Cystic Fibrosis Update: Quality Improvement, Newborn Screening and Novel Therapies
- Adrienne Prestridge Savant, MD
- Attending Physician, Pulmonary Medicine; Co-Director, Cystic Fibrosis Center, Ann & Robert H. Lurie Children's Hospital of Chicago; Assistant Professor of Pediatrics, Northwestern University Feinberg School of Medicine
- Disclosure: Dr. Prestridge has no industry relationships to disclose. She refers to an off-label product, ivacaftor, in the context of its FDA approval and ongoing clinical trials.
- Susanna McColley, MD
- Head, Pulmonary Medicine; Director, Cystic Fibrosis Center, Ann & Robert H. Lurie Children's Hospital of Chicago; Professor of Pediatrics, Northwestern University Feinberg School of Medicine
- Disclosure: Dr. McColley has received an honorarium from Vertex Pharmaceuticals for consulting in clinical trial design. She refers on an off-label product, ivacaftor, in the context of its FDA approval and ongoing clinical trials.
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At the conclusion of this activity, participants will be able to:
- Recognize the importance of quality improvement efforts in improving adherence to guidelines for cystic fibrosis leading to improved long term outcomes, such as survival
- Assess the implications of a positive newborn screening test for cystic fibrosis and select the appropriate additional testing
- Discuss the most recent updates in clinical management of patients with cystic fibrosis, including important screening tests and new therapies
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Cystic fibrosis (CF) is a common inherited genetic disorder with a birth frequency of 1/3200 in Caucasians, 1/9200 in Hispanics and 1/15000 in African Americans. CF is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, which codes for a protein that is both a chloride channel and a regulator of other apical ion channels. In a cell with normal CFTR, chloride and sodium move into the extracellular space, such as the respiratory tract lumen, allowing for adequate hydration of the mucosal surface. When CFTR is absent or abnormal, chloride does not exit the cell normally, and CF occurs. Abnormal or absent CFTR leads to abnormal ion conductance, dehydrated airway secretions, and chronic airway infections leading to progressive bronchiectasis. Secretion inspissation in other organs leads to pancreatic insufficiency, hepatobiliary system abnormalities, and male infertility. Median survival has increased significantly over the last 20 years, from around 25 years in 1985 to over 37 years in 2012. Advances in survival and clinical status are associated with a comprehensive quality improvement strategy, early diagnosis via newborn screening, and both refining old and developing new therapies for CF.
Quality improvement in cystic fibrosis
In 1957, the annual mortality for patients with CF was over 20% (average life expectancy 3 years); however, one center boasted an outcome of less than 2% mortality annually. In order to test this claim, a patient registry, tracking clinical and treatment data, was developed in 1964 with the goal of showing improvements in mortality rate. CF Centers started to evolve a comprehensive treatment program for CF care and by 1966 mortality had dropped, increasing the average life expectancy to10 years. The patient registry, which has been refined over time, provided the early foundation for robust quality improvement in CF. Accredited Cystic Fibrosis Foundation Care Centers submit data on individual patients who have (or whose parents have) provided consent for this, allowing for thorough and accurate assessment of care processes and outcomes.
The Cystic Fibrosis Foundation (CFF) asserts that “additional years of life expectancy can be added by improving practice with currently available approaches and therapies” through the principles of quality improvement (QI). In 2006, the CFF made the registry data publicly available, with each center in the country showing risk-adjusted data for key care processes and outcomes (http://www.cff.org/). The CFF has continued to support numerous efforts to provide education, support and resources to the care centers in order to improve the delivery of care to patient.
Improving nutrition in children with cystic fibrosis
The CF Center at Ann & Robert H. Lurie Children’s Hospital of Chicago participated in the CFF-funded National Initiative for Children’s Healthcare Quality (NICHQ) collaborative, “Improving Care for Children with CF,” starting in 2002. The primary goal of the collaborative was to improve nutrition. Studies have shown the significant effect that optimal weight has on long term outcomes; the weight a child achieves at age 3 correlates with lung function at age 6, higher BMI at all ages is associated with higher lung function, and higher nutritional parameters are associated with improved survival. It is important for the general pediatricians to partner with the CF Center to ensure adequate nutritional outcomes, with the specific goal of BMI>50th percentile.
During this collaborative, we developed processes to consistently classify nutritional status, establish self-management goals, and to evaluate for comorbidities in patients at nutritional risk. Enhancing communication with primary care pediatricians about the importance of higher BMI and engaging pediatricians in nutrition follow-up was one of many strategies used.
By 2006, our CF Center achieved a marked decrease in the proportion of children classified as “urgent need” (BMI < 10th percentile) and an increase in our median BMI percentile from the 43rd to the 52nd percentile (by CDC growth charts), compared to the national U.S. CF Center average of the 44th percentile. We have since maintained our BMI percentile for our center at > the 50th percentile for over 5 years. For the past 2 years, our center was in the top 10 of US CF Centers for BMI percentile for patients between the ages of 2-19 years (Figure 1).
Reducing healthcare acquisition of CF-specific bacteria
We have continued to perform quality improvement in all areas of CF care. We have implemented a process to match our outpatient care with the evidence based infection control guidelines for CF. Reducing healthcare acquisition of CF-specific bacteria can improve the health of our patients and is a stated goal of the CFF quality strategic plan. Since we implemented this new process, we have seen our Pseudomonas aeruginosa rate drop from an average of 30% to 19% in children and have been able to sustain this rate for 2.5 years.
Improving screening of patients for CF-related diabetes
Our most recent project, supported by a grant from the CFF, is to improve screening of patients for CF-related diabetes (CFRD). CFRD is one of the most common CF comorbidities and has been associated with decreased lung function, increased pulmonary exacerbations, poor nutritional outcomes, and decreased survival. Early diagnosis and therapy for CFRD reduces these severe consequences. It is rare for a patient to have symptoms, but clinicians should be aware that polyuria, polydipsia and unexplained weight loss are clinical findings in some patients presenting with CFRD.
It is important for the clinician to realize that hemoglobin A1C is not a sensitive screening tool in CFRD and is not recommended. Since the majority of patients are asymptomatic when diagnosed with CFRD, annual screening using oral glucose tolerance testing, starting at age 10 years when the incidence begins to rise, has been a longstanding evidence based recommendation. Unfortunately, this recommendation is not easily implemented in clinical practice, as demonstrated by a national average screening rate of only 31.5% in 2011. We noted, through our CFF Patient Registry data, that our center was below this national average. We developed a system to improve outpatient screening for CFRD, including structured education, communication with families, and processes for scheduling laboratory appointments. After initiation of this new system, our screening rate increased from 2% of eligible patients during the 18 weeks prior to the start of our initiative to 76% during the 18 weeks of our initiative (p<0.0001). As with our nutrition and infection control initiatives, we have been able to sustain this increased rate of screening since starting the initiative (Figure 2).
Diagnosis of CF through newborn screening improves outcomes and has been adopted in all U.S. states. It has been shown to improve long term nutritional status, decrease healthcare utilization, maintain lung function, and possibly improve survival. The newborn screening test for CF measures immunoreactive trypsinogen (IRT) from the standard heel stick blood spot. During fetal life, there is leakage of trypsinogen into the blood due the underlying pancreatic abnormality in all patients with CF, leading to significantly elevated blood trypsinogen levels. In Illinois, infants who have an IRT in the top 4% on a given day have DNA testing for common CFTR gene mutations from the same blood spot. An elevated IRT and at least 1 gene mutation, or an extremely high IRT alone, constitutes a positive screening test; a sweat test is mandatory for confirmation of the diagnosis. This CF newborn screening method has >98% sensitivity and a positive predictive value of 15.2%.
After a positive newborn screen, the diagnostic test for CF is the quantitative pilocarpine iontopheresis sweat test, which should be done at a CFF accredited CF Center to ensure lab proficiency and quality control. Most patients who have positive newborn screens and negative sweat tests are carriers. Infants with negative newborn screens who have siblings with CF should always undergo sweat testing; to date, at least 2 CF siblings born in Illinois had negative newborn screens but positive sweat tests.
At Lurie Children’s, we have a comprehensive diagnostic and counseling service for the families of infants with positive newborn screens. Parents receive genetic counseling while waiting for the sweat test results and receive the results within an hour of completion. A member of the CF team will see infants with positive sweat tests immediately to discuss test results and offer clinical assessment.
If the results are indeterminate (sweat chloride > 30 but < 60mEq/L), the family receives information about further monitoring and testing. Their primary care physician should monitor infants with indeterminate sweat tests for signs of poor weight gain, steatorrhea or persistent respiratory symptoms. Infants who have persistently indeterminate sweat tests after 6 months of age, or who have 2 CFTR mutations with 1 or both being of unclear significance, are diagnosed with “cystic fibrosis related metabolic syndrome.” Regular follow-up at a CF Center is recommended for these infants, but initiation of CF therapies is dependent on the development of signs or symptoms of CF.
Quality improvement in CF newborn screening
It can be difficult to obtain adequate sweat samples from infants during the first month of life. Information from the CFF suggests that, based on achievement in CF Centers, infants < 3 months of age who undergo sweat testing should have “quantity not sufficient” (QNS) rates of < 10%. After initiation of newborn screening in the State of Illinois, it was quickly noted that many programs were achieving QNS sweat test results in > 10% of cases. Statewide, rates were as high as 27%. In 2010, the CF Center at Lurie Children’s received a grant from the CFF for “Improving CF Newborn Screening in Illinois.” With assistance from the Illinois Department of Public Health, the CF Center has led twice monthly conference calls to review State and program-level data and discuss best practices. The grant has also funded a sweat testing expert (Vicky LeGrys, MD) to visit 4 CF programs that were achieving consistently high QNS rate; recommendations were shared with all other programs. For more than 1 year, sweat test QNS rates have been < 10% statewide, and nearly all programs have improved.
Increased life expectancy in CF has occurred without therapies that treat the underlying cause of the disease. The goals of CF care include achieving and maintaining normal growth; maintaining normal pulmonary function; avoiding and, when necessary, treating chronic infection; and rigorously evaluating for complications of the disease so they may be treated before severe consequences occur. Today, as in the past, the fundamentals of CF care include provision of pancreatic enzyme supplements, a high calorie and liberal fat diet, maintaining adequate fat soluble vitamin levels, often including high dose Vitamin D supplementation, frequent monitoring and counseling, and sometimes supplemental tube feeding; medication to improve mucociliary clearance along with physical methods of airway clearance; and antibiotics for suppression of Pseudomonas aeruginosa and for treatment of acute pulmonary exacerbation.
While fundamental treatment has not changed since the 1980s, it has been markedly refined. The first drug specifically created to treat CF lung disease, rh-DNase, was approved by the U.S. FDA in 1993 after clinical trials showed improvement in pulmonary function and reduction in infectious exacerbations in patients receiving the drug compared to placebo. More recently, inhaled 7% hypertonic saline has been shown to benefit CF lung disease.
Treatment of chronic infection has been markedly improved by the introduction of 2 inhaled anti-Pseudomonal antibiotics: tobramycin solution for inhalation in 1999, and aztreonam inhalation solution in 2011. Both drugs were studied using a 28 day on/ 28 day off regimen and showed improved pulmonary function, reduced exacerbation frequency, and other clinically important benefits. Tobramycin inhalation solution, which has been available for more than a decade, is associated with decreased mortality in CF patients. Clinical trials are currently under way to evaluate whether alternating these antibiotics, so that there is no “off treatment” period, adds benefits compared to a single drug given alternate months.
Chronic use of the macrolide antibiotic, azithromycin, improves pulmonary function and reduces exacerbation frequency in patients with chronic P. aeruginosa infection. In those who do not have chronic P. aeruginosa, it still reduces pulmonary exacerbation frequency.
Airway clearance continues to evolve, with a variety of devices and patient or caregiver delivered techniques available. No technique has been shown to be superior to another, so patient and family preference, portability, and ease of use are taken into consideration when prescribing these therapies. Regular exercise can augment airway clearance and is an ever important recommendation for people with CF.
Since the discovery of the CFTR gene in 1989, basic and clinical research strategies have worked towards treatment of the basic defect. In 2012, the first “CFTR modulator” drug, ivacaftor, an oral agent given in tablet form, was approved for patients with CF caused by the second most common CFTR gene mutation, G551D. This mutation is a “gating mutation,” which creates CFTR that sits in the apical cell membrane but does not conduct chloride. In clinical trials, both children (aged 7 years and older) and adults had substantial improvement in pulmonary function, quality of life, and weight gain, along with reduction in pulmonary exacerbation frequency while taking ivacaftor twice daily, compared to placebo. Ivacaftor is currently being studied for other CFTR gene mutations that reside in the cell membrane but do not conduct chloride normally.
The most common gene mutation, F508del, is misfolded and destroyed intracellularly, and thus never reaches the apical cell membrane. An experimental drug, lumacaftor, improves protein folding. A recent phase 2 trial of ivacaftor plus lumacaftor showed promising results in patients homozygous for F508del; a phase 3 trial is underway.
The outlook for infants born with CF has never been brighter; those born today will benefit from comprehensive care, a robust registry, ongoing efforts to improve quality of care, and research aimed at a “functional cure”. Those living with CF have ever-increasing treatment options. The goal of a normal life expectancy for people with cystic fibrosis may be achieved within the next decades; expert, compassionate care is essential for that goal to be met.
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