Interstitial Lung Disease in Children

Transcription

1 Interstitial Lung Disease in Children Sankaran Krishnan, MD, MPH, FAAP Associate Professor, Pediatrics and Public Health Associate Program Director, Pediatric Pulmonology New York Medical College Maria Fareri Children s Hospital

2 Case 1 48 day old full term infant, presented as TTNB at birth. Persisted to have tachypnea and hypoxemia. Surfactant trial had no effect. Oxygen dependent. Failure to thrive. Sepsis ruled out Empiric treatment of pneumonia Viral studies negative BAL increased macrophages and lymphocytes, non-specific Surfactant genetics sent Grant, Roselyn /28/2003 F Page: 1 of 1 WESTCHESTER MEDICAL CENTER CHEST PORTABLE 7/30/ :59: S: 303 Z: 0.65 C: 512 W: 1024 Compressed 32:1 IM: 1001

3 Case 2 Wahab, Akim /2/2004 M Page: 1 of 1 WESTCHESTER MEDICAL CENTER CHEST PORTABLE 8/3/ :35: S: 1052 Z: 0.78 C: 512 W: 1024 Compressed 32:1 IM: month presented with tachypnea noted by mom at 2 months of age, persisting. Poor weight gain. Cardiac eval mild pulmonary hypertension, structurally normal heart CT showed diffuse interstitial lung disease Viral studies negative BAL non-specific Surfactant genetics sent Thoracoscopic lung biopsy done

4 2.5 yr old, history of bronchiolitis at 19 months of age Persistent tachypnea Remained oxygen dependent, failure to thrive CT chest diffuse interstitial lung disease with areas of atelectasis, small cysts BAL increased lymphocytes Thoracoscopic lung biopsy done

5 Case 4 15 year old, previously healthy girl, diagnosed clinical pneumonia 1 yr ago 3 months later, pneumonia, RLL; 6 months later, pneumonia RLL At presentation, SOB with minimal exertion, O2 sats 95%, drops to low 80 s with walking CXR RLL bronchiectasis, ILD CT confirms ILD CF, PCD, immune def, hypersensitivity pneumonitis ruled out BAL - negative Thoracoscopic lung biopsy done patchy interstitial fibrosis with adjacent relatively preserved lung tissue with fibrotic and honeycomb changes

6 Outline Definition/Terminology Classification Pathophysiology Diagnosis Clinical Presentation Studies (Laboratory, Genetic, Imaging, Biopsy) Treatment Specific child diseases

7 Definition Diverse group of conditions that primarily involve the alveoli and perialveolar tissues, leading to derangement of gas exchange, restrictive lung physiology, and diffuse infiltrates on radiographs.

8 Terminology (ATS Guideline Feb 2013) Term "interstitial" is misleading because most of these disorders are a/w extensive alteration of alveolar and airway architecture, in addition to changes in the interstitial compartment. Diffuse lung disease (DLD)- considered ILD based upon similarities in the clinical presentation and diagnostic evaluation, even though the primary pathology may occur outside of the interstitium

9 child Diverse group of rare disorders involving the pulmonary parenchyma (remodeling of the lung interstitium and distal airspaces) a/w interference with gas exchange Similar clinical, radiographic, physiologic or pathologic manifestations Some conditions that cause ILD in children and adults are similar, however they occur in different proportions in each age group, and certain diseases are unique to infants

10 An Official American Thoracic Society Clinical Practice Guideline: Classification, Evaluation, and Management of Childhood Interstitial Lung Disease in Infancy

11 Diagnostic Criteria for child child syndrome - at least 3 of the following 4 criteria are present: (1) Respiratory symptoms (cough, rapid and/or difficulty breathing, or exercise intolerance); (2) Respiratory signs (tachypnea, adventitious sounds, retractions, digital clubbing, failure to thrive, or respiratory failure) (3) Hypoxemia (4) Diffuse abnormalities on CXR or CT scan

12 Types of Childhood ILD and DLD Disorders With Primary Pulmonary Involvement Alveolar hemorrhage syndromes Aspiration syndromes Disorders of lung growth and development Drug or radiation induced lung disease Infectious or post-infectious chronic lung disease Hypersensitivity pneumonitis Neuroendocrine cell hyperplasia of infancy (NEHI) Pulmonary alveolar protenoisis (PAP) Pulmonary infiltrates with eosinophilia Pulmonary interstitial glycogenosis (PIG) Pulmonary vascular disorders (proliferative and congenital) Pulmonary alveolar microlithiasis Genetic disorders of surfactant production and metabolism (SFTPB, ABCA3, SFTPC, NKX2.1/TTF1

13 Types of Childhood ILD and DLD Systemic Disorders with associated pulmonary involvement Brain-lung-thyroid syndrome with ILD due to NKX2.1/TTF1 gene mutations Connective tissue disease (SLE, polymyositis/dermatomysositis, sytemic sclerosis, mixed CT disease, systemic JIA) Dyskeratosis congenita Immunodeficiency and lymphoproliferative disorders Langerhans cell histiocytosis Lymphatic disorders Storage disease (Niemann-Pick, muchopolysaccharidosis, others) Malignancies Neurocutaneous syndromes Sarcoidosis Other inborn errors of metabolism (lysinuric protein intolerance)

14 Pathophysiology Understanding of mechanisms underlying development and progression of ILD remain elusive Result of chronic inflammation following an initial injury to the alveolar epithelial lining By targeting the inflammatory response, the belief is that fibrosis could be prevented or controlled (i.e. antiinflammatory therapy)

15 Pathophysiology Multiple factors may injure the alveolar epithelium and initiate the development of ILD The initiating injury can be introduced through the airways and the circulation, or can occur as a result of sensitization. Apoptosis plays a central role in lung remodeling associated with ILD An important molecule in the events associated with epithelial cell apoptosis is TGF-β, which is overexpressed in ILD

16 Mechanisms and pathways involved in the response of the alveolar structure of the lung to injury Clement et al. Orphanet Journal of Rare Diseases :

17 Pathophysiology Genes associated with lung development and embryonic pathways could be involved in aberrant epithelium-mesenchymal crosstalk and epithelial plasticity, and could participate in the development of chronic ILD Surfactant dysfunction plays an important role in the development & progression of ILD

18 Clement et al. Orphanet Journal of Rare Diseases :

19 Clinical Presentation Subtle, non specific, insidious onset Variable Asymptomatic with radiographic findings Respiratory symptoms and signs such as cough, tachypnea, frequent respiratory infections, increased work of breathing and exercise intolerance

20 Signs & Symptoms Cough 75% of patients, non-productive and does not disturb sleep. Tachypnea 80% of patients, earliest and most common respiratory sx Exercise Intolerance Unexplained fever (~1/3 of infants) Failure to thrive (37%), tiring during feeding and weight loss, mainly in young patients. Wheezing Hx may be elicited in almost 50% of the patients, documented by PE in only 20% of the cases Inspiratory crackles (44%) GERD Digital clubbing & Cyanosis (late findings)

21 Laboratory Studies Routine laboratory evaluation rarely establishes the diagnosis of a specific ILD purpose is to screen for evidence of systemic or multiorgan system disease, to assess complicating factors Hematologic tests, evaluation for infectious etiologies, immune function, serologic studies investigating possible autoimmune disorders, and testing for hypersensitivity pneumonitis

22 Genetic testing Can identify the common genetic mutations that cause surfactant dysfunction and avoid the need for more invasive evaluations such as lung biopsy Suggested for infants presenting with acute respiratory failure in the absence of other explanations, or in older children with chronic presentation or family history of ILD

23 Pulmonary function tests Complete lung function testing (spirometry, lung volumes, diffusing capacity) should be obtained if possible, depending upon the age and ability Helpful in characterizing disease physiology and in assessing severity of illness Characterized by restrictive lung disease FEV1, FVC, Normal or FEV1/FVC & TLC, RV DLCO Some forms of childhood ILD may include obstructive lung physiology: bronchiolitis obliterans, follicular bronchiolitis, and sometimes hypersensitivity pneumonitis.

24 Pulmonary Hypertension Hypoxemia and structural changes in the lung contribute to increased PA pressure >25 % of children with ILD have pulmonary HTN at presentation Due to impact on prognosis, early evaluation is recommended Echocardiography preferred (noninvasive) cardiac catheterization may be needed to accurately assess PA pressures

25 Diagnostic Imaging- CXR Typically abnormal, rarely specific Infiltrates predominantly interstitial (75%), alveolar (8%), and mixed (13%) An exception is NEHI, CXR often normal or shows hyperinflation or peribronchial cuffing consistent with peripheral airway disease

26 HRCT Correlates better with the extent, distribution, and severity of disease Findings are specific for some types of ILD, and may reduce need for lung biopsy (i.e. NEHI) If biopsy is needed, imaging information is useful to direct the choice of surgical biopsy sites In children with prominent tachypnea, anesthesia or controlled ventilation HRCT (CV-HRCT) techniques may be needed to reduce motion artifact and enable inspiratory imaging.

27 Bronchoscopy and BAL To rule out alternative diagnoses or comorbid conditions that may contribute to pulmonary sx BAL is used mainly to dx infection and detect aspiration or hemorrhage. May help dx certain specific conditions Langerhans cell histiocytosis, pulmonary alveolar proteinosis, lysosomal storage diseases, sarcoidosis, hypersensitivity pneumonitis

28 Lung Biopsy Considered the gold standard for diagnosis of ILD prior to the availability of clinical genetic testing because the diagnostic categories of ILD were based upon histopathologic description. Currently, many forms of ILD are diagnosed and categorized based on the mechanism of disease or CT appearance Remains the means of definitive dx for forms of ILD for which the cause is unknown and the CT patterns have not been determined or validated, such as pulmonary interstitial glycogenosis.

29 Lung Biopsy To maximize diagnostic yield of lung biopsies, standardized published protocols for tissue processing should be utilized, including fixation for electron microscopy (EM) VATS= procedure of choice Because of the relative rarity of pediatric lung biopsies, cases should be interpreted by a pathologist experienced with pediatric lung disease

30 Treatment Supportive therapy and pharmacologic interventions tailored to the type of ILD In most cases, treatment is based upon anecdotal evidence There have been no controlled treatment trials in children with ILD

31 Supportive Therapy Limiting exposure to cigarette smoke and other inhaled irritants Nutritional support as needed Oxygen therapy for hypoxemia Supervised exercise (for older children) Bronchodilators for reversible airway obstruction Aggressive treatment of intercurrent infections Standard childhood vaccinations Annual influenza vaccinations RSV Immunoprophylaxis

32 Specific Treatment Specific treatment is available for some ILD disorders Examples include antimicrobials for certain infections, management of swallowing dysfunction and/or reflux in patients with chronic aspiration, avoidance of the offending antigen in hypersensitivity pneumonitis, and whole lung lavage or GMCSF for older children with pulmonary alveolar proteinosis

33 Pharmacologic Therapy Glucocorticoids are the mainstay of therapy for many children with ILD because inflammation and inappropriate cellular proliferation are thought to play an important role in pathogenesis No studies to inform dosing or duration of treatment. Clinical practice generally consists of prednisone (1 to 2 mg/kg per day) or an equivalent glucocorticoid for six to eight weeks Pulse therapy w/iv methylprednisolone (10 to 30 mg/kg per day [maximum 1000 mg], administered over one hour, for three consecutive days each month or a single dose weekly) is an alternative to daily therapy, and may be equally or more effective with fewer side effects.

34 Conditions that Respond to Glucocorticoids ILD associated with connective tissue disease Hypersensitivity pneumonitis Some surfactant protein deficiency syndromes Lymphocytic interstitial pneumonia Cryptogenic organizing pneumonia (previously known as bronchiolitis obliterans organizing pneumonia) Eosinophilic pneumonia Sarcoidosis Capillaritis

35 Other Pharmacologic Therapies Hydroxychloroquine (10 mg/kg per day) is used most frequently for attempted empiric therapy and/or steroid-sparing effect. In case reports, chloroquine or hydroxychloroquine have been associated with improvement in cases reported as DIP, LIP, nonspecific interstitial pneumonitis, pulmonary hemorrhage syndromes/capillaritis, and in surfactant dysfunction disorders The variable natural history of some of these disorders makes outcome assessments challenging. Azithromycin three times a week (10 mg/kg or 250/500 mg) Methotrexate Cyclosporin

36 Lung Transplant An option for children who have severe and progressive disease and no response to therapy Timely referral may improve outcome The survival rate for children with ILD is similar to that of pediatric lung transplantation for all indications ~ 50 percent at five years Only effective treatment for some highly lethal diseases such as surfactant protein B (SFTPB) and ABCA3 mutations, and alveolar capillary dysplasia with misalignment of the pulmonary veins

37 Specific child Syndromes

38 Surfactant Deficiencies Pulmonary surfactant is a unique mixture of lipids and proteins that reduces surface tension at the air-liquid interface, preventing collapse of the lung at the end of expiration. SP-B and ABCA3 are required for the normal organization and packaging of surfactant phospholipids into specialized secretory organelles, known as lamellar bodies Both SP-B and SP-C are important for adsorption of secreted surfactant phospholipids to the alveolar surface

39 SP-B Deficiency First reported genetic cause of lethal RDS in infants Respiratory failure within the first hrs of life Autosomal recessive Histology: PAS-positive eosinophilic material in alveoli, epithelial cell desquamation, enlarged alveolar macrophages with lamellar inclusions, accumulation of SP-A Milder mutations have been found Only tx: Lung transplant

40 SP-C Deficiency Milder, heterogenous phenotype Autosomal dominant Variable age of presentation Newborn to over 70 years of age Histopathology age dependent Infants: chronic pneumonitis of infancy, desquamative interstitial pneumonia or nonspecific interstitial pneumonia Adults: pulmonary fibrosis with NSIP or UIP Pathogenesis: intracellular misfolded protein accumulation leading to inflammatory response Tx: corticosteroids, hydroxychloroquine,

41 Surfactant protein C deficiency. (A) There is diffuse interstitial thickening and type II pneumocyte hyperplasia without significant alveolar proteinosis or desquamative pneumonia. (B) Type II pneumocyte hyperplasia and thickened interstitium containing scattered chronic inflammatory cells.

42 ABCA3 Mutations Transporter that moves substances across biological membranes Highly expressed in lung tissue Helps organize and store surfactant within lamellar bodies More than 150 mutations Autosomal recessive Majority of cases a/w surfactant deficiency, respiratory distress, and failure in the neonatal period or in infancy Tx: Lung transplant, corticosteroids

43 ABAC3 deficiency Interstitial thickening with florid type II pneumocyte hyperplasia, pulmonary alveolar proteinosis. Eosinophilic debris within alveolar spaces has characteristic glassy appearance. Abundant intra-alveolar macrophages. Hyperplasia of interstitial smooth muscle

44 Pulmonary hypertensive disease Pulmonary hypertensive disease without prominent venous disease Congenital heart disease with left-to-right shunts Idiopathic Familial (BMPR2 gene/other defects) Pulmonary hypertensive disease without prominent venous disease Congenital heart disease with left-sided obstruction Heart failure Veno-occlusive disease Pulmonary hypertensive disease with peripheral muscular arteries PPHN associated with meconium aspiration, sepsis, hypoxia

45 Pulmonary arterial hypertension Cellular intimal thickening of small muscular pulmonary arteries. Plexiform lesions. The parent artery shows mild intimal thickening. Branches present in adventitial coat show severe concentric, fibrous and myxoid intimal thickening with deposition of fibrinoid.

46 Lymphangiectasia Primary Associated with other disorders Noonan s Down s syndrome

47 Lymphangiectasia Bronchovascular bundle showing large numbers of greatly dilated lymphatic vessels ramifying in the collagen surrounding the bronchiole and muscular pulmonary artery

48 NEHI Presentation in infants similar to other interstitial lung diseases Symptoms: tachypnea, hypoxemia, crackles, retractions, and failure to thrive Initially, labeled chronic idiopathic bronchiolitis of infancy. The histology of NEHI is mostly normal or has minor abnormalities. Bombesin staining shows increased numbers of neuroendocrine cells Most patients with NEHI have typical CT findings with ground-glass opacities confined to the middle lobe, lingula, and paramediastinal lung areas. Additional CT abnormalities may include consolidation, bronchial wall thickening, and interlobular septal thickening. Prognosis of infants generally considered favorable; difficult to argue for open lung biopsy to confirm the diagnosis if classic CT findings.

49 Outcome of cases Case 1 (48 day old, persistent TTNB ) Surfactant protein C deficiency. Pulse steroids, hydroxychloroquin, azithro x 6 months. Good response. Off O2. Thriving. Case 2 (5 mo old, persistent tachypnea from 2 mo age) NEHI. Supportive Rx. Now well Case 3 (2.5 yr old, persistent tachypnea after bronchiolitis at 19 mo age) Obliterative bronchiolitis. Pulse steroids, hydroxychloroquin, azithro. O2-dependent, improved Case 4 (15 yr old, post-infectious ILD with bronchiectasis) Idiopathic ILD with bronchiectasis. Dramatic response to pulse steroids, normal PFTs

50 Take home messages Think of common things first: BPD, Infection (viral), Hypersitivity pneumonitis, Congenital heart disease, Aspiration syndromes, Association with systemic disease Think of surfactant protein deficiency syndromes. Some disorders like NEHI may be diagnosed without lung biopsy (surfactant protein deficiency syndromes with genetics, NEHI with characteristic CT)