Disclosure Statement

• I do not have any conflict of interest, nor will I be discussing any off-

label product use.

• This class has no commercial support or sponsorship, nor is it co-

sponsored.

Objectives

• Review basic multi-organ pathophysiology

in Cystic Fibrosis (CF)

• Summarize newborn screening algorithm

for CF

• Describe common treatment modalities for

CF lung disease and pancreatic

insufficiency including new highly effective

modulator therapy

• Identify resources for support of care for

patients with CF in the community,

including guidelines of care

Cystic Fibrosis: History

• Condition appears to be first described as

early as 3,000 BCE

• 1857 Almanac of Children’s Songs and

Games from Switzerland:

“Woe to the child who tastes salty from a kiss

on the brow, for he is cursed and soon must

die”

May CD. Cystic Fibrosis of the Pancreas in Infants and Children 1954.

Courtesy of Jon Cogen MD

Cystic Fibrosis: History

1950’s: Cystic Fibrosis Foundation (CFF) founded (1955)

1960’s: CFF establishes accredited care center network (1961)

Median age of survival is 10 (1962)

CFF launches CF patient data registry (1966)

1980’s: Median predicted age of survival is 18 in 1980, improves to 29 by 1989

CF gene discovered (1989)

1990’s: Dornase alfa (1993), Therapeutics Development Network (1997), inhaled tobramycin (1997)

2000’s: Median predicted age of survival is 32 (2000)

Hypertonic Saline (2004), inhaled aztreonam (2010), development of CFTR modulators

(ongoing)

Cystic Fibrosis: Today

• Predicted median survival 47.4 years old if born in 2018

CF Patient Registry 2018

CF: Multi-Organ Disease

Cutting, GR. (2015). Cystic fibrosis genetics: from molecular understanding to clinical application. Nat. Rev. Gen, 16(1), 45-56.https://www.clinicalkey.com/#!/content/medline/2-s2.0-25404111

• Life-shortening, multi-system disease caused by a

defect in the gene that codes for the CFTR protein

on chromosome 7

• CFTR = Cystic Fibrosis Transmembrane

Conductance Regulator

• CFTR responsible for Cl- and HCO3- transport

across cell membranes in exocrine ductal

epithelial tissue in the respiratory, GI, and

reproductive tracts

• Defective CFTR causes dehydration and

increased viscosity of secretions produced by

these organs

Cystic Fibrosis: Genetics

CFF.org

• Autosomal recessive inheritance

• Predominance in Caucasians but occurs in all racial/ethnic groups

• >1800 variants/mutations identified (not all disease causing)

• F508del most common at ~85%

• ~1 in 35 Americans are asymptomatic carriers

10 million carriers in the US• 1 in 29 Caucasian-Americans• 1 in 40 Hispanic-Americans• 1 in 65 African-Americans• 1 in 90 Asian-Americans

CFTR Variants

CFF.org

Cystic Fibrosis: Epidemiology

CF Patient Registry, 2018

• ~200 patients followed at SCH CF Center

Diagnosing CF: Early is better

CF Patient Registry, 2018

• Early diagnosis leads to early interventions

and improved outcomes

• 67% of all individuals in 2018 CF Patient

Registry were diagnosed in the first year of life

Farrell, P., White, T., Ren, C. et al. (2017). Diagnosis of cystic fibrosis: guidelines from the cystic fibrosis foundation. J. Pediatr,181(s), s1-s15.

https://www.cff.org/Care/Clinical-Care-Guidelines/Diagnosis-Clinical-Care-Guidelines/CF-Diagnosis-Clinical-Care-Guidelines/

CFF.org

CF Newborn Screening (NBS)

• Started in WA State in 2006

• Performed by all states by 2010

• Basis of all CF NBS is detection on elevated immunoreactive trypsinogen

(IRT) in dried blood spots (marker of pancreatic injury)

• Most states use IRT-DNA algorithm

• If IRT elevated on 1st blood spot genetic testing for CFTR variants (DNA)

• High sensitivity (~97-98%) but detected carriers at ~ 10:1 compared to CF cases

• WA State originally chose IRT-IRT- sweat test algorithm

• Elevated IRTs collected on two blood spots collected 1-2 weeks apart were a positive

screen sweat chloride test

• 95-96% sensitivity while minimizing carrier detection

• Follow up often delayed due to age, birth weight, or clinical

• status (must be >2kg and at least 36 weeks corrected gestational

• age for sweat test)

CFF.org

CF Newborn Screening

• Originally developed in CO, used in TX

and other states

• Persistently elevated IRT run 40

variant DNA panel from blood spot

• Will run on 1st blood spot if 2nd not

received by 16 days of life

• 96-98% sensitivity without huge increase

in carrier detection

• Variants found by NBS must be confirmed

by CLIA certified lab

Used with permission from Margaret Rosenfeld, MD

• WA State changed to IRT-IRT-DNA algorithm

October 2019

CF Lung Disease

CF Patient Registry, 2018

CF Lung Disease

• Progressive obstructive lung disease hallmark of cystic fibrosis

• FEV1 used to trend lung disease (start spirometry at 4yo)

• Cough most common manifestation of early disease

• Other signs include hypoxemia, exercise intolerance, weight loss, and

decreased pulmonary function testing

• Rare, life-threatening pulmonary complications include pulmonary hemorrhage

or pneumothorax

• Goal of therapy is prevention of lung injury and

preservation of lung function

CF Lung Disease

Courtesy of Chelsea Davis MDStoltz, Meyerholz et al. (2015) origins of cystic fibrosis lung disease. N Eng J Med. 372, 351-362https://www.nejm.org/doi/full/10.1056/NEJMra1300109

CF Lung Disease

Normal CFTR Function Cell with CF

Videos courtesy of CFF/NACFC 2008

CF Microbiology

CF Patient Registry, 2018

• Endobronchial infection begins early in life, usually with S. aureus and H. influenza• Pseudomonas aeruginosa (Pa) is an important pathogen in CF lung disease

• Prevalence in airway cultures with age• Chronic Pa infection is associated with early morbidity and mortality• Early Pa infection more amenable to eradication

Managing CF Lung Disease

• Monitor Clinical Symptoms and PFTs Quarterly

• Optimize Nutritional Status

Pancreatic enzymes

High caloric intake

• Minimize Exposure to Airway Irritants

Respiratory viral illnesses (influenza vaccine/ synagis –

done at PCP)

Environmental factors

CFF.org

Managing CF Lung Disease

Medications:

• Bronchodilators/ Anti-inflammatory

Albuterol

Steroids (inhaled/oral)

High Dose Ibuprofen

• Mucolytics/Hydration

Dornase alfa QD

7% Hypertonic Saline BID

• Antibiotics

Maintenance

Inhaled tobramycin solution BID 28 days on/off

Inhaled aztreonam TID 28 days on/off

Azithromycin M,W,F

Intermittent- treat acute exacerbations

Oral, Inhaled, or IV

Managing CF Lung Disease

Optimize Airway Clearance Therapies (ACT) 2-4 times/day

• Use hydrators/ mucolytics

• Airway Clearance Technique of choice

• Exercise

Chest Physical Therapy/ Clapping/Active Cycle of Breathing

Oscillating Positive Expiratory Pressure (PEP) Devices

High Frequency Chest Wall Oscillating Devices

Photos courtesy of CFF.org

Pulmonary Exacerbation

• Change in respiratory signs and symptoms from patient’s baseline

necessitating treatment

• Increased exacerbations are associated with worse lung function

Mild:

May be treated over the phone by the CF team

• Increased mucus production and cough

• Fever

• Mild increased RR, WOB

• Decreased exercise tolerance

• Generalized fatigue

• Loss of appetite/ weight loss

• Treatment: oral/inhaled antibiotics and

increased ACT

Severe:

Mild symptoms AND:

• Decreased FEV1>10 %

• Rales and rhonchi

• Leukocytosis

• Decrease in oxygen saturation

• New infiltrate on CXR

• Hemoptysis

• Treatment: IV antibiotics and

increased ACT, optimize nutrition

CF Infection Prevention

• All patients with CF are in contact isolation when

on SCH Campus

• Patients are to wear masks anywhere in the hospital except in

clinic/ inpatient rooms

• SCH CF Infection Control policy has guidelines for both

inpatient and in clinic areas

http://child.seattlechildrens.org/search.aspx?searchText=cystic%20fibrosis&searchType=

d;w&Catalog=Policies%20and%20Procedures

• CFF Infection Prevention Guidelines have recommendations for

outside of healthcare facilities, including schools

https://www.cff.org/Care/Clinical-Care-Guidelines/Infection-Prevention-and-Control-

Clinical-Care-Guidelines

CF Nutrition

CF Patient Registry, 2018

CF Nutrition/ GI Issues

• Nutrition= better lung function

• Goal: BMI percentile >50th percentile.

• ~85-90% of patients with CF are pancreatic insufficient• Impairs digestion of fats and protein

• Malabsorption of fat soluble vitamins

• Malnutrition and growth failure

• Crampy abdominal pain, excessive flatus, frequent bulky stools, rectal prolapse

Decreased caloric intake• Malabsorption• Loss of appetite• Coughing to emesis

Increased caloric need• Increased metabolism• Chronic infection/ increased

caloric expenditure

Nutrition Management

• Increase Caloric Intake (1.5 x RDA for ideal body weight= estimated caloric needs)

• Increase Protein, fat, and sodium intake

• Pancreatic Enzyme Replacement (lipase, amylase, protease)

• Vitamin Supplements (A, D, E, K)

• Salt supplementation for infants

• Commercial Oral Supplements

• Tube Feedings

Gastrostomy tube

Continuous drip feeds at night or daytime boluses

• Total Parenteral Nutrition (TPN)

Rarely used

GI Pathophysiology

• Meconium Ileus/ DIOS

• Occurs in 15-20% of cases

• Obstruction/partial obstruction of meconium/mucus/partially digested food

• Essentially diagnostic of CF in newborn

• Not fully understood in older children

• CF Related Diabetes

• Occurs in 10-20% overall (35% in patients >25 years)

• insulin deficiency VS insulin resistance

• Screen annually for CFRD with OGTT for outpatients, inpatient pre/post prandial glucose for 48 hours

• CF Liver Disease

• Most CF patients will develop evidence of mild focal biliary fibrosis

• 3-5% will develop severe biliary cirrhosis with portal hypertension

• Quarterly examination of abdomen for organomegaly and annual LFTs

• Ursodeoxycholic acid (ursodiol) improves LFTs but does not stop disease progression

New CF Medications

• CFTR Modulators

CFF.org

CFTR Modulators

• Medications that work to restore

CFTR function

• There are two main types of

CFTR modulators currently

available:

• Potentiators-work at the cell

surface to help chloride flow

through the CFTR protein channel

by opening the “gate” of the CFTR

channel

• Correctors- help the CFTR protein

to fold correctly so that it is able to

move -- or traffic -- to the cell

surface.

CFF.org

CFTR Modulators

Potentiator:

• Ivacaftor (Kalydeco) 2012

• Originally approved for patients with at least 1 copy

of Class III gating mutation- G551D (4%), now

expanded to 38 mutations

• Currently approved for patients >6 months of age.

• 1 tablet/ granule packet twice a day with fat

containing foods

• FEV1 improved by 10.6%

• 55% reduction in pulmonary exacerbations

• 2.7kg weight gain

• Limited side effects: headache, rash, dizziness

• Monitor LFTs, cataracts

Highly effective modulator therapy, but limitedpatient eligibility!

CFTR Modulators

• Lumacaftor + Ivacaftor (Orkambi) 2015

• Approved for patients with two copies of

F508del >2 years

• 2 tablets/ 1 granule packet twice daily

with fat containing foods

• FEV1 improved by 2.6-3%

• Decreased rate of pulmonary

exacerbations by 30-40%

• Lots of drug-drug interactions

• Chest tightness, dyspnea, nausea,

elevated LFTs

• Monitor LFTs, bili, cataracts

• Tezacaftor + Ivacaftor (Symdeko) 2017

• Approved for patients >6 year of age

homozygous F508del, or one of 26

responsive mutations

• 1 tablet twice daily with fat containing food

• FEV1 improved by 4%

• Rate of pulmonary exacerbation decreased

35%

• Less drug-drug interactions

• Dizziness, headache, nausea

• Monitor LFTs, bili, cataracts

Corrector + Potentiator Combinations

More patients eligible, but not highly effective!

CFTR Modulators

• Elexacaftor + Tezacaftor+ Ivacaftor (Trikafta) 2019

• Approved for patients with at least one F508del mutation >12 years old

• ~90% of patients with CF qualify for this medication

• 2 tablets in AM and 1 in PM daily taken with fat containing food

• Dramatic improvements in FEV1, sweat chloride, and quality of life

• Reduction in pulmonary exacerbations by 63%

Middleton, PG, Mall, MA, Drevinek et al. (2019). Elexacaftor-Tezacaftor-Ivacaftor for cystic fibrosis with a singlePhe508del allele. N. Engl. J. Med. 381(19), 1809-1819. https://www.clinicalkey.com/#!/content/medline/2-s2.0-31697873

Improvement in FEV1 14%!

CFTR Modulators

• Elexacaftor + Tezacaftor+ Ivacaftor (Trikafta) 2019

• Less drug-drug interactions

• Headache, stomach pain or diarrhea, flu-like symptoms

• Monitor LFTs, bili, cataracts

Highly effective modulator therapy for~90% of patients!

Resources: http//:www.cff.org

Resources: http//:www.cftr2.org

Resources: SCH

• Pulmonary Tool Kit on CHILD • SCH CF Team

Cystic Fibrosis Center ph 206-987-2024Janine.Cassidy@seattlechlidrens.org

Any Questions?

References

Cutting, GR. (2015). Cystic fibrosis genetics: from molecular understanding to clinical application. Nat. Rev. Gen, 16(1), 45056.

Farrell, P., White, T., Ren, C. Hempstead, S., Accurso, F., Derichs, D., Howenstine, M., McColley, S., Rock, M., Rosenfeld, M.,Sermet-Gaudelus, I.,

Southern, K., Marshall, B., & Sonsey, P. (2017). Diagnosis of cystic fibrosis: guidelines from the cystic fibrosis foundation. J. Pediatr,181(s), s1-s15.

Middleton, P., Mall, M., Drevinek, P., Lands, L., McKone, E., Polineni, D., Ramsey, B., Taylor-Cousar, J., Tullis, E., Vermeulen, F., Margowida, G.,

McKee, C., Moskowitz, S., Nair, N., Savage, J., Simard, C., Tian, S., Waltz, D., Xuan, F., Rowe, S., & Jain, R. (2019). Elexacaftor-Tezacaftor-Ivacaftor

for cystic fibrosis with a single Phe508del allele. N. Engl. J. Med. 381(19), 1809-1819.

Ramsey, B., Davies, J., McElvaney, G. et al. (2011). A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N. Engl. J. Med. 365,

1663-1672.

Stoltz, D., Meyerholz, D. & Welsh, M. (2015). Origins of cystic fibrosis lung disease. N.Eng.J.Med. 372, 351-362.

Taylor-Cousar, J., Munck, A., McKone, E., van der Ent, C., Moeller, A., Simard, C., Wang, L., Ingenito, E., McKee, C., Lu, Y., Lekstrom-Himes, J, &

Elborn, S. (2017). Tezacaftor-Ivacaftor in patients with cystic fibrosis homozygous for phe508del. N.Eng.J.Med.377, 2013-2023.

Wainwright, C., Elborn, S.,Ramsey, B., Marigowda, G., Huang, X., Cipolli, M., Colombo, C., Davies, J., De Boeck, K., Flume, P., Konstan, M.,

McColley, s. et al. (2015). Lumacaftor-Ivacaftor in patients with cystic fibrosis homozygous for phe508del. N.Engl.J.Med. 373, 220-231.