcription factor-1 (TTF-1) regulates the production of all the surfactant proteins and ABCA3. Mutations in any of these four proteins can lead to ChILD. Recognizing and identifying these genetic disorders have important implications for the patient and the extended family.

SP-B deficiency is a rare recessive disorder with clinical estimates of 1 per million live births.27 The presentation is similar to infants with respiratory distress syndrome (RDS), with respiratory failure within the first few hours of life and the development of significant pulmonary hypertension. In contrast to RDS, patients with mutations in SP-B are born at term, and their illness progressively worsens and does not resolve. The disease is fatal without lung transplantation.27

SP-C deficiency has a variable presentation ranging from birth, child-hood and even into adulthood. The onset of symptoms often occurs in term neonates who present with clinical symptoms similar to RDS or in young children as persistent hypoxemia. Treatment is supportive with outcomes covering a spectrum. Some require lung transplantation, while others improve over time and no longer require supplemental oxygen.27 Many infants and young children with SP-C will improve over time with aggressive pulmonary and nutritional support.28,29

ABCA3 deficiency can present similarly to either SP-B or SP-C deficiency. Presentation can be in the newborn period with a clinical picture of RDS in a term infant; patients can also present later with findings typical of ILD. Treatment is generally supportive with outcome ranging from fatal in the newborn period to some variants with a milder course surviving into adulthood.20

A new entity described clinically as brain, thyroid, lung syndrome has also been increasingly recognized to result in ChILD. This disorder is associated with mutations or deletions in the thyroid TTF-1 or NKX2-1 gene. Any children with RDS who present with abnormalities in thyroid function tests (especially on newborn screen), findings of even subtle hypotonia or chorea, and lung disease should be considered for testing.

Besides the above known mutations, there are also other cases of ILD that pathologically mimic the surfactant-related gene mutations, without no mutation being found. Other forms of ILD that arise in infancy include granulocyte-monocyte cell-stimulating factor (GM-CSF) receptor deficiency and lysinuric protein intolerance, both of which are quite rare.

Treatment and Management

Unfortunately, treatment for ILD is limited. The mainstay of treatment is supportive, specifically supplemental oxygen to relieve hypoxemia and tachypnea. Most children are tachypneic to maintain their oxygen saturations because of difficulty with diffusion of oxygen across the alveolar capillary barrier and significant ventilation-perfusion mismatch.

Besides oxygen therapy, maintaining adequate nutrition, treatment of underlying disease, whether due to reflux and/or aspiration, immunizing against respiratory pathogens, aggressive treatment of intercurrent illnesses, and avoidance of environmental tobacco smoke and other pollutants is best practice.30 All patients and families with genetic mutations should have genetic counseling. Clinical improvement can be judged by decreases in symptoms, most specifically dyspnea, improvements in pulmonary function tests and saturation; however, radiographic changes do not occur quickly enough to follow frequently.30

Beyond supportive care and disease-specific treatment, many therapeutic modalities have been tried. Immunomodulating agents have been reported as therapeutic agents for ILD, most frequently corticosteroids, which have a highly variable response. Glucocorticoid treatment regimens range from daily oral doses to monthly intravenous pulses of steroids. The optimal dose, frequency, and duration of therapy, as well as when to initiate or discontinue therapy and the relative harm compared with side effects, still remain unclear.30

Other treatments have been tried on a case-by-case basis, such as hydroxychloroquine, azathioprine, cyclophosphamide, methotrexate, cyclosporine, and intravenous immunoglobulin (IVIG).8 In life-threatening autoimmune collagen-vascular disease and pulmonary hemorrhage syndromes, aggressive treatment with immunosuppression, cytotoxic agents, and glucocorticoids is required.

Outcomes from individual diseases are variable. There is a significant overall mortality rate of 15%, determined from a retrospective review of 99 general ILD cases and a probability of survival of 83%, 72%, and 64% at 2, 3, and 4 years, respectively.3

In a more recent retrospective review of children younger than 2 years and using more current pediatric classification schemes, only 30% died, but 50% had ongoing pulmonary symptoms at follow-up. Certain diseases had no mortality, while some were 100% fetal.1 Specifically, neonatal disease with ACDMPV, ABCA3, and SP-B mutations are highly fatal, while later presentation with ABCA3 or SPC deficiency, PIG, and NEHI have lower mortality rates.

Lung transplantation is a treatment option for progressive ILD with respiratory failure. Although average survival rates for pediatric lung transplant recipients are about 4.5 years,31 some children survive much longer and are able to enjoy many aspects of life. Complications from lung transplantation are common, with a high percentage of patients developing bronchiolitis obliterans.30

Variation in outcome stresses the importance of having a specific diagnosis to best counsel patients on long-term prognosis. Some particularly well-designed sources of family and patient education material are the American Thoracic Society Patient Information Series: “What is Interstitial Lung Disease in Children?”32 and the ChILD Foundation’s “Get up and Go with ChILD” Parent Resource Guide.33 Research is desperately needed for this large collective cohort of children with ChILD.

Conclusion

Primary care physicians who see infants and children have a key role to play in recognizing children with ChILD syndrome in the differential diagnosis of patients with pulmonary complaints, such as in the example case. The case illustrates an infant with ChILD syndrome who should be evaluated for specific disorders found in infancy. Patients can present insidiously with complaints, such as tachypnea and diffuse infiltrates found on radiographic evaluation. Any infant or child who presents with persistent crackles, tachypnea, hypoxemia, or diffuse infiltrates requires further evaluation.

Diagnosis can occur after exclusion of known etiologies through various laboratory, genetic testing, radiographics, and, when needed, the gold standard of lung biopsy. Referral to a center with expertise in ChILD is advisable. The diagnosis is especially important in light of recent advances in knowledge that long-term outcomes are variable and most patients do not die.

References

  1. Deutsch GH, Young LR, Deterding RR, et al. ChILD Research Co-operative. Diffuse lung disease in young children: application of a novel classification scheme. Am J Respir Crit Care Med. 2007;176(11):1120–1128. doi:10.1164/rccm.200703-393OC [CrossRef]
  2. Deterding R, Fan LL. Surfactant dysfunction mutations in children’s interstitial lung disease and beyond. Am J Respir Crit Care Med. 2005;172(8):940–941. doi:10.1164/rccm.2507004 [CrossRef]
  3. Fan LL, Kozinetz CA. Factors influencing survival in children with chronic interstitial lung disease. Am J Respir Crit Care Med. 1997;156(3 Pt 1):939–942.
  4. Clement A; ERS Task Force Task force on chronic interstitial lung disease in immunocompetent children. Eur Respir J. 2004;24(4):686–697. doi:10.1183/09031936.04.00089803 [CrossRef]
  5. Glasser SW, Hardie William D., Hagood James S.Pathogenesis of Interstitial Lung Disease in Children and Adults. Pediatric Allergy, Immunology and Pulmonology. 2010;23(1):9–14. Available online at: www.liebertonline.com/ped. Accessed Nov. 16, 2010. doi:10.1089/ped.2010.0004 [CrossRef]
  6. Dinwiddie R, Sharief N, Crawford O. Idiopathic interstitial pneumonitis in children: a national survey in the United Kingdom and Ireland. Pediatr Pulmonol. 2002;34(1):23–29. doi:10.1002/ppul.10125 [CrossRef]
  7. Langston C. Interview with the Expert: Claire Langston, MD. Pediatric Allergy, Immunology and Pulmonology. 2010;23(1):5–8. Available online at: www.liebertonline.com/ped. Accessed Nov. 16, 2010. doi:10.1089/ped.2010.2303 [CrossRef]
  8. Fan LL, Deterding RR, Langston C. Pediatric interstitial lung disease revisited. Pediatr Pulmonol. 2004;38(5):369–378. doi:10.1002/ppul.20114 [CrossRef]
  9. Nogee LM. Genetic Basis of Children’s Interstitial Lung Disease. Pediatric Allergy, Immunology and Pulmonology. 2010;23(1):15–24. Available online at: www.liebertonline.com/ped. Accessed Nov. 16, 2010. doi:10.1089/ped.2009.0024 [CrossRef]
  10. Deterding RR. Infants and Young Children with Children’s Interstitial Lung Disease. Pediatric Allergy, Immunology and Pulmonology. 2010;23(1):25–31. Available online at: www.liebertonline.com/ped. Accessed Nov. 16, 2010. doi:10.1089/ped.2010.0011 [CrossRef]
  11. Vece TJ, Fan Leland L.Interstitial Lung Disease in Children Older than 2 years. Pediatric Allergy, Immunology and Pulmonolgy. 2010;23(1):33–41. Available online at: www.liebertonline.com/ped. Accessed Nov. 16, 2010. doi:10.1089/ped.2010.0008 [CrossRef]
  12. Fan LL, Langston C. Chronic interstitial lung disease in children. Pediatr Pulmonol. 1993;16(3):184–196. doi:10.1002/ppul.1950160309 [CrossRef]
  13. Fauroux B, Epaud R, Clément A. Clinical presentation of interstitial lung disease in children. Paediatr Respir Rev. 2004;5(2):98–100. doi:10.1016/j.prrv.2004.01.003 [CrossRef]
  14. Clement A, Henrion-Caude A, Fauroux B. The pathogenesis of interstitial lung diseases in children. Paediatr Respir Rev. 2004;5(2):94–97. doi:10.1016/j.prrv.2004.01.002 [CrossRef]
  15. Guillerman RP. Imaging of Childhood Interstitial Lung Disease. Pediatric Allergy, Immunology and Pulmonology. 2010;23(1):43–68. Available online at: www.liebertonline.com/ped. Accessed Nov. 16, 2010. doi:10.1089/ped.2010.0010 [CrossRef]
  16. Brody AS. Imaging considerations: interstitial lung disease in children. Radiol Clin North Am. 2005;43(2):391–403. doi:10.1016/j.rcl.2004.12.002 [CrossRef]
  17. Long FR, Castile RG. Technique and clinical applications of full-inflation and end-exhalation controlled-ventilation chest CT in infants and young children. Pediatr Radiol. 2001;31(6):413–422. doi:10.1007/s002470100462 [CrossRef]
  18. Kerby G, Wilcox SL, Heltshe SL, Accurso FJ, Deterding RR. Infant Pulmonary Function in Pediatric Interstial Lung Disease. Am J Respir Crit Care Med. 2005;2(Abstracts):A474. Abstract presented at the American Thoracic Society International Conference. .
  19. Fan LL, Kozinetz CA, Wojtczak HA, Chatfield BA, Cohen AH, Rothenberg SS. Diagnostic value of transbronchial, thoracoscopic, and open lung biopsy in immunocompetent children with chronic interstitial lung disease. J Pediatr. 1997;131(4):565–569. doi:10.1016/S0022-3476(97)70063-5 [CrossRef]
  20. Prestridge A, Wooldridge J, Deutsch G, Young LR, Wert SE, Whitsett JA, Nogee L. Persistent tachypnea and hypoxia in a 3-month-old term infant. J Pediatr. 2006;149(5):702–706. doi:10.1016/j.jpeds.2006.07.032 [CrossRef]
  21. Langston C, Patterson K, Dishop MK, et al. ChILD Pathology Co-operative Group. A protocol for the handling of tissue obtained by operative lung biopsy: recommendations of the ChILD pathology co-operative group. Pediatr Dev Pathol. 2006;9(3):173–180. doi:10.2350/06-03-0065.1 [CrossRef]
  22. Stankiewicz P, Sen P, Bhatt SS, et al. Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am J Hum Genet. 2009;84(6):780–791. doi:10.1016/j.ajhg.2009.05.005 [CrossRef]
  23. Deterding RR, Pye C, Fan LL, Langston C. Persistent tachypnea of infancy is associated with neuroendocrine cell hyperplasia. Pediatr Pulmonol. 2005;40(2):157–165. doi:10.1002/ppul.20243 [CrossRef]
  24. Brody AS, Guillerman RP, Hay TC, et al. Neuroendocrine cell hyperplasia of infancy: diagnosis with high-resolution CT. AJR Am J Roentgenol. 2010;194(1):238–244. doi:10.2214/AJR.09.2743 [CrossRef]
  25. Popler J, Gower WA, Mogayzel PJ Jr, et al. Familial neuroendocrine cell hyperplasia of infancy. Pediatr Pulmonol. 2010;45(8):749–755. doi:10.1002/ppul.21219 [CrossRef]
  26. Canakis AM, Cutz E, Manson D, O’Brodovich H. Pulmonary interstitial glycogenosis: a new variant of neonatal interstitial lung disease. Am J Respir Crit Care Med. 2002; 165(11):1557–1565. doi:10.1164/rccm.2105139 [CrossRef]
  27. Hamvas A. Inherited surfactant protein-B deficiency and surfactant protein-C associated disease: clinical features and evaluation. Semin Perinatol. 2006;30(6):316–326. doi:10.1053/j.semperi.2005.11.002 [CrossRef]
  28. Thouvenin G, Abou Taam R, Flamein F, et al. Characteristics of disorders associated with genetic mutations of surfactant protein C. Arch Dis Child. 2010;95(6):449–454. doi:10.1136/adc.2009.171553 [CrossRef]
  29. Gower WA, Poplar J., Hamvas A., Deterding R. R.. Clincial Improvement in Infants with ILD due to Mutations in the Suractant Protein C Gene (SFTPC). Am J Respir Crit Care Med. 2010;181(Online Abstracts Issue):A6733. Abstract presented at the American Thoracic Society International Conference. .
  30. Clement A, Eber E. Interstitial lung diseases in infants and children. Eur Respir J. 2008;31(3):658–666. doi:10.1183/09031936.00004707 [CrossRef]
  31. Schecter MG, Elidemir O, Heinle JS, McKenzie ED, Mallory GB Jr, . Pediatric lung transplantation: a therapy in its adolescence. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2008:74–79.
  32. patients.thoracic.org/information-series/en/resources/interstitial-lung-disease-in-children.pdf. Accessed Nov. 12, 2010.
  33. www.childfoundation.us/library.html. Accessed Nov. 12, 2010.

CME Educational Objectives

  1. Describe the clinical signs and symptoms that raise suspicion of interstitial lung disease in an infant or child.

  2. Understand how to evaluate a patient with suspected interstitial lung disease with appropriate radiographic, laboratory, and pathologic evaluation.

  3. Recognize the long-term outcome of patients with interstitial lung disease.

Sidebar.

  1. Disorders more prevalent in infancy

    1. Diffuse developmental disorders

    2. Growth abnormalities reflecting deficient alveolarization

    3. Specific conditions of undefined etiology

    4. Surfactant dysfunction

      1. Surfactant protein B

      2. Surfactant protein C

      3. ATP binding cassette A#

      4. Thyroid transcription factor-1 (NKX-2)

      5. Congenital GMCSF receptor deficiency

      6. Histology consistent with surfactant dysfunction disorder without a yet recognized genetic etiology

      7. Lysinuric protein intolerance

  2. Disorders related to systemic disease processes

    1. Immune mediated/collagen vascular disorders

    2. Storage disease

    3. Sarcoidosis

    4. Langerhans cell histiocytosis

    5. Malignant infiltrates

  3. Disorders of the normal host, presumed immune intact

    1. Infectious/post infectious process

    2. Related to environmental agents

      1. Hypersensitivity pneumonitis

      2. Toxic inhalation

    3. Aspiration syndromes

    4. Eosinophilic pneumonia

    5. Acute interstitial pneumonia/Hamman-Rich syndrome/Idiopathic diffuse alveolar damage

    6. Nonspecific interstitial pneumonia

    7. Idiopathic pulmonary hemosiderosis (bleeding in the lung)

  4. Disorders of the immunocompromised host

    1. Opportunistic infections

    2. Related to therapeutic intervention

    3. Related to transplantation and rejection

    4. Lymphoid infiltrates related to immune compromise (for non-transplanted patients)

    5. Diffuse alveolar damage, unknown etiology

  5. Disorders masquerading as ILD

    1. Arterial hypertensive vasculopathy

    2. Congestive changes related to cardiac dysfunction

    3. Veno-occlusive disease

    4. Lymphatic disorder

    5. Pulmonary edema

    6. Thromboembolic

Authors

Adrienne Prestridge, MD, is Assistant Professor, Pulmonary Medicine, Children’s Memorial Hospital, Chicago, IL. Robin R. Deterding, MD, is Professor, Pulmonary Medicine, The Children’s Hospital of Denver, CO.

Dr. Prestridge and Dr. Deterding have disclosed no relevant financial relationships.

Address correspondence to: Adrienne Prestridge, MD, Children’s Memorial Hospital, 2300 Children’s Plaza #43, Chicago, IL 60614; fax: 773-880-6300; e-mail: .aprestridge@childrensmemorial.org

10.3928/00904481-20101116-08

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