NEWS

S P R I N G 2 0 0 6

CYSTIC FIBROSIS CENTER

New imaging techniques pioneered at Stanford are revealingpreviously undetected structural lung changes early in the lifeof persons with CF. Imaging of the chest using computedtomography (CT) is proving to be a sensitive tool forevaluating CF lung disease and measuring the impact oftreatments, especially early in the disease process before lungfunction is impaired. In the past, measurement of CF lungdamage has relied on less sensitive measures — chest x-raysand pulmonary function tests (PFTs) — that do not pick upearly or subtle structural changes. Dr. Terry Robinson and theCystic Fibrosis Foundation (CFF) Therapeutics DevelopmentNetwork have developed techniques using whole lung CTimaging to precisely measure structural changes. The resultsare underscoring the benefits of early, aggressive treatment ofinfections and strict adherence to CFF clinical guidelines, evenwhen traditional measures indicate no or minimal lungdisease. Results also suggest an important “window ofopportunity” when lung damage may be reversible withaggressive treatment.

The Role of Imaging in CFHistorically, imaging has played a limited role in CF

diagnostics. The CFF recommends chest radiography (x-rays)every 2–3 years for persons with stable lung function, andannual x-rays for persons with declining lung function or acuteexacerbations to document disease progression or response totherapies. Systems for scoring changes in chest x-rays such asthe Brasfield Score, measure and rate the severity of lung andairway abnormalities. But x-rays generally change slowly over

Terry Robinson, MD,

with 12-year-old

Amanda Dobson in

the LPCH spiral

CT Scanner.

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High Tech Imaging Charts New Course for CF Caretime and do not pick up subtle damage. In the last ten yearsthin slice chest CT (also called high-resolution or HRCT) hasincreased our understanding of disease progression in CF usingscans to score different aspects of disease such as bronchialairway wall thickness, bronchiectasis (loss of airway structuralintegrity), mucus plugging, and air trapping. CT technologyalso reveals regional changes in specific areas of the lungsbefore changes can be seen in PFTs or chest x-rays.

The new chest CT scoring systems and computerizedanalysis developed by Dr. Robinson and others preciselymeasure bronchial wall thickening related to airwayinflammation, bronchiectasis, mucus plugging, air trappingand regional abnormalities that correlate strongly with diseaseseverity. Dr. Robinson notes, “PFTs provide an overview of allregions of the lung; a person can have severe structural damagein one region yet have perfectly normal PFTs because the lunghas such tremendous reserves. However, we are finding thatalthough the lungs can sustain significant damage and stillfunction normally, at some point in disease progressiondamage can reach a critical point, the reserve capacity nears itslimit and lung function becomes severely compromised. ChestCT allows us to identify and document this process with adegree of specificity that can be lost in PFTs, particularly earlyin the course of CF. The information may allow us to shift theclinical care paradigm from treating damage to actuallyreversing the disease process and preventing bronchiectasis.” HRCTs also are being used to identify potential biomarkers that measure the success of treatment regimens, such asPulmozyme™ and TOBI™, and to measure the specific impacts of different types ofbacteria on the lungs ofpeople with CF.

CT scanners have evolvedto allow low dose scans ofthe entire chest in 8–10seconds using a techniquecalled spiral CT that

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provides exquisite detail of the lungs. The radiation dose ofthese scans is estimated to be 1/3 the average annualbackground radiation in the United Sates, (and only 1/6th ofthe natural dose in Denver).

Early Changes in CF LungsCT scans have unmasked early, previously undetectable

changes to prove that structural changes in the CF lung precededetectable changes in lung function. Early CF disease causeschanges in submucosal glands, depletion of airway surfaceliquid and ineffective mucus clearance that lead to air trappingand bronchial wall thickening, both of which affect theefficiency and capacity of the lungs. These symptoms areprecursors to the airway “remodeling” and scarring thatcharacterizes advanced CF lung disease. HRCT scoringsystems enable measurement of changes using a compositeCT/PFT score that is more sensitive than traditional PFTs inidentifying early or mild disease. More recent volumetric spiralCT imaging allows three-dimensional analysis of the lung.New studies show significant CF lung disease in children withmild to moderate CF who have no significant declines (and insome cases even improvement) in PFTs, suggesting thatpulmonary function measurements do not always track withstructural damage in the lungs. Chest HRCT/spiral CTs areparticularly sensitive in evaluating progressive lung changes.

Tracking Treatments & Disease Reversibility Dr. Robinson has demonstrated reversible changes

in HRCT scores after treatment with IV antibiotics and Pulmozyme™ — revealing reduced mucus plugging,improvement in airways, and reduced air trapping. Otherresearch also suggests that bronchiectasis may be reversible inchildren with early/mild disease. Scientists suggest a newparadigm for CF lung disease as a spectrum with profoundtreatment implications: early pre-bronchiectasis defined by bronchial wall thickening followed by HRCT/CT-definedbronchiectasis with initial mild bronchial dilation (wideningof the airway), and finally established bronchiectasis that doesnot resolve with specific interventions. They propose thatreversal of airway disease may be possible in the first two phases: after one year of treatment, subjects gettingPulmozyme ™ showed a 2–4% improvement in the extent andseverity of bronchial wall thickness scores and a 6–9% declinein the extent and severity of bronchiectasis scores comparedwith essentially no change or worsening findings for theplacebo group. The Pulmozyme™ study also demonstrated a9–13% drop in quantitative air trapping at three months anda 15–16% drop at 12 months in subjects receiving the drug,compared with a 43–48% increase in air trapping at threemonths and a 50–61% increase at 12 months for the placebogroup. These findings suggest a critical period for reducingand even reversing damage to CF lungs.

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“Window of Opportunity” for Reversal of Disease

Early Disease UnderestimatedThese findings have significant implications for

early treatment of persons with CF who have little apparentlung disease. PFTs underestimate the presence of mild and moderate disease. CFF-supported scientists recentlyhypothesized that more sensitive biomarkers are needed toassess new therapies and monitor disease because:

1. CF lung disease progresses despite stable or improving PFTs.

2. CF disease starts early, likely beginning with regional air trapping and bronchial wall thickness, progressing to bronchiectasis.

3. Progression may relate to bacterial colonization,especially Pseudomonas.

4. The “Window of Opportunity” is an important, newconcept for clinical care.

To summarize, Dr. Robinson suggests, “If we are to addressearly changes in CF lung disease in order to prevent or possiblyreverse early structural lung changes such as bronchiectasis, wehave to be able to measure precisely and accurately thestructural findings encountered in early CF lung disease. CToffers the technology to do this.”

STRUCTURAL CHANGES PRECEDE PFT CHANGES

HRCT analysis of the Stanford-led AAV gene therapy studysubjects revealed:

• Mucus plugging in 40% of subjects with FEV1greater than

or equal to 90% predicted and 73% of subjects with FEV1

between 60–80%

• Significant elevated HRCT scores in 15 subjects with FEV1

greater than 90% predicted

• In 60 CF children with mild disease (Mean FEV1= 102%):

• 63% had air trapping

• 35% had bronchiectasis

• 15% had mucus plugging

• In 37 subjects with PFT scores greater than or equal to85%, 30% had bronchiectasis, including 17% in 4 or morelobes of the lungs.

Mild CylindricalBronchiectasis

VaricoseCystic Bronchiectasis

“Window of Opportunity”

Early Disease Moderate to Progressive

MP Large Airway Severe MP

Severe Global ATModerate AT

Severe Progressive Disease

PROGRESSION OF CF STRUCTURAL LUNG DISEASE

CF lung disease is a continuum of progressive structural lung changes that occurs over time.

Progressive BWT

Regional Air Trapping (AT)

Bronchial WallThickening (BWT) • Regional • Peripheral

Minimal Mucus Plugging (MP)

Atelectasis/Collapse/Scarring

Severe BWTSTAGES OF STRUCTURAL DAMAGE

CF Pulmonary Disease Progression

Birth Childhood Adult

Normal Airway

ComplicationsLateBronchiectasis

EarlyBronchiectasis

Mucus Plugging

RegionalDifference in Airway

Thickening

Air Trapping

Prevention Correction of Reversible

Changes

ExacerbationTherapy

Chronic Stabilization

Treatment ofComplications

TREATMENT PARADIGMS

Baseline before Therapy After 3 Months Therapy

High Tech Imaging Charts New Course for CF Care

Continued from previous page

Severe Bronchiectasis Minimal Brochiectasis

Lucile Packard Children’s Hospital and Stanford University School of Medicine worked with VIDA Diagnostics to improve CT diagnostics for CF.

Implications for Clinical CareCF lung disease starts early in life with structural changes

preceding changes in PFTs. Scientists hypothesize that there isa critical “window of opportunity” for therapies directed atprevention or potential reversal of early and progressivedisease. These findings suggest that early, continuousassessment and monitoring is important, and that moreaggressive intervention is critical to maintain optimum healthin CF. Parameters to monitor may include:

• Low dose chest CT scanning and infant PFTs for earlyassessment with periodic follow up;

• Aggressive surveillance of respiratory cultures to detectnew infections quickly;

• Aggressive early intervention with antibiotic eradicationprotocols, mucolytics (e.g Pulmozyme™ and hypertonicsaline), anti-inflammatory drugs (e.g. Zithromax™ and/oribuprofen), and airway clearance modalities.

Concerns about exposure to radiation have been addressedwith new CT technology and lower dose protocols.Nonetheless, the expense and relatively early stage of theresearch mean that routine use of CT/HRCT has not beenembraced. Stanford and the CFF plan further research toidentify and document the value of CT in understanding theprogression of CF and the effectiveness of various treatments.Drs. Robinson and Moss have been awarded a multi-year grantfrom Novartis Pharmaceuticals to document the naturalhistory of CF in children with mild lung disease using CT,PFTs, bacterial cultures and other biomarkers.

Cystic Fibrosis creates unique nutritional needs that impactdaily care and quality of life. Inadequate metabolism of manyvitamins and minerals poses health risks, especially with thepancreatic insufficiency that affects 85–90% of people withCF. Without sufficient enzymes in the small intestines,valuable nutrients can’t be absorbed from food, including thefat–soluble vitamins (A, D, E, and K) and other vitamins andminerals such as B-6 and zinc. In addition, chronicinflammation and an increase in oxidative stress occurs in thelungs of persons with cystic fibrosis, possibly increasing theneed for antioxidant vitamins such as vitamin C, vitamin E,beta-carotene (a precursor to vitamin A), zinc, and selenium.Research is revealing that some of these chemicals, also calledmicronutrients because of the very small quantities needed fornormal functioning of the body, may play crucial roles in earlylung development and even immune system function. Thisarticle initiates a series in our newsletter on the roles thatvitamins and minerals play in CF, as well as current ideas onhelpful — and harmful — dosing.

How are vitamins and minerals monitored?

Because of the well-known risk for deficiency of fat-solublevitamins, the CFF Clinical Practice Guidelines recommendthat blood levels of vitamins A, D, E and K be monitoredannually. Other vitamin and mineral levels typically are onlymeasured if symptoms suggest deficiencies.

Why can’t food provide enough vitamins?

Even with the best enzyme therapy, some people withCF may fail to absorb 20% or more of the nutrients containedin food. Furthermore, nutrient losses vary since people differin their degree of pancreatic insufficiency. In other words,adequate vitamin supplementation can be different fromperson to person, hence the need for regular monitoring of

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CF Newborn Screening Legislation Proposed

which includes more than 50% Hispanic births. The stateproposes a new “California CF Gene Panel” comprised of 37severe mutations that will identify 95% of cases in California.In its analysis of California CF births since 1992, Kharrazi’sgroup found that only 56% of Hispanic CF mutations wereidentified by the currently available commercial gene panels.

Implementation ChallengesThe proposed program was designed to balance sensitivity —

i.e. identification of as many cases as possible — and specificity— i.e. minimizing the number of inaccurate diagnoses. Costconsiderations are of central concern to the state and to CFcenters who will need to provide initial genetic counseling andreferral to infants testing positive. Of the 560,000 infants borneach year in California, screening will identify an estimated 100 CF cases. The average age of diagnosis should decreasefrom 3.3 years to only two weeks, thus enabling quick referralto a CF specialist for ongoing follow-up and care.

Your Efforts Can HelpPersonal stories of the impact of delayed diagnosis will be

compelling as we work to pass the legislation. 18-year-oldMolly Pam, a high school senior, wrote an editorial about herlate diagnosis at age nine years that was read on public radio.In December she spoke to a state meeting and more recentlyhelped LPCH in a story broadcast on Bay Area Fox television.If you have a personal experience illustrating the problems ofdelayed diagnosis and treatment of CF, please considersubmitting it to our legislative task force. At the right time,letters to legislators and the governor may be helpful. Keep in touch with how you can help on our CF Center website, or send us your contact information or story toScreenForCF@gmail.com.

blood levels. That’s also why we recommend fat-solublevitamin supplements for pancreatic insufficiency to ensureadequate absorption of vitamins. Commercial vitaminpreparations of the fat-soluble vitamins are available indifferent forms and flavors that are tailored to persons with CF(sometimes called ADEKs). Our CF Center dietitian, JulieMatel, can help you select the right one. The CFFrecommendations for fat-soluble vitamins are shown in thetable below.

Vitamins and Minerals: An Important Link to Good Health

LPCH is spearheading new legislation to initiate universalnewborn screening for CF in California. A group coalescedjust three weeks before the deadline for the introduction ofnew bills, due to publicity initiated by Stanford CF patientMolly Pam on public radio in October 2005. CFRI is the leadsponsor of the bill, with assistance from CFF, Californiachildren’s hospitals, the March of Dimes and the CFcommunity. The action follows completion of a Departmentof Health Services report to the legislature that outlines a planto begin screening within 12–24 months after passage of thelaw. Newborn screening provides early diagnosis that enablestimely intervention and preventive care that reducescomplications, and even early death and disability.

Growing Support for ScreeningCF was not included last year when California expanded its

newborn screening program, however the state legislaturerequested a report on costs, benefits and recommendations.That report echoes recommendations adopted by the Centersfor Disease Control, the American College of MedicalGenetics, the March of Dimes and others to implementuniversal CF newborn screening. Recent studies documentsignificant benefits from early detection that include saving atleast two lives per 100 children up to the age of 10 with CF,improved lung function and nutritional status, fewerhospitalizations, and improved cognitive outcomes.

California’s Unique DemographicsMartin Kharrazi, Ph.D., Chief of the Program Research and

Demonstration Unit of the Genetic Disease Branch of theCalifornia Department of Health Services, lead the researchteam for the state. The study provides new details on thegenetic profile of California’s ethnically diverse population,

FAT– SOLUBLE VITAMIN DAILY SUPPLEMENTATION REQUIREMENTS BY AGE

*International Units of measure

Stay TunedFuture newsletters will highlight a vitamin or mineraleach issue with current information on how they areused in your body, dosing, sources, and risks of overor under consumption.

18-year-old Molly Pam recorded an

editorial “Perspective” on KQED Public

Radio in October to advocate for

universal CF newborn screening in

California. She was invited to address a

statewide meeting of CF Center

directors and policymakers to discuss the

personal cost of late diagnosis.

Age Vitamin A (IU)* Vitamin E (IU) Vitamin D (IU) Vitamin K (mg)

0–12 months 1,500 40–50 400 0.3 mg

1–3 years 5,000 80–150 400–800 0.3 mg

4–8 years 5,000–10,000 200–400 400–800 0.3 mg

> 8 years 10,000 200–400 400–800 0.3 mg

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DR. JEFF WINE’S CF Research Laboratory(CFRL) at Stanford has been awarded a 5-yearNational Institutes of Health grant to clarify thefunctional role of CFTR in airway submucosalglands. This work is important because mostpeople with cystic fibrosis (CF) die fromcomplications caused by chronic infections ofbacteria that reside in the mucus that is primarilyproduced by airway submucosal glands. Members ofCFRL have developed optical methods to measuresecretion rates from single glands and have shownthat CF glands fail to respond to certain kinds ofstimulation. To further clarify the role of CFTR inglands, CFRL will use an array of methods.Hallmarks of this research are the use of humantissues, dynamic imaging of cellular responses inliving human glands, and direct comparisonsbetween CF and non-CF glands.

DR. RICHARD MOSS served on the scientific

organizing committee and attended the 2nd Annual

Advances Against Aspergillus Conference in Athens,

Greece in February, where he reviewed drug trials

for ABPA.

DR. TERRY ROBINSON presented a talk

entitled “Clinical Applications & Indications of

HRCT/CT Scanning in Evaluation of CF and Lung

Transplant Patients” in January. He also presented

“Early Intervention In CF Care: A Paradigm Shift”

at a CF Research Group University Meeting at

UCSF, at John's Hopkins University, National

Medical Center in Washington D.C. and at A.I.

Dupont Hospital for Children in Delaware.

DR. JOHN MARK presented a series of talks

on complementary and alternative medicine and

lung related issues to pediatric residents and at

Grand Rounds at Packard, as well as at community

hospitals in Salinas, Santa Cruz, Stockton,

San Ramon and San Francisco.

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Stanford sent a large contingent to the NACFC in October.Dr. Carol Conrad’s N-acetyl-cysteine [NAC] study resultswere a featured highlight. Subjects receiving pharmaceuticalquality NAC experienced significant increases in GSH(glutathione) and decreases in neutrophil counts, elastase andIL8 in the lungs, all indicators of inflammation. Results weredose-dependent, and NAC was well-tolerated. To hear Dr.Conrad’s talk, visit www.cff.org/research/2005_nacfc/.Results of the study recently were published in the prestigiousjournal Proceedings of the National Academy of Sciences.

New studies presented at the conference and subsequentlypublished in the New England Journal of Medicine, confirmedthe efficacy of inhaled hypertonic saline (HS). Smallimprovements in PFTs, significant reductions in exacerbationsand improved quality of life with twice daily 7% HSinhalation were found in the large, multi-center placebocontrolled trials.

Dr. Carol Conrad was a featured speaker at the National Conference.

North American CF Conference Highlights Stanford In the News

The CFF announced a major initiative to raise the bar onnutritional status through aggressive patient education,nutritional counseling and intervention. Growing evidenceindicates early intervention to maintain weight improves lungfunction. The CFF is recommending use of Body Mass Index(BMI) standards rather than Ideal Body Weight (IBW) whichis less sensitive to height since many persons with CF havelower than normal stature. A BMI greater than the 50thpercentile is recommended for children, as well as goals of 23or higher for men and 22 or higher for women. New protocolsrecommend earlier use of appetite stimulants and/or tubefeedings before nutritional failure sets in. Closer monitoring ofglucose tolerance is recommended, since CF-related diabetesmay be a long-term consequence of malnutrition.

EPIC TRIAL UNDERWAY

The Early Pseudomonas Infection Control (EPIC) clinical

trial is recruiting subjects in 60 CFF sites, including

Stanford.The goal of the study is to determine the best

approach to treating first acquisition of Pseudomonas

aeruginosa (PA).The study enrolls patients when they first

culture PA into one of four treatment groups.All patients

culturing PA will receive inhaled tobramycin (TOBI™), with

variations on duration of treatment (intermittent versus

initial plus upon reoccurrence) and inclusion of a course of

the oral antibiotic Cipro™.The study will be comparing

time to a subsequent PA culture and differences in clinical

outcomes between the treatment groups.The study will

yield important data to determine the most effective

treatment for early PA acquisition so that consistent

standards of care can be established and published for

reference by physicians and insurance carriers.

CURRENT RESEARCH STUDIESPlease consider participating in a clinical trial for CFresearch. For more information, visitwww.cfcenter.stanford.edu, contact our researchcoordinators or talk to your physician.The following trialsare currently underway (“closed” indicates that recruitmentis complete and a trial is in progress):

• Infant and toddler pulmonary testing (closed)

• Induced sputum: evaluation of anti-inflammatory agents

• Inspire drug for correction of salt and waterabnormalities (closed)

• CF pre-diabetes intervention trial

• NAC (closed)

• Aztreonam for inhalation (closed)

• EPIC trial for early treatment of pseudomonas

• Upcoming Phase III trials at Stanford in mid-2006:TOBI™

dry powder inhaler from Chiron, denufosol from Inspire,new pancreatic enzymes from Altus and Eurand

Initial Hyper tonic Saline dosing

should be taken during a CF clinic

visit so that dose tolerance and

airway reactivity can be monitored

before treatment is initiated.

Dr. Richard Moss

Basic science advances announced at the meeting includedmultiple sessions on biomarkers and proteomics in CF.Biomarkers are anatomic, physiologic, biochemical, ormolecular parameters associated with the presence and severityof specific disease states and clinical symptoms. They aredetectable and measurable by a variety of methods includingphysical examination, laboratory assays and medical imaging(such as the CT scoring system discussed in the cover story).Examples of biomarkers include tumor antigens in cancer, orchanges in PFTs in CF. To study the effects of new drugs ortreatments in clinical trials, traditional trial endpoints such asmorbidity (e.g. number of hospitalizations or rate of decline inFEV1) and mortality (death), can be subjective, difficult toevaluate, or require large numbers of participants and very longtimeframes to achieve statistical significance. Biomarkers inimaging may, in many instances, provide objective endpointsthat may be confidently evaluated in a reasonable timeframewith smaller numbers of subjects. Proteomics is a growing aspectof biomarker research that identifies the thousands of proteinsexpressed in body tissues, fluids or even gases such as exhaledbreath. A large body of research is underway to determine therole of these proteins in physiology and pathology of conditionssuch as CF. Dr. Moss attended a proteomics biomarkerworkshop at CFF in late November 2005.

CYSTIC FIBROSIS CENTER AT STANFORD

Center Physicians: Richard Moss, Director; Carol Conrad,Terry Robinson, Lauren Witcoff, Nanci Yuan, John Mark,David Cornfield, Paul Mohabir (Adult CF physician)

Clinic E Scheduling (650) 497-8841Clinic Fax (650) 497-8837Miguel Huerta, Patient Services Coordinator (650) 498-2655Katherine Boyle, RN Pediatric Coordinator (650) 736-1359Mary Helmers, RN Adult Coordinator (650) 736-1358Kristin Shelton, Respiratory Coordinator (650) 724-0206Julie Matel, Nutritionist, Dietitian (650) 736-2128Joanne Asano, Social Work (650) 736-1905Research Coordinators (650) 736-0388For Urgent Issues:Monday–Friday 8:30–5:00 pm contact RN Coordinator

All Other Times (ask for Pulmonary Physician On-Call) (650) 497-8000

Visit our website at http://cfcenter.stanford.edu for moreinformation about our center and CF.We gratefully acknowledge the leadership of friend and parentPenny Stroud in producing this publication.

To subscribe to this newsletter please call or email Judy Kirby at(650) 724-3474 or jkirby@stanford.edu

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PAIDPalo Alto, CAPermit No. 29

CF Center at Stanford701 Welch Road, Suite 3328Palo Alto, CA 94304

Letters will be followed up by calls from our nurses tounderscore the importance of regular visits and to assistin making appointments.The LPCH physician appointmentcalendar has been revised to allow scheduling of physicianvisits six months in advance. Patients will also beencouraged to make their next appointment at the endof each visit. Patients now receive annual lab test ordersseveral months in advance to facilitate scheduling andreceipt of results prior to the annual visit.

Help us to help you become part of a topperforming CF Center! Quarterly and Annual CF visits are important!

Clinic Initiative to Improve Care Management & Outcomes

The CFF Clinical Guidelines recommend a minimumof four visits to your CF Center each year to ensureearly detection and prompt treatment of developingproblems such as lung function declines, newlyacquired bacteria and weight loss.Visit frequencyconsistently ranks as the single most importantvariable in health outcomes across CF centers aroundthe world. It is also an area in which our Center fallsshort and must improve if we want to be among thebest centers for outcomes.We need your help toimprove visit frequency so that we can improve yourclinical outcomes.

Peer Group/Measure LPCH/ National Top 10 Stanford Average Centers

Children5–17 yrs FEV

1Greater than 90% 53.3% 56.4% 86.7%

5–17 yrs FEV1Less than 90% 44.7% 64.7% 91.1%

Adults aged 18+FEV

1Greater than 70% 37.0% 41.9% 74.3%

FEV1Less than 70% 54.5% 53.0% 83.6%

2004 CFF Registry Visit Comparisons Percent Meeting CFF Guidelines for 4+ Clinic Visits,

1+ Sputum Cultures & 2+ PFTs Annually

Dollars for ScholarsGo to the following websites to apply for scholarships for people with CF:www.elizabethnashfoundation.orgwww.cfscholarships.comwww.solvaypharmaceuticals-us.com/products/scholarships

Pediatric patients who have not been seen at leastquarterly, and all adult patients, will receive a lettersummarizing the CFF Clinical Care Guidelines.