A clinical approach to Paediatric Interstitial Lung Disease (PILD)

1. A clinical approach to Paediatric Interstitial Lung Disease (PILD) Dr Robert Dinwiddie Respiratory Unit Great Ormond Street Hospital for Children London

2. Prevalence of PILD 1/100000 children in UK and Ireland Ref: Dinwiddie et al Ped Pulmonol 2002; 34: 23-29

3. Aetiology all types • Idiopathic • Non-idiopathic – specific diagnosis • Sharief et al 1996 42 cases 40% specific diagnosis • Clement et al 2004 177 cases 59% specific diagnosis

4. Interstitial Lung Disease Aetiology • Infection - eg CMV EBV Adenovirus HIV • Other disease - eg sarcoidosis, pulmonary haemosiderosis, pulmonary alveolar proteinosis, histiocytosis, lymphangiomatosis • Genetic – eg surfactant protein deficiency • New associations – PIG NEHI • Aetiology unknown – idiopathic ILD (IILD) Desquamative interstitial pneumonitis (DIP) Fibrosing alveolitis (FA)

5. Clinical presentation • Age at diagnosis 2 months to 18 years • 58 (31%) present under the age of 2 years

6. Familial incidence • Parental consanguinity 7% • Siblings affected by similar disease 9.7% Message Familial incidence is around 10%

7. Sarcoidosis

8. Sarcoidosis

9. Sarcoidosis • Treatment • Oral steroids - short courses during exacerbations or alternate days in severe cases • Rare in childhood • Prognosis in childhood good • May leave lasting effects – pulmonary fibrosis Baculard A et al ERJ 2001; 17: 628-635

10. Pulmonary haemosiderosis • Recurrent intrapulmonary bleeds • With or without haemoptysis • Anaemia – moderate or profound • Pulmonary fibrosis long-term if not controlled • Oral steroids intermittent or long-term • 25-50% mortality in 5 years Pattishal et al Ped Pul 1996; 22: 195-203 Godfrey S Ped Pul 2004; 37: 476-484

11. Extrinsic Allergic Alveolitis n=5 • 80% due to pigeon breeder’s lung • CXR showed reticulonodular shadowing • Oxygen saturations 85-93% • Positive anti-pigeon precipitins • Prednisolone 2mg/kg/day for 4 weeks – excellent response Grech V et al Ped Pul 2000; 30: 145-148

12. Steroid Treatment iv Message • Pulsed methylprednisolone 10mg/kg/day for 3 days per month for 6 months • Increase to 20mg/kg/day if no initial response • 30mg/kg/day if necessary

13. Steroid treatmentOral Prednisolone Message • 1-2mg/kg per day for up to 6 weeks • Reduce to lowest dose which controls the disease – alternate day therapy if possible

14. Hydroxychloroquine Message • 6.6 mg/kg/day in 2 divided doses • Up to 10mg/kg/day has been used • Side effects – abdominal pain • Start with half dose for one week then increase • Ophthalmic review every 2 years

15. Other treatments • Azathioprine • Cyclophosphamide • Ciclosporin • Methotrexate • Mycophenolate mofetil • Plasmapheresis • GM-CSF • Tacrolimus • Colchicine

16. Outcome • 74% resolved • 11% chronic long-term disease • 15% mortality in UK-Irish series Dinwiddie et al Ped Pul 2002; 34: 23-29

17. Aetiology • New understanding of “idiopathic” cases • Surfactant protein deficiencies • Cellular interstitial pneumonitis/pulmonary interstitial glycogenosis - PIG • Persistent tachypnoea of infancy Neuroendocrine cell hyperplasia of infancy “NEHI” Fan et al Ped Pulmonol 2004;38:369-378

18. Surfactant protein mutation analysis Surfactant protein B SP-B Surfactant protein C SP-C GM-CSF receptor ABCA3 protein

19. SURFACTANT PROTEIN B DEFICIENCY (SP-B)CONGENITAL PULMONARY ALVEOLARPROTEINOSIS (PAP) • Neonatal onset – RDS in term infants • Fatal – unless transplanted • Recessive mutations in SP-B gene – on chromosome 2 • Unstable mRNA • Diagnosis by absence of SP-B on BAL, lung biopsy or mutation analysis on blood • Mutation frequency 1 in 3000 Ref: Fan et al Ped Pulmonol 2004;38:369-378

20. SP-B DEFICIENCY IN OLDER CHILDREN • 2 children • Chronic ILD and Respiratory failure • One survived for several years • Abnormality on exon 7 Ref: Dunbar et al Ped Res 2000;48:275-282

21. SP-C DEFICIENCY • Seen in Adult and Paediatric ILD • Sporadic or Autosomal Dominant mutation • Variable expression in adults and children • Several familial cases reported • Biopsies described as UIP in adults and NSIP in children • Outcome – long term chronic ILD, sometimes fatal even in adult life Ref: Amin et al J Pediatr 2001;139:85-92

22. SURFACTANT PROTEIN DEFICIENCYABCA3 • 16 term infants with severe neonatal RDS – surfactant deficiency • ABCA3 transporter protein deficiency • Ultrastructure on lung biopsy shows markedly abnormal lamellar bodies – (surfactant delivery systems) • Homozygous for ABCA3 surfactant protein genes • Recessive in familial cases • Outcome – usually fatal in first three months Shulenin et al NEJM 2004;350:1296-1303

23. ABCA3 DEFICIENCY • One patient found with an ABCA3 mutation on one allele and an unknown mutation on the other allele still alive at 6 years with chronic lung disease • “All ABCA3 mutations are not fatal” Shulenin et al NEJM 2004;350:1296-1303

24. Pulmonary Interstitial Glycogenosis (PIG) • 7 infants – tachypnoea, hypoxaemia • Diffuse infiltrates and hyperinflation on CXR • Increased glycogen in interstitial mesenchymal cells • 6 did well Refs: Canakis et al Am J Respir Crit Care Med 2002;165:1557-1565

25. Persistent Tachypnoea of InfancyNeuroendocrine Cell Hyperplasia of Infancy “NEHI” • Presentation in first few months of life • Term infants • Tachypnoea, retractions, crackles and hypoxia • Interstitial shadowing and hyperinflation on CXR and CT scan • Biopsy minimal change only but increased numbers of bombesin containing neuroendocrine cells in distal airways

26. NEHIPersistent tachypnoea of infancy • Outcome: Gradual improvement in early years of life • No deaths up to age 7 • Most came off oxygen by age 5 • Most had normal spirometry at age 5 Deterding et al Ped Pulmonol 2005;40:157-165

27. Could some cases of chronic bronchiolitis be NEHI?

28. Conclusions • PILD represents a wide spectrum of pathologies • Mutation analysis for surfactant proteins is leading to major advances in our understanding of the basic pathophysiology • Ultrastructural cell analysis is increasingly important in understanding the aetiology of individual cases • This knowledge can also be applied to the understanding of adult disease as well as in children • These advances should lead to increasingly specific and better treatments in the future