Cystic Fibrosis as it relates to the neonate MARIANNE MUHLEBACH, MD PROFESSOR, DEPT. PEDIATRICS UNC CHAPEL HILL

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1 Cystic Fibrosis as it relates to the neonate MARIANNE MUHLEBACH, MD PROFESSOR, DEPT. PEDIATRICS UNC CHAPEL HILL

2 Objectives: At the end of the presentation the listeners will Be able to describe neonatal presentation of symptomatic and diagnosis of non-symptomatic newborns with cystic fibrosis Understand how newborn screening and novel therapies have changed the life for patients with cystic fibrosis Understand the need for a team based approach, treatment at CF centers and their contribution to outcomes and prognosis

3 Diagnosis and Presentation of CF US National Data In 2013 approx. 950 infants were diagnosed with CF and 62% of these were diagnosed by NBS 72.4% diagnosed in 1 st year 87.9% of these infants were born at term Median BW 3.3. kg Median length 50.6 cm

4 Symptoms at presentation Most of these infants are asymptomatic but may have Meconium ileus Steatorrhea / abnormal stools Failure to thrive Respiratory problems Meconium ileus May be noticed as hyper-echogenic bowel seen on 3 rd trimester ultrasound. If mother has one CF mutation i.e. carrier is known in parent, ~52% chance of being CF. If no CF mutation detected, risk for CF is as low as 6%

5 Meconium Ileus Present in about 20% of patients i.e. neonates with CF Pathogenesis: Dessicated intestinal secretions leading to obstruction and secondary inflammation. Can cause perforation and/or calcification in utero Management: Supportive for bowel obstruction. Gastrograffin enema or if unsuccessful laparotomy with or without ileostomy Complications: surgical ones; refeeding, microcolon; slow transit etc Cholestatis in neonates with CF: occurring in about 5% - with higher OR in those with MI (27.1% vs. 1.2%, with vs. without MI). Most of these resolved by 9-10 months of age. Carlyle B., Brorwitz D. et al; J. Ped. Surgery 2012

6 Prematurity and CF Frequency of premature births with CF: Study in Tuscany (2005) showed increased rate of prematurity with CF compared to non-cf. US Registry starting to collect Gestational Age showing 12% prematurity compared to 11.4% in general population (CDC 2013) Complications: High rate of mortality Respiratory immaturity combined with abnormal mucus leading -> obstructive lung disease, difficulty ventilating. Although not approved in this age group and not-tested use of hypertonic saline and/or DNase is frequent GI: Increased incidence of abdominal obstruction and feeding difficulties Lu K; Engmann C; Moya F; Muhlebach. J. of Perinatology 2011

7 CF Newborn Screening Rationale / outcomes Alleviates stress for family, avoids repeat hospitalizations May lead to diagnosis in older, affected but undiagnosed siblings 1, may help future family planning Earlier diagnosis results in improved long-term nutritional and pulmonary outcome Improved nutritional status (Accurso, 2005 J Pediatr) Better growth (Farrell, 2001 Pediatrics) Fewer hospitalizations (Accurso 2005, Wilcken 1985, Siret 2003) Delayed diagnosis Cognitive dysfunction, (vitamin E deficiency) nutritional failure (Farrell 2005) Decreased risk of life-threatening complications or death from CF in infancy or early childhood (Lai, 2004 Am J Epidemiol, Doull, 2001 Pediatr Pulmonol)

8 Newborn Screening for CF: Methodology in NC Immunoreactive trypsinogen (IRT) Trypsinogen is pro-form of trypsin in pancreas When pancreatic injury occurs IRT is elevated and remains high ~ 4 weeks ELISA measures active trypsin in blood spot on Guthrie cards Samples with values above 95% are tested in a second fashion IRT/ IRT Requires repeat blood sample IRT / DNA Requires panel of CFTR mutations + IRT / DNA notify CF center and LMD

9 Definitive diagnosis of CF: Sweat Test Quantitative pilocarpine iontophoresis sweat chloride test QI needs: Age of patient: >48 hr > Amt 2kg, > 36 wks PMA of sweat collected 75mg or 15 μl Duplicate samples (R/L arm) Studies show better performance with frequent use and experience For NBS ideally between days of life

10 Consensus guidelines for new diagnosis of CF After diagnosis is established Family meets with CF care team (MD, CF nurse, Social Work, Nutrition, Physiotherapy) Assessment of pancreatic status with fecal elastase As indicated enzyme replacement therapy Salt supplementation for all infants Fat soluble vitamins as indicated Robinson K et al J Pediatrics :S94-105

11 Case Presentation: CF diagnosis in NICU Parents known carriers of CF. Presented with meconium ileus and microcolon, asymmetric IUGR Resection of atretic bowel and ileostomy and appendectomy DOL 2 (IV albumin, hyperglycemia). TPN x 14 days, then transition to p.o. Hosp DC on fortified breastmilk and taking pancreatic enzymes DOL 26 with ileostomy Age 4 mo: Ileostomy take-down complicated by repeat bowel obstruction suspected to be small bowel. Transfer to UNC resolution of symptoms with medical therapies (acetylecysteine and glycolax) Discharge on oral feeds, ~ 8 BM/day, positive reflux Respiratory: On room air, Xrays normal,

12 Case presentation outpatient FU Continued to be seen monthly at UNC for input from CF Nutritionist and Pulmonologist Cough improves on PPI Upper respiratory infections age 10 and 13 months with prolonged cough Improving absorption ~15 month of age. 20 months: P aeruginosa on OP swab which is confirmed by bronchoscopy. Tx with inhaled tobramycin Intermittent positive for P aer. X 6 months. Age 4 years: normal growth (BMI 90%ile), P aer negative and normal acting toddler

13 Nutrition and GI in CF Matters early and throughout life Pancreatic insufficiency Abnormal intestinal hydration, motility, bacterial composition Increased stomach ph Enzyme therapy: start symptom based but test is fecal elastase ~2000 U lipase/kg/meal titrate as needed to max 2600 Antacids: likely enhances effectiveness of enzymes which should be activated in alkaline environment of duodenum Fat soluble vitamins: start early (ADEK drops) Goals: Wt/Ht or BMI %ile at or above 50%ile

14 Pathogenesis CF airway disease in relation to therapies Increased Na+ absorption (Cl, HCO3) N Antibiotics CF Inadequate surface hydration Enhanced mucus adherence to airway Chest PT Infection Inflammation a complex spectrum of other factors Hypertonic saline DNase

15 Hypertonic Saline Clinical Studies Lung function Mucociliary clearance Donaldson et al. NEJM 2006:19;354(3):241-50

16 DNase Basic Concept Infection attracts neutrophils, which release DNA in airway. DNA very viscous DNase cleaves this and reduces viscoelasticity and adhesiveness of secretions Therefore main indication should be in viscous secretions where infection i.e. neutrophil influx is expected CF is a prime disease as airway inflammation is neutrophil dominated

17 Mutation categories and therapies Mutations are grouped into 5-6 categories: IV, V are non-classical CF Multi-national trial of ivacaftor in patients with G551D mutation showed dramatic benefit for lung and GI Now FDA approved for patients Therapy: Phase II-III on market with class ~III, IV, V mutations Amaral MD 2015 J Int Med. Ramsey B 2012 NEJM (~5% of the CF population

18 The CF team CF is a multi-system disease, therefore needs multi-system approach Improved outcomes of patients in CF center References: Standards of care for patients with cystic fibrosis: a European consensus. Kerem E. et al J Cyst Fibros Improving the quality of care for patients with cystic fibrosis J Cyst Fibros.. Schechter M. et al Curr Opin Pediatr Current issues in quality improvement in cystic fibrosis. Quinton H. et al. Clin Chest Med Team members include: Nurses, RT, PT, Dietician, Social work, Physicians, Researchers, Microlab.

19 Prognosis Survival & Quality 49.7% of patients are adults (2013) Typical treatment regimen: Airway clearance BID Mucolytic Inhaled Antibiotic Enzymes, vitamins Maybe insulin Cause of death: 68% pulmonary / resp. failure 12% transplant related 3% liver disease

20 Multiple other medications in pipeline pipeline

21 Conclusion Key message to parents in NICU CF is a serious life long disease affecting especially lungs and GI Expect a significant time commitment for treatments and visits to the CF center will be frequent especially in the 1 st year However, outcomes have and keep improving and there is a strong community for CF patients and the CF care teams If you surf the web, use cff.org - they also have patient hotline, legal/insurance hotline etc (There is reason for hope with so much improvement seen and more in the pipeline the pediatric goal is to keep the child healthy until definitive CFTR correcting therapies are available for all mutations)