Infants that do not have a diagnostic sweat chloride value (≥ 60 mmol/L) or have one or two CFTR mutations present the clinician and family with a diagnostic dilemma. In some patients, signs and symptoms may ultimately lead to a diagnosis of CF. Others will develop symptoms such as pancreatitis or male infertility.  Still many will never develop symptoms. Infants identified by CF newborn screening (CFNBS) programs where CF cannot be diagnosed or clearly ruled out are given the designation CFTR-related metabolic syndrome (CRMS).  The diagnosis of CRMS can be very confusing and stressful for the families as well as healthcare professionals. Since CFNBS is now practiced in all the states in the US, an increasing number of infants with CRMS are being recognized. It is recommended that infants with initial sweat chloride values in the intermediate range (30-59 mmol/L) have a repeat sweat test by 2 months of age.  Symptom free infants with CRMS should be seen by the CF center at least twice during the first year of life and once a year thereafter. Because families will be making more visits to primary care office’s than to the CF specialist, primary care physician’s involvement in these patients’ care is crucial.  Contact the CF care center if an infant with CRMS is not gaining weight, has loose stools and/or flatus, has abdominal pain or has respiratory symptoms such as coughing or wheezing that do not resolve in 2 weeks. These principles continue to be true throughout the individual’s entire life, as symptoms may not develop until after the first few years of life.  Although rare, clinicians should be aware that to make a definitive diagnosis of CF or CRMS, it may take months with repeat sweat chloride testing and parental genotyping.

CF newborn screening (CFNBS) is a screening tool and not a diagnostic test. Therefore, a positive screen needs to be investigated further to make a definitive diagnosis. The time between a positive screen and sweat testing to confirm a CF diagnosis is stressful for parents and families. Therefore, consider informing parents that a positive screen for CF means the newborn may have CF, but that most do not. Only a small percentage of (approximately 10%) infants with positive CFNBS are eventually diagnosed with CF while the majority are diagnosed as CF carriers. Healthcare providers need to be aware of this stressful time as they assist parents to obtain the appropriate follow up tests without causing alarm.

Despite the universal CF newborn screening, the sweat chloride test is still the gold standard for the diagnosis of CF.  Each infant with positive CF newborn screening should undergo sweat testing. Positive sweat test results (>60 mmol/L) is needed to make a diagnosis of CF.  Currently all states in the US are universally practicing CF newborn screening for the diagnosis of CF. A CF diagnosis can still be made symptomatically; especially in children born in Arkansas before July 2008.

Currently, there is no cure for CF; however, improved medical care specific to CF and aggressive drug treatments along with optimal nutrition can significantly improve the clinical outcome and the quality of life for individuals with CF. The new breakthrough medications CFTR modulators are currently the standard treatment of individuals with CF who carry certain CFTR mutations. Although CF gene therapy has been at the forefront of gene therapy research since cloning of the CFTR in 1989, the lung is a difficult target organ and currently, lung gene therapy product is not available.

An Australian study compared different CFNSB screening strategies and found that IRT and one CFTR mutation analysis (p.F508del) had 89.9% sensitivity and 99.9% specificity. IRT and 12 CFTR mutation analysis had 95.8% sensitivity and 99.9% specificity. Arkansas uses IRT and expanded DNA protocol that includes the most common CFTR mutations.  Therefore the sensitivity of this test is expected to be higher than 95.8%.  Due to high sensitivity of CFNBS, the screening captures mutations with unknown significance resulting in detecting infants with CFTR mutations with an unknown clinical impact and outcome, such as CFTR related metabolic syndrome (CRMS).

It is not possible to accurately predict how long a person who has CF will live. Many different factors, such as severity of disease and age at diagnosis, can affect an individual’s health and the course of the disease.The CF Foundation collects information on the health of people treated at CF Foundation-accredited care centers. According to the most recent data, the median predicted age of survival for people with CF is in the early 40s, and this number has been increasing steadily. Today, approximately half of all individuals with CF in the United States are 18 years or older.  The steady “aging” of the CF population reflects the remarkable progress that has been made in understanding the disease and its treatment.

Most CF newborn screening programs incorporate immunoreactivetrypsinogen (IRT) as a first tier test and a limited DNA panel as a second test. Both tests are performed on a single drop of blood absorbed on a Guthrie filter paper sent to the Arkansas Department of Health. If the IRT results are > or = to 100ng/mL and those results in the top 2% will undergo additional DNA mutation testing. If one or more CF mutations are identified, you will be notified to schedule sweat testing at an accredited CF Care Center to confirm diagnosis or to help differentiate whether the baby is a carrier.  Arkansas Children’s’ is the only accredited CF Center that performs sweat tests in the state.  Primary care physicians should call the UAMS/ACH Newborn Screening Coordinator to schedule an appointment for genetic counseling and a sweat test. If an infant is diagnosed with CF, then referral to an accredited CF Foundation Care Center is strongly recommended.

Although the immune system of children with CF is intact, they tend to get respiratory infections with pathogens specific to CF. Infection control practices have been crucial since the first time it was shown that CF-related deleterious pathogens, especially Burkholderia cepacia and Pseudomonas aeruginosa, can be transmitted horizontally from one patient with CF to another. CF Foundation recommends 6 feet distance between individuals with CF.  People with CF should also avoid people with acute respiratory illness.  When patients with CF are admitted to the hospital, they are contained in a single room with strict contact isolation precaution measures to prevent them from acquiring pathogens from the hospital and personnel as well as spreading pathogens to other patients with CF. When people with CF visit a healthcare facility they should wear a mask.  Healthcare providers should perform contact isolation by wearing gowns and gloves when they enter the person’s exam or hospital room.  Diligent hand washing should be performed by both people with CF and healthcare providers before and after encounters.

Studies have shown that babies who are diagnosed with CF through newborn screening and treated before symptoms appear are healthier. Their nutritional status can be monitored closely and interventions started as soon as necessary. CF newborn screening also has implications for parents as they consider more children.  Parents may choose to be genetically tested for a CF gene mutation even if their child does not have CF. Parents who either have a child with CF or are carriers of a CF mutation should be referred to a genetic counselor familiar with CF.

Children with CF should be followed by a CF care centers accredited by the CF Foundation. CF centers have multidisciplinary teams with specialized training in comprehensive screening and treatment of people with CF.  Arkansas Children’s Hospital has the only CFF accredited pediatric CF care center in the state. UAMS has the only CFF accredited adult CF care center in the state.  The CF Foundation recommends people with CF be followed by the CF center monthly for the first year of life and then quarterly thereafter. During each clinic visit, nutritional and respiratory status are evaluated while lung function tests and respiratory cultures are obtained. Annually, more comprehensive tests are performed including oral glucose tolerance screening, chest imaging, lung volume measurements, fat soluble vitamins measurement, and liver functions assessment

Collaboration between the primary care physician (PCP) and the CF care center is important since these patients may require frequent clinic visits and hospitalization.  Children with CF should be followed up regularly by their PCP and receive routine immunizations. Annual influenza vaccination is recommended for infants >6 months of age as well as for all household members and all healthcare providers caring for these infants. For infants <2 years of age, the CF Foundation recommends that use of palivizumab be considered for prophylaxis of respiratory syncytial virus (RSV). CFF guidelines recommend human milk as the initial type of feeding.For infants <2 years of age, the CF Foundation recommends supplementation with 1/8 teaspoon table salt per day starting at diagnosis, increasing to 1⁄4 teaspoon of table salt per day at 6 months of age. It is important to remember that although salt supplementation is not recommended >2 years of age, appropriate hydration and salt replacement may be required in some patients during hot times of the years and following strenuous exercise. Families should be counselled about second hand smoke exposure.

Newborns with CF are born with healthy lungs. However, lung disease may be present in infants within the first weeks of life.The limited data available suggest that structural lung disease, as seen on chest computed tomography (CT), may be present in children as young as 10 weeks old. Approximately 85% of infants are born with pancreatic insufficiency and will need pancreatic enzyme replacement therapy early in life.

Most families will meet with a genetic counselor to discuss a positive CF newborn screening and subsequent diagnosis immediately following their sweat test at Arkansas Children’s Hospital.  If schedules prohibit this important interaction, then a referral to Arkansas Children’s Hospital Genetics Clinic is strongly recommended.  Genetic counseling is available through Arkansas Children’s Hospital, UAMS Adult Genetics Clinic, and UAMS Reproductive Genetics Clinic.