Cystic Fibrosis and the Role of Newborn Screening

Cori Daines, MD

October 6, 2009

Objectives

• Understand the genetics of CF

• Recognize how to diagnose CF

• Understand newborn screening for CF

• Understand the pathophysiology associated with CF

• Become familiar with the treatments used in CF

Outline

• Genetics• Incidence• Basic defect• Diagnosis• Newborn Screening• Pathogenesis• Clinical Manifestations• Treatments• Outcomes

Genetics

• Autosomal recessive inheritance• Chromosome 7• Codes for CFTR, a chloride channel• Over 1600 known mutations of the gene• Five classes of mutations: 1--protein

production, 2--defective processing, 3--defective regulation, 4--defective conduction, 5--reduced CFRT production

CFTR Genetics• CFTR gene:

– q31.2 locus on the long arm of chromosome 7– 230,000 base pairs long– CFTR is 1,480 amino acids long– Most common mutation, ΔF508 is a deletion (Δ) resulting in

a loss of the amino acid phenylalanine (F) at the 508th (508) position on the protein

• Approximately 1:30 Non-hispanic Caucasians are carriers of a CFTR disease causing mutation

CFTR

Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.

Classes of Mutations

http://www.cysticfibrosismedicine.com/htmldocs/CFText/genetics.htm

Inheritance

CC

Normal

Cc

Carrier

cC

Carrier

cc

Affected

Mother carrier

Fathercarrier

C

c

C c

Incidence

• 1 in 3100 for Caucasians

• 1 in 9200 for Hispanics

• 1 in 10,900 for Native Americans

• 1 in 14,400 for African Americans

• 1 in 31,000 for Asian Americans

Basic Defect

Diagnosis

• One or more clinical features of CF

PLUS– Two CF mutations

OR– Two positive sweat tests

OR– Abnormal nasal potential difference

Traditional Presentation

• Recurrent Pneumonia• Chronic sinusitis• Nasal polyps• Failure to thrive• Meconium ileus• Dehydration• Hepatitis• Infertility

Diagnostic Testing

• Sweat chloride testing– Quantitative pilocarpine iontophoresis

• Genetic testing– Genzyme– Ambry

• Nasal potential difference

• Newborn screening

Sweat test

http://www.nucleusinc.com Illustration copyright 2003 Nucleus Communications, Inc.

CF-NBS History• Multiple techniques evaluated• Immunoreactive trypsinogen (IRT) on NBS blood spot

testing now standard• IRT is elevated due to pancreatic duct dysfunction • IRT is increased in both pancreatic sufficient and

insufficient CF newborns• Screening first started in Australia (NSW: 1981) and

in USA (CO: 1982)• 49 states plus DC currently and likely all states by

end of 2010

IRT-DNA NBS Strategy

Sharp JK, Rock MJ. Clinic Rev Allerg Immunol 35:107, 2008.

Wisconsin Cystic Fibrosis Wisconsin Cystic Fibrosis Neonatal Screening StudyNeonatal Screening Study

• Control Group was diagnosed 15 months later on average (P<0.001)

• No differences in sex, cf care site, or pancreatic insufficiency (83%) between groups

• delF508 was more common in Early Diagnosis Group• Height for age, Weight for age, Head Circumference

percentiles all significantly lower at diagnosis in the Control Group

• Shwachman–Kulczycki scores significantly lower at diagnosis in the Control Group (87 vs 92; P<0.006) primarily due to differences in weight

Farrell PM et al. N Engl J Med 337:963,1997.

Pancreatic Insufficient CF Patients

Weight for Age Percentile

%le

%le

Height for Age Percentile

Farrell PM et al. N Engl J Med 337:963,1997.

NBS vs Control all at least P<0.01 or better

WCFNSS and Pulmonary Status

• NBS Group median time to acquisition of P. aeruginosa (PA) was 3.0 years compared to 6.0 years in the Control Group– Site of care with increased exposure– More delF508 in NBS group with PA acquisition

3.5 years earlier than in non-delF508 patients

• Both groups received quality CF care, and although effective, we cannot prevent decline in lung function at this time

Newborn Screening: CDC 2004

• Consider state resources/priorities• Collect follow-up data in collaboration with CF

Centers• Collaboration between states with optimization of

strategies• Rigorous infection control practices to prevent early

acquisition of organisms from older patients• Parent and provider education• Prompt referral to diagnostic centers

– Skilled in sweat testing– Counseling to families including false positives

CDC: Risks of CF-NBS• Infants Affected with CF and Their Families

– Altered Parent-Child Relationships - Not supported– Person-to-Person Transmission of Infectious Agents – Concern

• Infants with False-Positive CF Screens and Their Families – Psychological Distress from Screening – Concern– Misunderstanding of Carrier Status - Concern – Other Implications to Families of Carrier Identification - Not supported

• Health-Care System – False-negative results might experience a delay in diagnosis - Concern. – Diversion of health-care system resources - Concern

False Positives: IRT/DNA• Wisconsin study of 63 families with positive IRT/DNA test results*

– 6% of families thought that being a carrier could cause illness

• Wisconsin study of 138 families conducted after CF screening with positive results**

– Only 2/3rd had genetic counseling from healthcare professional– 88% understood that their child was a carrier– 11% either believed that their child would have CF subsequently or did not

know whether that could happen – 50% felt feeling confused– Only 25% reported feeling no anxiety about carrier status– Less than 50% understood that they were at increased risk of having a child

with CF whether or not they received counseling

* Mischler EH et al. Pediatrics 102:44,1998.** Ciske DJ et al. Pediatrics 107:699,2001.

CFF Guidelines for Newborn Screening

Farrell PM et al. J. Pediatr 153:S4,2008.

CFF Guidelines for Newborn Screening

• Caveats– Infant should be > 2kg and at least 36 weeks

corrected gestation for sweat chloride determination

– Minimum sweat weight is 75mg per sample– Two ‘disease causing’ mutations should be

considered diagnostic – Even with negative sweat chloride

(<29 mmol/l) if two CF mutations are in trans then diagnosis is strongly suggested

Farrell PM et al. J. Pediatr 153:S4,2008.

CF Disease Causing Mutations

Farrell PM et al. J. Pediatr 153:S4,2008.

IRT-DNA NBS Strategy

Sharp JK, Rock MJ. Clinic Rev Allerg Immunol 35:107, 2008.

Arizona CF NBS Program

• Started in November 2007• IRT/DNA strategy with 46 mutations chosen

to represent ethnic/racial makeup of Arizona’s population

• Primary care provider based• Involvement of CF Centers at Phoenix

Children’s Hospital and at the University of Arizona

Arizona CF NBS Program

• Specimen screened for IRT with cutoff at 2.2% of values for the day

• Specimens with IRT in the top 2.2% are screened with a panel of 46 mutations

• Outcomes:– No mutations: CF is not indicated– One mutation: CF may be present– Two mutations: CF is likely

Positive Results• Primary care provider and family notified of

positive screen by mail/fax• Regional CF Center notified by fax/email• CF Centers are responsible for initial follow-

up with PCP to ensure positive screen is proceeding to sweat testing

• CF Centers notify AzDHS of results of sweat tests, diagnoses, and care onset

• AzDHS will track down missed cases

IRT + Two Mutations• CF Center will contact PCP ASAP• Information for Family and PCP includes

contact information for CF Center as well• PCP refers for confirmatory sweat testing at

reference laboratory (UMC or TMC)• CF Center follows up with PCP on parental

notification and sets up a clinic visit• CF Center sees family and child in CF clinic

with infection control/cohorting

IRT + One Mutation• CF Center will contact PCP• PCP refers for diagnostic sweat testing at reference

laboratory (UMC or TMC)• CF Center follows up results with PCP and

communicates with AzDHS– If sweat chloride positive, then PCP/CF Center proceed with

notification and setting up care– If sweat chloride negative, then PCP follows up with family

and counsels them regarding carrier status

• Positive or borderline sweat chlorides with one mutation will lead to further in-depth genetic testing conducted in consultation with the regional CF Center

False Positives

• Primary care provider delivers information to family– Negative sweat test results– Carrier status

• No disease (or very, very unlikely)• Implications for future pregnancies/children• Family may request genetic testing to determine whether both

parents are carriers similar to carrier detection situation in pregnant women

• Family may request / PCP may recommend formal genetic counseling

• Should the child be informed of carrier status when older?

False Positives• 1/10 to 1/20 pregnancies have different biological

father than is socially apparent and this has implications for carrier testing in parents

• Data following up false positives suggests that part of future routine visits should be to clarify that the child does not have cystic fibrosis to allay concern

• One mutation does place the child at higher risk such as idiopathic pancreatitis or congenital absence of the vas deferens

• The appearance of symptoms suggestive of cystic fibrosis should lead to consultation and re-testing

AZ CF-NBS Results• November 1st, 2007 to October 21st, 2008• 94,885 samples screened by IRT• ~1,900 DNA test samples (top 2.2% IRT) • 206 DNA analysis samples with one or two

mutations

AZ CF-NBS Results

• 17 infants diagnosed – 7 infants were delF508 homozygotes– 6 infants were compound heterozygotes– 4 infants were diagnosed with one mutation and

positive sweat chloride

• Average age to first CF clinic: 30 days• No infants diagnosed since inception of NBS

who were part of NBS program; i.e. false negatives

Southern AZ Results

• November 1st, 2007 to February 1st, 2009• 6 children diagnosed with two mutations• 55 children had only one mutation

– 45 children with negative sweat test– 2 children with positive sweat test / diagnosis– 6 children still being worked up– 2 children lost to follow-up – AzDHS referred

• Thus, of 47 children with one mutation and definitive outcome information, only 2 or 4.3% had cystic fibrosis

CFTR Gene Defect

Defective Ion Transport

Airway surface liquid depletion

Defective mucociliary clearance

Mucus obstruction

Inflammation Infection

Pathophysiology

Pulmonary Manifestations

• Chronic symptoms– Productive cough, wheeze, recurrent

exacerbations

• Obstructive lung disease

• Bronchiectasis

• Infection

Bronchiectasis

From: http://www.meddean.luc.edu/lumen/meded/elective/pulmonary/cf/cf_f.htm

Infection

Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of Pulmonary Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.

Sinus Disease

• Develops in most CF patients• 90-100% of patients older than 8

months develop panopacification of the paranasal sinuses

• Nasal polyposis in 10-32%– Associated with chronic inflammation– Cause obstruction, headache, drainage– Often require surgery

Pancreatic Disease

• Pancreatic insufficiency at birth in 85%– Mucus plugging of pancreatic ducts with

autolysis of the pancreas

• Malabsorption– Failure to thrive– Fat soluble vitamin deficiencies

• Chronic pancreatitis• Diabetes

Diabetes

• Occurs in as much as 40% of patients by adulthood

• Delayed and diminished insulin response

• OGTT testing starting at age 10 every 2 years

• Insulin therapy for fasting glucose >140

Intestinal manifestations

• Meconium ileus– 10-20% of infants with CF– Virtually pathognomonic of CF

• Distal intestinal obstructive syndrome– Small bowel obstruction due to dehydrated

intestinal contents

• Rectal prolapse– Straining from too many or too few enzymes

Biliary Disease

• Focal biliary cirrhosis due to inspissated bile

• Portal hypertension in 2-5% of patients– May lead to need for liver transplant

• Cholelithiasis in up to 12% of patients

Electrolyte Abnormalities

• Excessive excretion of sodium and chloride in the sweat– Basis of sweat test

• Hypochloremic dehydration with metabolic alkalosis

Reproductive Manifestations

• Men– Congenital absence of the vas deferens in

97-98%

• Women– 20% may be infertile– Secondary amenorrhea– Tenacious cervical mucus

Other Manifestations

• Osteoporosis, osteopenia– Increased risk of pathological fractures

• Clubbing

• CF-associated arthropathy– 2-9% of patients

From: Fawcett et al., 2004

CFTR Gene Defect

Defective Ion Transport

Airway surface liquid depletion

Defective mucociliary clearance

Mucus obstruction

Inflammation Infection

Treatment-LungsGene therapy, potentiators, activators

Alternative channelactivators

Rehydrationtherapy

Airway clearance,Bronchodilators,Mucolytics

Anti-infectives

anti-inflammatory

Exacerbations

• Changes in symptoms and signs from baseline– Cough, sputum, lung function, crackles

• Treatment options– Inpatient IV therapy– Outpatient IV therapy– Outpatient Oral therapy

Lung Transplant

• 5 year survival slightly better than 50%

• New organ allocation system

• Controversial for pediatric patients

• Expensive, problematic but may be the only option for some patients

Sinus Disease

• Nasal corticosteroids• Sinus washes

– Saline– Antibiotics

• Antihistamines, if allergic• Surgery

– Polypectomy– Washes and windows

Pancreatic disease

• Pancreatic Enzyme Replacement– Given with all meals and snacks– Dosed according to patient weight, 1000-

2500 Units Lipase/kg body weight– Assessment: fecal elastase, quantitative

72-hour fecal fat– Adjunctive use of H2 blockers, PPI’s– Name-brand only

Nutritional Support

• Specific guidelines– BMI at 50th% or above

• Supplement fat-soluble vitamins

• Nutritional supplements– High calorie oral supplements: shakes,

additives– Tube feedings: Nasogastric, gastrostomy

Diabetes

• Close monitoring– Yearly OGTT if intolerance noted– Home glucose monitoring

• Insulin– Dosed with carbohydrate counting– Role in growth, lung health

• Limit sugars, not calories• Closely associated with outcomes

Intestinal Disease

• Hydration• Limit pain medication• Activity• Medications

– Miralax– Stool softeners– Golytely

• Enemas, including gastrografin• Surgery

Biliary Disease

• Ursodiol– Increases bile flow– Reduces toxicity of bile acids

• Sclerotherapy, esophageal banding

• Portosystemic shunts

• Liver transplant

Electrolyte Abnormalities

• Hydration

• Addition of salt to diet, especially infant, especially in summer

Infertility

• Microsurgical or percutaneous epididymal sperm aspiration

• In vitro technology

• Genetic testing

Other

• Calcium supplements

• Osteo

• Treatment for anemia

• Concurrent diseases

Psychosocial Issues

• Quality of Life– Hospitalizations, daily therapy burden, morbidity,

limitations

• Normal growth and development• Transitions• Adherence• Financial issues, insurance• Family planning• End of life issues

Teamwork

• Physicians– Pulmonary, Primary MD, Gastroenterology,

ENT, Surgery, Endocrine, Infectious Disease, plus

• Nurses• Respiratory Therapist• Nutrition• Social work

QuickTime™ and a decompressor

are needed to see this picture.

Median predicted survival of patients with cystic fibrosis

Data from Cystic Fibrosis Foundation, 2007.

Outcomes