INTRODUCTION — Cystic fibrosis (CF) is a multisystem disorder caused by pathogenic mutations of the CFTR gene (CF transmembrane conductance regulator). Typical symptoms and signs include persistent pulmonary infection, pancreatic insufficiency, and elevated sweat chloride levels. However, many patients demonstrate mild or atypical symptoms, and clinicians should remain alert to the possibility of CF even when only a few of the usual features are present . Diagnosis of CF is based upon the finding of genetic and/or functional abnormalities of the CFTR gene.
An overview of the clinical manifestations and diagnosis of CF will be presented here. CF-associated lung disease is discussed in the following topic reviews:
The pathophysiology of CF and its manifestations in other organ systems are also discussed separately:
EPIDEMIOLOGY — In the United States, CF occurs in approximately 1:3200 White Americans, 1:10,000 Hispanic Americans, 1:10,500 Native Americans, 1:15,000 Black Americans, and 1:30,000 Asian Americans [2,3]. CF is increasingly recognized worldwide, not only in North America, Europe and Australia (regions most familiar with CF) but also in South and East Asia, Africa, and Latin America, although the known prevalence in these regions is lower [3-7]. Prevalence estimates are likely to rise with increasing recognition of disease in all populations, use of newborn screening, and increasing recognition of individuals with mild disease or disease limited to one organ system.
Cystic fibrosis — The classic or typical form of CF is diagnosed if a patient demonstrates clinical disease in one or more organ systems (as described below) and has elevated sweat chloride (≥60 mmol/L). Most of these patients have disease manifestations in multiple organ systems (upper and lower respiratory tract, pancreas, gastrointestinal tract, and male reproductive tract). (See 'Overview of clinical features' below.)
Approximately 2 percent of patients meet diagnostic criteria for CF but lack one or more of the classic features described above. They may have mild clinical symptoms and/or a normal or intermediate sweat chloride result (table 1). These patients may still be diagnosed with CF if they meet the genetic or functional criteria for the diagnosis, including two copies of a disease-causing mutation in the CF transmembrane conductance regulator (CFTR) gene on each parental allele (ie, in trans) or abnormal nasal potential difference (NPD). These patients are more likely to present later in childhood or adulthood and to have unusual CFTR mutations, which may not be included in the standard CF screening panel . In the past, these phenotypes were called "nonclassic" or "atypical" CF [9,10], but these terms are now discouraged because they are imprecise and refer to a variety of clinical phenotypes . (See 'Molecular diagnosis' below.)
CFTR-related disorder — A CFTR-related disorder is defined as clinical disease limited to only one organ system associated with some evidence of CFTR dysfunction that does not meet full genetic or functional criteria for a CF diagnosis. Clinical manifestations may include isolated obstructive azoospermia, chronic sinusitis, chronic pancreatitis, or pulmonary disease that presents in adulthood. In such patients, testing may identify only one disease-causing mutation in CFTR and intermediate sweat chloride and NPD measurements. These patients should have complete gene sequencing, including evaluation for gene duplications or deletions, to confirm the absence of two disease-causing mutations. If two disease-causing mutations are present, the patient should be diagnosed with CF, rather than CFTR-related disorder.
Individuals in this category should be followed periodically to ensure that new manifestations of disease do not occur and should receive genetic counseling. The estimated prevalence and disease manifestations of individuals with CFTR-related disorder may change in the future, as diagnostic methods for CFTR mutations and dysfunction become more sensitive and are more broadly applied.
Other disease entities are known to be influenced by the CFTR genotype but do not fit the criteria for diagnosing CF or CFTR-related disorder; these depend upon non-CFTR genes and environmental exposures in addition to CFTR dysfunction [10,11]. For example, the incidence of chronic rhinosinusitis, bronchitis, bronchiectasis, and allergic bronchopulmonary aspergillosis is increased among individuals in whom only one CFTR mutation is identified . (See "Pancreatitis associated with genetic risk factors", section on 'CFTR gene' and "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis".)
CRMS/CFSPID — CFTR-related metabolic syndrome (CRMS) is a term that describes infants and children with an equivocal diagnosis following newborn screening for CF and is found in 3 to 4 percent of infants with a positive newborn screen [11,13,14]. The term "CF screen positive, inconclusive diagnosis" (CFSPID) is equivalent and is used in Europe [11,15].
●Intermediate sweat chloride results (30 to 59 mmol/L) on two separate occasions and fewer than two CF-causing mutations
●Normal sweat chloride results (≤29 mmol/L) on two separate occasions and two CFTR mutations, at least one of which is not clearly categorized as CF-causing
Because the natural history of infants with these characteristics is unpredictable, CRMS/CFSPID is a provisional diagnosis and requires follow-up monitoring and testing at a center with CF expertise, including at least one additional sweat chloride test (see 'Interpretation' below) . Some may go on to develop a positive sweat test and clinical characteristics of CF (although the disease is often mild) [17,18], others may develop symptoms of CFTR-related disease including isolated male infertility, and others may remain entirely asymptomatic. Consensus statements for evaluation and management of infants with CRMS have been published in Europe and in the United States [19-21].
The frequency with which CRMS/CFSPID is identified may be affected by the type of neonatal screening employed in a given region and by the demographic diversity of the population . In several studies, CRMS/CFSPID was diagnosed approximately five times less frequently than CF and between 10 and 48 percent were later diagnosed with CF, many within the first year of life [13,22-25]. These individuals had a somewhat milder CF phenotype compared with infants who were diagnosed with CF by newborn screening. Substantially higher rates were reported by a newborn screening program in California, which identified 1012 infants with two CFTR mutations over a six-year period, of which 345 (34 percent) were ultimately diagnosed with CF, 533 (52 percent) were diagnosed with CRMS, and 132 (7.7 percent) were determined to be CF carriers . The high rate of CRMS was partially attributable to routine screening for 40 mutations (as opposed to the more typical 28) and to further evaluation with full gene sequencing in selected cases. In this very diverse population, more than 70 novel genetic variations were observed in the CFTR sequence, along with many other known but uncommon ones. Determining the clinical significance of such sequence variations can be difficult, especially in the absence of obvious symptoms. Therefore, there was inadequate information to classify the patients as having true CF or as carriers of a single mutation, and the CRMS label was used more frequently. This strategy leads to increased early identification of children with true CF but increases the risk of falsely identifying children who will turn out to be carriers or unaffected individuals.
OVERVIEW OF CLINICAL FEATURES — CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) protein, a complex chloride channel and regulatory protein found in all exocrine tissues [27-29]. Deranged transport of chloride and/or other CFTR-affected ions, such as sodium and bicarbonate, leads to thick, viscous secretions in the lungs, pancreas, liver, intestine, and reproductive tract and to increased salt content in sweat gland secretions [1,28]. The typical CF patient develops multisystem disease involving several or all of these organs (table 3). (See "Cystic fibrosis: Genetics and pathogenesis".)
An overview of these clinical features is presented below, and details of the pathogenesis, diagnosis, and management are discussed in the linked topic reviews.
Presentation — In the past, most patients were diagnosed with CF after presenting with symptoms. Because of the expansion of newborn screening programs during the past 20 years, there has been a dramatic increase in the number of CF cases identified before presenting with symptoms. In 2001, fewer than 10 percent of CF cases in the United States were diagnosed on the basis of newborn screening programs . By 2021, 64.4 percent of total new CF diagnoses and 93.8 percent of diagnoses among infants under six months old were detected by newborn screening . There is evidence that individuals diagnosed prior to the onset of symptoms have better lung function, neurocognitive testing scores, and nutritional outcomes later in life and less utilization of health care resources (figure 1) .
Prenatal findings — Some cases of CF present with abnormal findings on routine prenatal ultrasonography, including hyperechogenic bowel. The risk of CF is highest if there is evidence of meconium peritonitis (scattered calcifications are seen throughout the fetal peritoneum), bowel dilatation, or absent gallbladder (see "Fetal echogenic bowel" and "Fetal abdomen: Differential diagnosis of abnormal echogenicity and calcification"). If these findings are present on fetal ultrasonography, we suggest offering the parents prenatal CF carrier screening. (See "Cystic fibrosis: Carrier screening".)
In addition to the specific findings described above, CF may be associated with preterm birth and low birth weight. In a large registry study, the effect of CF on birth weight was estimated to be approximately -200 g; only 40 percent of this effect on birth weight was explained by earlier gestational age . The mechanisms for these effects on fetal growth are not established .
Symptomatic presentation in infants and children — Prior to the implementation of widespread newborn screening in the United States and many other countries, infants and children were typically diagnosed with CF after presenting with one or more of the following symptoms :
●Meconium ileus – 20 percent of patients
●Respiratory symptoms – 45 percent of patients
●Failure to thrive – 28 percent of patients
For infants presenting with meconium ileus, the median age of diagnosis was two weeks. For those presenting with other symptoms, the median age of diagnosis was 14.5 months (interquartile range 4.2 to 65 months). These clinical presentations are still relevant for populations that do not undergo routine newborn screening for CF.
Infants with severe untreated pancreatic insufficiency occasionally present with a syndrome of edema with hypoproteinemia, electrolyte loss, anemia, alopecia, dermatitis, and failure to thrive due to malabsorption and malnutrition, including deficiencies in essential fatty acids, zinc, vitamins, and proteins. (See 'Pancreatic disease' below and 'Electrolyte abnormalities' below.)
Symptomatic presentation in adulthood — Patients presenting with CF later in life are more likely to have atypical symptoms [36-38]. One large retrospective cohort study of more than 1000 patients with CF found that 7 percent were diagnosed at age ≥18 years . Patients diagnosed in adulthood were more likely than children to present with gastrointestinal symptoms, diabetes mellitus, and infertility. In addition, adults presenting with CF were more likely than children to have unusual genetic mutations, normal pancreatic function, and equivocal results on sweat chloride tests.
Respiratory tract involvement — Typical respiratory manifestations of CF include a persistent productive cough, hyperinflation of the lung fields on chest radiograph, and pulmonary function tests that are consistent with obstructive airway disease. The onset of clinical symptoms varies widely due to differences in CFTR genotype and other individual factors, but pulmonary function abnormalities often are detectable even in the absence of symptoms. As an example, in a cohort of infants largely identified by newborn screening, 35 percent had respiratory symptoms (cough, wheezing, or any breathing difficulty); mean pulmonary function scores were abnormal by six weeks of age and declined during the subsequent two years . As the disease progresses, patients develop chronic bronchitis with typical organisms, as discussed below. Repeated infections, with aggregation of inflammatory cells and release of their contents, causes damage to the bronchial walls, with loss of cartilaginous support and muscular tone, eventually leading to bronchiectasis. Disease progression includes acute exacerbations with cough, tachypnea, dyspnea, increased sputum production, malaise, anorexia, and weight loss. These events are associated with acute, transient loss of lung function that improves with treatment but which lead to permanent loss of lung function over time. Digital clubbing is often seen in patients with moderate to advanced disease (figure 2). The clinical manifestations of pulmonary disease in CF are discussed in detail separately. (See "Cystic fibrosis: Clinical manifestations of pulmonary disease".)
Transient infection of the airway with pathogenic bacteria often occurs early in life. Eventually, over years and varying widely among individuals, chronic airway infection with either Staphylococcus aureus or gram-negative bacteria is established, often with radiographic evidence of bronchiectasis. S. aureus and nontypeable Haemophilus influenzae are common pathogens during early childhood, but Pseudomonas aeruginosa is ultimately isolated from the respiratory secretions of most patients (figure 3). S. aureus, and particularly slow growing or "small colony" variants, continues to cause significant morbidity in older children and adults with CF . Other microbes to which CF patients appear susceptible to colonization and infection include Stenotrophomonas maltophilia, Achromobacter xylosoxidans, Burkholderia cepacia complex, nontuberculous mycobacteria (especially Mycobacterium avium complex and Mycobacterium abscessus), and the filamentous fungus Aspergillus fumigatus. This predisposition to P. aeruginosa infection may be in part because of impaired clearance directly induced by a defect in CFTR. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection", section on 'Pathogens'.)
Advances in treatment, including the use of CFTR modulators, have led to dramatic increases in predicted survival for individuals with CF (figure 4). The treatment of CF lung disease is discussed in detail separately. (See "Cystic fibrosis: Overview of the treatment of lung disease" and "Cystic fibrosis: Management of pulmonary exacerbations" and "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection" and "Cystic fibrosis: Treatment with CFTR modulators".)
Sinus and nasopharyngeal disease — The majority of CF patients develop sinus disease . Radiographs reveal panopacification of the paranasal sinuses in 90 to 100 percent of patients older than eight months of age . Nasal polyposis is seen in 10 to 32 percent of patients and is caused by chronic rhinosinusitis [43-45]. Clinical manifestations of nasal/sinus polyps range from an asymptomatic finding on physical examination to mild or severe symptoms including rhinorrhea, nasal congestion, nasal obstruction, postnasal drip, snoring, obstructive sleep apnea, hyponasal speech, epistaxis, hyposmia/anosmia, ageusia, facial pain or headache, pain over the upper teeth, sense of pressure over the forehead and face, double vision, and widening of the nasal pyramid. Sinus disease can present with chronic nasal congestion, headaches, cough caused by chronic postnasal drip, and sleep disturbance. Sinus infections can trigger lower respiratory exacerbation in some patients, although organisms found in the sinuses do not always match those recovered from the lungs [46-49]. The course of sinus disease has changed in the era of treatment with CFTR modulators. Prior to the advent of CFTR modulators, the treatment of sinus disease and nasal polyposis typically was unsatisfying, with patients rarely receiving prolonged relief of symptoms [50-52]. With the initiation of CFTR modulator therapy, many people with CF experience sustained relief from chronic rhinosinusitis and nasal polyposis .
Some individuals with isolated chronic rhinosinusitis have evidence of CFTR dysfunction that does not meet the diagnostic criteria for CF; these patients are said to have CFTR-related disorder (see 'CFTR-related disorder' above). One case-control study of patients with chronic rhinosinusitis found a significantly higher proportion of patients with a single CFTR mutation among those with chronic rhinosinusitis than in the general population (7 versus 2 percent) . Evaluation of a child with rhinosinusitis is discussed in a separate topic review. (See "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis".)
Pancreatic disease — CF is associated with several different types of pancreatic disease:
●Pancreatic insufficiency – Insufficiency of the exocrine pancreas is present from birth in approximately two-thirds of patients with CF. An additional 20 to 25 percent develop pancreatic insufficiency during the first several years of life, so that most patients have fat malabsorption by one year of age . Pancreatic disease tends to be progressive; many of the patients with apparently normal or marginal pancreatic function at birth will develop overt evidence of pancreatic insufficiency in childhood or adulthood. Clinically significant pancreatic insufficiency eventually develops in approximately 85 percent of individuals with CF . The remaining 10 to 15 percent of patients with CF remain pancreatic sufficient throughout childhood and early adulthood; these individuals are at risk for pancreatitis.
Common symptoms and signs of pancreatic insufficiency include steatorrhea, characterized by frequent, bulky, foul-smelling stools that may be oily, and failure to thrive or poor weight gain due to malabsorption of fat and protein. In a patient with a clear diagnosis of CF, the diagnosis of pancreatic insufficiency usually can be established based upon these clinical symptoms, a clinical response to pancreatic enzyme replacement therapy, and/or laboratory testing (eg, fecal elastase). Infants with severe untreated pancreatic insufficiency occasionally present with a syndrome of edema, hypoproteinemia, electrolyte loss, and anemia, due to malabsorption of macro- and micronutrients. Such patients also may present with symptoms caused by deficiencies of the fat-soluble vitamins A, D, E, and K. Vitamin K deficiency can present as a coagulopathy and vitamin D deficiency with rickets. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency" and "Cystic fibrosis: Nutritional issues".)
●Pancreatitis – The defective ductular and acinar pancreatic secretion causes progressive pancreatic damage. This can lead to acute or recurrent pancreatitis. Pancreatitis develops in approximately 10 percent of CF patients with pancreatic sufficiency but is rare among those with symptomatic pancreatic insufficiency . (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Pancreatitis'.)
●CF-related diabetes (CFRD) – Patients with exocrine pancreatic insufficiency often develop dysfunction of the endocrine pancreas, leading to glucose intolerance and CFRD. Approximately 25 percent of patients develop CFRD by 20 years of age, and up to 50 percent of adults with CF have CFRD . (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Cystic fibrosis-related diabetes'.)
Meconium ileus and distal ileal obstruction — Meconium ileus is characterized by obstruction of the bowel by meconium in a newborn infant. It is the presenting problem in 10 to 20 percent of newborns with CF . Conversely, 80 to 90 percent of infants with meconium ileus have CF, although premature infants may be more likely to have meconium ileus without CF [59,60]. Meconium ileus can occur in patients with a variety of CFTR mutations. A high familial recurrence rate suggests that other genetic modifiers predispose to the development of meconium ileus [61,62]. In approximately 40 percent of cases, there is associated perforation or jejunal or ileal atresia. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Meconium ileus'.)
Episodes of small bowel obstruction may also occur in children and adults. These are known as distal intestinal obstructive syndrome (DIOS) and should be considered in any CF patient presenting with abdominal pain. DIOS occurs in approximately 15 percent of adult patients with CF and is more common in patients with severe CFTR genotypes and advanced lung disease. Pancreatic insufficiency is present in many, but not all, patients with DIOS. When identified early, DIOS can usually be controlled medically. Surgical intervention is sometimes required to alleviate severe obstruction and may be complicated by recurrent symptoms caused by adhesions. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Distal intestinal obstruction syndrome'.)
Rectal prolapse — Rectal prolapse now occurs rarely in children with CF [63,64]. It appears to be related to constipation and/or malnutrition and is more likely if effective pancreatic enzyme therapy has not been established. In the past, rectal prolapse was much more common, occurring in up to 20 percent of individuals with classic CF, presumably because of later diagnosis and possibly suboptimal treatment with pancreatic enzyme therapy as compared with more current practice. (See "Rectal prolapse in children", section on 'Cystic fibrosis' and "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Rectal prolapse'.)
Hepatobiliary disease — Focal biliary cirrhosis caused by inspissated bile is present in many patients and may cause elevations of serum alkaline phosphatase and lobular hepatomegaly. Asymptomatic liver disease is a common finding at autopsy. In a minority of patients, the liver disease is progressive, with periportal fibrosis, cirrhosis, symptomatic portal hypertension, splenic sequestration, and variceal bleeding. CF is the third leading cause for liver transplantation in late childhood. (See "Cystic fibrosis: Hepatobiliary disease".)
Cholelithiasis has been reported in up to 12 percent of patients, which may result from excessive loss of bile acids in the stool with consequent production of lithogenic bile . If symptoms develop, they typically include right upper quadrant or epigastric discomfort, sometimes with nausea or vomiting. If the biliary stones migrate into and obstruct the bile duct (choledocholithiasis), laboratory abnormalities typically include elevated serum bilirubin, alkaline phosphatase, and aminotransferases. Asymptomatic cholelithiasis generally does not require treatment, although prophylactic cholecystectomy is performed in such patients prior to lung transplantation in some centers. (See "Overview of gallstone disease in adults" and "Choledocholithiasis: Clinical manifestations, diagnosis, and management".)
Infertility — More than 95 percent of men with CF are infertile because of defects in sperm transport, although spermatogenesis is not affected [66-68] (see "Causes of male infertility"). Most of these men have incompletely developed Wolffian structures, most commonly, absent vas deferens. These anomalies probably reflect a critical role for CFTR in the organogenesis of these structures. Nearly one-half of all men with congenital bilateral absence of the vas deferens and normal lung function have two CFTR mutations .
Females with CF are found to be less fertile than normal healthy women. The reduced fertility is induced primarily by malnutrition and the production of abnormally tenacious cervical mucus. Nonetheless, the assumption should always be that females with CF may become pregnant, and patients should be counseled accordingly about contraception and childbearing decisions [71,72]. When patients with CF become pregnant, maternal and fetal outcomes are generally favorable if the prepregnancy forced expiratory volume in one second (FEV1) exceeds 50 to 60 percent of the predicted value [73-76].
Treatment with CFTR modulator therapy appears to increase fertility rates [77,78]. As an example, pregnancy rates among women with the G551 mutation living in the United Kingdom increased by 50 percent after introduction of ivacaftor treatment in the United Kingdom . In addition, the number of pregnancies reported annually to the Cystic Fibrosis Foundation patient registry increased from 310 in 2019 to 675 in 2021, likely due to increased fertility associated with taking elexacaftor-tezacaftor-ivacaftor [31,78]. CFTR modulators are known to cross the placenta and to enter breast milk . The effects of CFTR modulators during pregnancy and lactation are discussed separately. (See "Cystic fibrosis: Treatment with CFTR modulators", section on 'Pregnancy and lactation'.)
Careful genetic counseling is essential for prospective parents with CF since all offspring of such individuals will be carriers of CF mutations and the risk of children affected with CF is high.
Musculoskeletal disorders — Patients with CF have reduced bone mineral content (osteopenia and osteoporosis) and increased rates of fractures and kyphoscoliosis. Clinically significant reductions in bone density are present in up to 30 percent of patients with CF across all age groups and up to 75 percent of adults with CF [80,81]. Several different mechanisms appear to contribute to the bone disease, including malabsorption of vitamin D, poor nutritional status, physical inactivity, glucocorticoid therapy, and delayed pubertal maturation or hypogonadism . Limited evidence suggests that patients homozygous for the F508del mutation are at particularly high risk of decreased bone mineral density . The pathogenesis, assessment, and prevention of bone disease in patients with CF are discussed separately. (See "Cystic fibrosis: Nutritional issues", section on 'Bone disease'.)
Hypertrophic osteoarthropathy is a syndrome characterized by abnormal proliferation of the skin and osseous tissue at the distal parts of the extremities, occurring in association with radiographically confirmed periosteal new bone formation. Clubbing of the digits and hypertrophic osteoarthropathy appear to be different manifestations of the same disease process (figure 2). Although clubbed fingers and toes are common in patients with longstanding CF, hypertrophic osteoarthropathy is uncommon (5 percent of patients) . (See "Malignancy and rheumatic disorders", section on 'Hypertrophic osteoarthropathy'.)
A CF-associated arthropathy occurs in 2 to 9 percent of patients and is characterized by brief episodes of pain and swelling of joints . These features are occasionally accompanied by painful nodular skin lesions and purpura.
Recurrent venous thrombosis — CF appears to be a risk factor for recurrent venous thrombosis, probably in part due to the frequent need for a central venous catheter (CVC) [85,86]. In a review of 120 children and young adults with acute venous thromboembolism, recurrent thrombosis occurred in 19. Among these, six had CF (compared with none of the patients without recurrence) and five of the six were infected with Burkholderia species (or B. cepacia complex) . Most, but not all, of the recurrent thrombotic events occurred in the presence of a CVC. Thus, the risk may be more related to the presence of the catheter than to the presence of CF, but clinicians should be aware of the association in their patients who have CVCs in place. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome".)
Anemia — Patients with CF are at risk for anemia, which is present in approximately 10 percent of children and is more common with advancing age and declining pulmonary function . Anemia is occasionally the presenting sign in an infant . Mechanisms for the anemia include:
●Deficiency of iron, caused by dysregulation of iron metabolism. In children, this does not seem to be related to poor nutritional status, and the mechanism by which iron deficiency occurs remains unclear .
●Anemia of chronic inflammation (also known as anemia of chronic disease), due to chronic and acute pulmonary disease.
●Iron deficiency due to blood loss, as in patients with hemoptysis or esophageal or gastric varices.
●Other contributors in some cases include renal failure, or bone marrow suppression in patients after transplantation.
Determining the cause or causes of anemia in an individual patient may be challenging. In patients with pulmonary inflammation, serum ferritin may be falsely normal or elevated. Chronic hypoxemia is a physiologic trigger for hemoglobin synthesis. Thus, patients with chronic hypoxemia and a normal hemoglobin may be considered to have a "relative" anemia, reflecting underlying iron deficiency or other impairment of hemoglobin synthesis .
Electrolyte abnormalities — Occasionally, individuals with CF may develop subacute or chronic hypovolemia with hyponatremia, hypochloremia, hypokalemia, and metabolic alkalosis (sometimes known as pseudo-Bartter syndrome) . In contrast with Bartter syndrome, urinary chloride excretion is low. (See "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations".)
This condition is caused by excessive loss of sodium and chloride in sweat and may develop in CF patients with inadequate sodium intake. Infants are particularly at risk because the salt content of breast milk or infant formula may be insufficient, and sodium supplementation is required. Occasionally, this is a primary presenting feature of CF . The condition may also develop in older children or adults under heat stress . Guidance for sodium supplementation is described separately. (See "Cystic fibrosis: Nutritional issues", section on 'Sodium'.)
Nephrolithiasis and nephrocalcinosis — Nephrolithiasis and nephrocalcinosis are common in patients with CF [94-96]. The reported prevalence of microscopic nephrocalcinosis ranges from 27 to 92 percent [96,97], and 3 and 6 percent of individuals with CF develop nephrolithiasis, compared with 1 to 2 percent of age-matched controls without CF . Enteric hyperoxaluria (due to fat malabsorption resulting from decreased secretion of pancreatic enzymes) and hypocitraturia (due to chronic metabolic acidosis) are putative risk factors . (See "Kidney stones in children: Epidemiology and risk factors", section on 'Hypocitraturia' and "Kidney stones in adults: Epidemiology and risk factors", section on 'High urine oxalate'.)
Aquagenic wrinkling — Aquagenic wrinkling of the palms (wrinkling and nodules that develop after several minutes of immersion in water (picture 1)) is associated with CFTR mutations . In one study, aquagenic wrinkling occurred after three minutes of submersion in 68 percent of children with CF, compared with 8 percent of heterozygotes (CFTR mutation carriers) and 0 percent of controls . After seven minutes of immersion, all of the children with CF had wrinkling and many had papules (94 percent), edema (56 percent), pruritus (14 percent), and pain (3 percent). Thus, aquagenic wrinkling may be sufficiently sensitive to serve as a screening tool for CF in low-resource settings.
NEWBORN SCREENING — Newborn screening for CF is now performed routinely in all 50 of the United States. Generally, screening is based on a combination of the biochemical marker and genetic assays described below. The exact sequence of screening studies varies from state to state, and clinicians who care for newborns should become familiar with the specific screening parameters in their area.
Rationale — The rationale for newborn screening is that early detection of CF may lead to earlier intervention and improved outcomes because affected individuals are diagnosed, referred, and treated earlier in life as compared with individuals who are diagnosed after presenting with symptomatic CF.
As examples, a meta-analysis of randomized trials examining newborn screening in Europe and Australia demonstrated a 5 to 10 percent reduction in mortality by 10 years of age in children with CF without meconium ileus . Similarly, several observational studies have shown that children with CF detected via screening demonstrate better lung function and improved growth parameters and require less intensive treatment than children diagnosed with CF on clinical grounds [102-108]. Early nutritional intervention appears to improve neurocognitive outcome in infants and young children diagnosed with CF through newborn screening [104,109-112]. Finally, screening programs also may be cost effective because of improved clinical outcomes .
In addition to allowing early identification and treatment of individuals with CF, neonatal screening identifies a population for studying the mechanism of early (preclinical) lung injury. In the future, the effectiveness of novel therapies to delay or prevent the onset of lung disease could be assessed in these patients with preclinical disease.
Concerns were initially raised that newborn screening might be associated with earlier acquisition of P. aeruginosa because of earlier exposure to other CF patients within the medical system . However, several subsequent studies showed that newborn screening is not a risk factor [115-117].
Techniques — Newborn screening typically employs two serial assays; infants with abnormal results for the first assay are retested with a second assay. The two assays used for newborn screening are serum immunoreactive trypsinogen (IRT) and deoxyribonucleic acid (DNA) analysis for mutations in the CF transmembrane conductance regulator (CFTR) gene. IRT is used as the initial screening test in many protocols and is followed by a second IRT test on a different sample from the infant (IRT/IRT protocol) or a DNA test on the initial sample (IRT/DNA protocol). An IRT/IRT screening protocol has somewhat lower costs but more delayed or missed diagnoses as compared with an IRT/DNA screening protocol .
●IRT assay – IRT is a precursor to trypsin. In infants with CF and pancreatic dysfunction, release of pancreatic enzymes is impaired and IRT is not readily removed from the blood stream for conversion to its active form. Therefore, most infants with CF (regardless of whether they are pancreatic insufficient or pancreatic sufficient) have elevated blood levels of IRT, which can be quantified by radioimmunoassay or by an enzyme-linked immunoassay [119-121]. IRT levels fall rapidly during infancy. After eight weeks of age, a negative result is not informative, although a positive result still strongly supports a diagnosis of CF [120,121]. The initial IRT test is approximately 80 percent sensitive for detecting CF using typical cutoff values, and additional patients are not diagnosed through the IRT/IRT protocol if a second sample is not returned for testing. In addition, the rates of false-positive and false-negative results are relatively high in many series [121-123]. The test is primarily used for neonatal screening but also may be useful for small or malnourished infants, in whom the sweat chloride test cannot be successfully performed.
●DNA assay – DNA analysis for mutations in the CF gene is used for newborn screening in most of the United States. This may be used as a secondary screen to confirm the diagnosis in patients with abnormal initial IRT assays (IRT/DNA protocol) or it may be used as a primary method of screening. Many IRT/DNA protocols use a floating IRT cutoff that improves sensitivity to as high as 96 percent . The DNA assays use panels to test for the most common CFTR mutations in the local population. The programs test for between 23 and 40 mutations, and some programs even perform adjunctive full gene sequencing. Screening for a greater number of mutations increases the likelihood of identifying infants with CF but also increases the identification of rare or unique sequence mutations, making interpretation of the result more complicated . Infants with one or more mutations are referred for sweat testing, which further helps to identify children with true CF. The remainder may be diagnosed as carriers or given the provisional diagnosis of CFTR-related metabolic syndrome (CRMS).
Infants with positive CF newborn screening results should undergo sweat chloride testing to determine whether they have CF . For optimal accuracy, sweat testing should be performed when the infant is at least two weeks of age and weighs >2 kg, using laboratory techniques stipulated by the Cystic Fibrosis Foundation. (See 'Sweat chloride' below.)
Since newborn screens became mandatory in all 50 United States, individuals with CF are increasingly identified before they become symptomatic. It is important to recognize that some cases of CF will be missed by the newborn screen, with the rate varying depending on the methods used. This is a particular concern in patients who have positive IRT on initial screen but negative secondary genetic screens. Since only a limited number of mutations are evaluated on the genetic screens, it is possible to miss the diagnosis. Indeed, genetic screens are more likely to miss the diagnosis in Black, Asian, or Hispanic infants (detects 42 to 93 percent of affected infants) compared with White infants (detects 88 to 97 percent) because of differences in the pathogenic variants that cause CF within these groups; this is a source of health care disparity . Thus, it is important to follow such children closely through the first year of life, with particular attention to weight gain and recurrent respiratory infections. Clinicians should consider CF in individuals with suggestive symptoms, even when results of the newborn screen are negative or equivocal.
Regional variation in screening — National programs for newborn screening with various combinations of IRT and DNA testing are in place in Australia, New Zealand, Northern Ireland, Wales, Scotland, France, and England [121,126-129]. Updated information about the screening programs in the United Kingdom is available online.
In the United States, the Centers for Disease Control and Prevention concluded in 2004 that CF screening programs were justified on the basis of moderate benefit and low risk of harm but noted that the decision to implement these programs was dependent upon the resources and priorities of individual states [130,131]. Statewide testing programs are in place in all states in the United States. An updated list of state screening programs and the years in which each was first implemented is available on the Cystic Fibrosis Foundation website (figure 1) [121,130-132]. The technique employed, and therefore the specificity of the screen, varies among states.
DIAGNOSIS — The diagnosis of CF is based upon compatible clinical findings with biochemical or genetic confirmation (algorithm 1) [36,133,134]. The sweat chloride test is the mainstay of laboratory confirmation, although tests for specific mutations, nasal potential difference (NPD), immunoreactive trypsinogen (IRT), stool fecal fat, or pancreatic enzyme secretion may also be useful in some cases.
●Clinical symptoms consistent with CF in at least one organ system, or positive newborn screen or having a sibling with CF
●Evidence of CF transmembrane conductance regulator (CFTR) dysfunction (any of the following):
•Elevated sweat chloride ≥60 mmol/L
•Presence of two disease-causing mutations in the CFTR gene, one from each parental allele
The accuracy of sweat chloride and NPD measurements are operator-dependent, so it is critical that testing be performed in experienced centers, following standard guidelines (see 'Technique' below). Interpretation of intermediate results of sweat chloride levels is discussed below; patients with intermediate results will require repeat sweat testing on a separate occasion. (See 'Interpretation' below.)
Laboratory testing — Evidence of CFTR dysfunction can be provided by sweat chloride testing, molecular testing for CFTR gene mutations, or measurements of NPD. In most cases, sweat chloride testing is the first and most important test. DNA testing is used for confirmation or for further investigation of patients with intermediate sweat chloride results and for prognostic and epidemiologic purposes in individuals with positive results of sweat chloride testing. The diagnostic approach is outlined in the algorithm (algorithm 1).
Sweat chloride — The sweat chloride test remains the primary test for the diagnosis of CF; sweat testing is performed by the collection of sweat with pilocarpine iontophoresis and by chemical determination of the chloride concentration .
Indications — Patients with the following characteristics should undergo sweat testing to clarify a diagnosis of CF:
●Infants with positive CF newborn screening results (perform after two weeks of age and >2 kg if asymptomatic)
●Infants with symptoms suggestive of CF (eg, meconium ileus)
●Older children and adults with symptoms suggestive of CF (eg, male infertility, chronic respiratory infections, or chronic sinusitis)
●Siblings of a patient with confirmed CF, if the diagnosis cannot be established based on genetic testing
Infants with positive CF newborn screening results should undergo sweat chloride testing to determine whether they have CF . For optimal accuracy, sweat testing should be performed when the infant is at least two weeks of age and weighs >2 kg. In symptomatic newborns (eg, those presenting with meconium ileus), sweat testing may be performed as early as the second day of life if adequate quantities of sweat can be collected, but the results are more likely to be inconclusive at this age.
●Normal – Sweat chloride ≤29 mmol/L is normal. This result is sufficient to rule out CF in most individuals.
Nonetheless, in patients with symptoms strongly suggesting CF, repeating sweat chloride and/or DNA testing may be warranted (algorithm 1). This is because a normal sweat chloride concentration is observed in approximately 1 percent of patients with CF, who have unusual genotypes such as the 3849 + 10kb C-T or poly-T defects .
Occasionally, infants with two disease-causing CFTR gene mutations on the newborn screen have normal sweat chloride results . In this case, the first step is to repeat the genetic testing by CFTR sequencing to ensure accuracy of the screening result. The next step is to perform DNA analysis of both parents. If both mutations were inherited from the same parent, the infant does not have CF.
●Intermediate – Sweat chloride 30 to 59 mmol/L is intermediate. This result suggests possible CF and calls for further evaluation by repeating sweat chloride testing and also CFTR sequencing (algorithm 1) . Approximately 20 percent of children with intermediate sweat chloride results will have DNA evidence of CF on expanded analysis . (See 'Molecular diagnosis' below.)
For asymptomatic infants with intermediate results, the sweat chloride test should be repeated at one to two months of age and then at 6- to 12-month intervals until the diagnosis is clear. In symptomatic infants or children, or for infants who were younger than two weeks old when first tested, it may be appropriate to repeat the sweat chloride test sooner.
The wide intermediate range is particularly important for newborns and young infants because sweat chloride concentrations in healthy newborns gradually decrease during the first weeks of life  and then rise slightly throughout childhood. Median sweat chloride concentrations in a healthy population rise from 13 mmol/L in mid-childhood to 23 mmol/L in young adults . In the past, United States guidelines used a different threshold (<39 mmol/L) for the upper limit of normal sweat chloride results for individuals >6 months of age. However, the wider range is now applied to all age groups because a definitive diagnosis of CF is sometimes appropriate in individuals with sweat chloride values in the 30 to 39 mmol/L range [11,140].
●Abnormal – Sweat chloride ≥60 mmol/L is abnormal. If confirmed on a second occasion, this is sufficient to confirm the diagnosis of CF in patients with clinical symptoms of CF. Clinical symptoms are not required for infants who were identified by newborn screening.
This value distinguishes most patients with CF from those with other forms of chronic pulmonary disease [141,142]. Despite the slight variations in sweat chloride concentrations with age that are described above, the cutoff of ≥60 mmol/L is highly specific for diagnosing CF in all age groups. A variety of other clinical conditions may be associated with elevated sweat chloride levels, but these typically are not readily confused with CF (table 5). Very rarely, apparently healthy individuals have sweat chloride values ≥60 mmol/L . Therefore, positive results of sweat testing should be further evaluated by CFTR sequencing and repeat sweat chloride testing (algorithm 1) . The possibility of non-CF conditions that can be associated with elevated sweat chloride should also be considered (table 5). Determining the CFTR genotype is important because the results may affect treatment choices as well as confirm the diagnosis. Emerging treatment strategies target specific CFTR mutations, using CFTR modulators. (See 'Molecular diagnosis' below and "Cystic fibrosis: Treatment with CFTR modulators", section on 'Introduction'.)
Asymptomatic infants with equivocal results of the diagnostic process (sweat chloride test and DNA analysis) are given a provisional diagnosis of CFTR-related metabolic syndrome (CRMS)/CF screen positive, inconclusive diagnosis (CFSPID). This is because the sweat chloride results and symptoms may change with age and because the clinical consequences of some CFTR gene variants are unclear. These infants should be referred for more complete evaluation and follow-up, including at least one repeat sweat chloride test at an accredited CF center, clinical evaluation by an experienced CF clinician, and possibly extended genetic testing or functional analysis (eg, NPD measurements) . Consensus statements describing the evaluation and management of these patients have been published [19,20]. (See 'CRMS/CFSPID' above.)
Both false-negative and false-positive results occasionally occur. (See 'Technique' below.)
Among older individuals, a few will also fail to have a clear diagnosis despite this evaluation. In this case, further clinical assessment performed at a specialized CF center contributes to a provisional diagnosis (algorithm 1). (See 'Other tests' below.)
Technique — Sweat testing is performed by the collection of sweat with pilocarpine iontophoresis and by chemical determination of the chloride concentration . The test is performed by applying pilocarpine to the skin to encourage sweat formation. A small collection system is applied at the same spot to the surface of the skin, and the whole is covered in plastic wrap to promote sweating and allow collection of the sweat. Samples should be collected and tested in duplicate, if possible, for quality assurance . A sufficient amount of fluid is usually obtained within approximately an hour. The test is painless but difficult to perform properly.
The sweat chloride test must be carried out meticulously and should be obtained by a laboratory that performs the assay regularly. Guidelines for diagnostic sweat testing are published by the Cystic Fibrosis Foundation, and adherence to these guidelines is required for accreditation as a CF center .
Improper technique can cause factitious elevation or depression in the sweat chloride level. Collection of insufficient quantities of sweat is a common problem, particularly in young infants; at least 75 mg of sweat (or 15 microliters using a Macroduct system) must be collected within a 30-minute period for the test to be valid. Hypoproteinemic edema and concurrent administration of steroids can decrease the sweat chloride concentration (false-negative test result) , while topiramate can increase sweat chloride (false-positive test result) .
Molecular diagnosis — Molecular diagnosis is a standard part of newborn screening in all of the United States, although the specific form and timing of analysis varies. If two CF-causing mutations are detected and the sweat test is intermediate or positive, the diagnosis of CF is confirmed. If two CF-causing mutations are not identified, the sweat test should be repeated . If CF cannot be definitively diagnosed or excluded, the infant is given the provisional diagnosis of CRMS (see 'CRMS/CFSPID' above), and further genetic evaluation should be undertaken.
●Genetic screening panels – Screening of newborn infants is typically performed with panels of CFTR gene mutations. The mutations included in the panel vary among states, depending on the ethnic diversity of their populations. Most states screen for at least 23 of the most common mutations, using a panel developed for population screening by the American College of Medical Genetics (ACMG) (table 6) . The ACMG panel identifies approximately 90 percent of CF-causing mutations in the general population (and 97 percent of mutations in families of Ashkenazi Jewish ancestry) . However, the panel may be less sensitive for other ethnic groups that have genetic diversity and a wider range of CF-causing mutations; in one study, it detected only 68.5 percent of CF-causing mutations in a Hispanic population . Several state screening programs have therefore expanded or modified the ACMG panel to suit multiethnic populations. For example, in the state of California, a panel of 40 mutations is employed to include CFTR gene mutations found to be more prevalent in non-European ethnicities .
●Gene sequencing – CFTR sequencing should be performed in individuals with any uncertainty in the diagnosis, including (algorithm 1):
•Patients with intermediate sweat chloride results (in addition to repeat sweat chloride testing).
•Patients with confirmed or suspected CF, if the genotype is not yet known. In these patients, the gene sequencing confirms the diagnosis and knowledge of the specific CFTR mutation also has important implications for treatment and prognosis [10,11].
•Patients with normal sweat chloride results if there is a strong clinical suspicion of CF.
CFTR sequencing is not mandatory for infants with positive results of sweat chloride testing if their genotype was definitively determined on the newborn screen. However, gene sequencing may still be considered for these infants to confirm the accuracy of the screening result. CFTR sequencing is readily available in commercial laboratories at a reasonable cost.
●Further molecular testing – If there remains a strong clinical suspicion of CF in the absence of two mutations, more extensive methods should be used to detect CFTR gene mutations. These tests include evaluation for deletions or duplications, using multiplex ligation-dependent probe amplification (MLPA).
●Resources – A list of laboratories that provide genetic testing is available online at the Genetic Testing Registry. The links between genetic and phenotypic information are collected by an international consortium (Clinical and Functional Translation of CFTR), and results are posted on the consortium's website. Information on specific phenotypic aspects of several hundred CFTR mutations has been elucidated to date and is presented in separate searchable formats for clinicians or the general public. The Cystic Fibrosis Mutation Database lists more than 1500 different mutations in the CFTR gene with potential to cause disease. (See "Cystic fibrosis: Genetics and pathogenesis".)
Additional information on genetic testing for carriers can be obtained from the Cystic Fibrosis Foundation. Linkage analysis can be performed for prenatal diagnosis or carrier detection in CF families carrying unidentified mutations . The indications for genetic screening and prenatal testing in the diagnosis of CF are discussed elsewhere (see "Cystic fibrosis: Carrier screening").
Further testing for patients with inconclusive results — Ancillary testing may be useful for selected patients in whom a definitive diagnosis cannot be made based on the combination of clinical criteria, sweat chloride testing, and molecular testing:
Nasal potential difference measurements — For patients with inconclusive results of sweat chloride and DNA testing, measurement of NPD can be used to further evaluate for CFTR dysfunction (algorithm 1) [11,150]. In patients with clinical symptoms, clearly abnormal NPD is sufficient to diagnose CF.
NPD measurements are performed by placing electrodes in the nasal cavity and measuring voltage in the basal state, after nasal perfusion with amiloride to block sodium transport (the major component of NPD) and after nasal perfusion with a chloride-free solution containing a cAMP agonist, such as isoproterenol, to stimulate CFTR-dependent chloride transport [134,151-153]. Patients with CFTR dysfunction have a high potential difference in the basal state, a greater decline than controls following amiloride, and minimal response to low chloride-isoproterenol perfusion (figure 5).
This test is not widely available and should only be performed in experienced centers because standardization of both solution preparation and potential difference measurement is necessary [152,154]. The presence of nasal polyps or inflammation may result in false-negative results. Only a few centers performing this test have adapted the technique for use in infants [124,155]. The degree of abnormality in NPD is not correlated with the severity of CF lung disease .
Other tests — For a few individuals, the diagnosis of CF remains unclear even after repeated sweat chloride testing and expanded DNA analysis. Such patients are not diagnosed with CF, because they do not have two CF-causing mutations on expanded DNA analysis. However, there is an ongoing clinical suspicion of CF either because of intermediate sweat chloride test results on repeated testing or because they have clinical features that are compatible with CF but normal sweat chloride on repeated testing.
For these patients, measurement of NPD provides an additional laboratory measure of CFTR function, as discussed above. In addition, a detailed evaluation should be performed to look for clinical evidence of CFTR-related disease (algorithm 1). The choice of tests depends upon the patient's age and clinical presentation but may include the following:
●Pancreatic exocrine function may be evaluated indirectly by measurement of fecal elastase, which is clinically practical but has limited accuracy . Low levels of fecal elastase suggest pancreatic insufficiency and support a diagnosis of CF. Normal levels of fecal elastase do not exclude the diagnosis, because pancreatic function is sufficient in a substantial fraction of individuals with CF.
Pancreatic exocrine function also can be measured directly by collecting duodenal fluid after stimulation with secretin and cholecystokinin. Decreased levels of pancreatic enzymes provide support for a diagnosis of CF. The technique is time-consuming, technically demanding, costly, and uncomfortable for the patient, so it is rarely performed for patients with CF.
Similar information can be gathered by calculating the percentage of ingested fat in a 72-hour stool collection; the value is elevated in individuals with pancreatic insufficiency. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency", section on 'Diagnosis'.)
●A detailed pulmonary evaluation may include pulmonary function testing (in infants, children and adults), respiratory tract culture for CF-associated pathogens, bronchoalveolar lavage for cytology and microbial cultures, and exclusionary testing for ciliary dyskinesia and immune deficiency . Most of these tests will not be appropriate for evaluation of an infant.
●Evidence of azoospermia (in sexually mature males), bronchiectasis, or recurrent or chronic pancreatitis also provides supportive evidence for a CFTR-related disorder.
●Computed tomography (CT) of the nasal sinuses. The presence of chronic pansinusitis provides support for CF or a CFTR-related disorder.
If this evaluation fails to provide convincing evidence of CF and the sweat chloride results are in the intermediate range, the individuals are at risk for CF and should be monitored periodically for the appearance of symptoms.
DIFFERENTIAL DIAGNOSIS — Symptoms of the following disorders may mimic symptoms of CF:
●Primary immunologic abnormalities, including severe combined immunodeficiency and common variable immunodeficiency, may present with recurrent sinopulmonary infections, similar to CF. (See "Primary humoral immunodeficiencies: An overview" and "Severe combined immunodeficiency (SCID): An overview".)
●Primary ciliary dyskinesia also causes recurrent sinopulmonary infections as well as male infertility. Affected patients are also prone to recurrent otitis media, and 50 percent have situs inversus. (See "Primary ciliary dyskinesia (immotile-cilia syndrome)".)
●Shwachman-Diamond syndrome can cause pancreatic insufficiency but is substantially less common than CF. The disorder is associated with chronic or recurrent hematologic abnormalities. (See "Shwachman-Diamond syndrome".)
●Causes of bronchiectasis in children unrelated to CF are discussed separately. (See "Bronchiectasis in children: Pathophysiology and causes".)
●Alpha-1 antitrypsin deficiency can present with different phenotypes of liver and lung disease, depending on the variant. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency".)
Diagnostic evaluation for these disorders should be considered when the diagnosis of apparent CF cannot be confirmed by laboratory testing.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cystic fibrosis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Cystic fibrosis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Overview of clinical features – Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) protein. Deranged chloride transport leads to thick, viscous secretions in the lungs, pancreas, liver, intestine, and reproductive tract. Most patients develop multisystem disease involving several or all of these organs (table 3). (See 'Overview of clinical features' above.)
•The diagnosis of CF requires clinical symptoms consistent with CF in at least one organ system and evidence of CFTR dysfunction (elevated sweat chloride, presence of two disease-causing mutations in the CFTR gene, or abnormal nasal potential difference [NPD]) (table 1). Clinical symptoms are not required for infants identified through newborn screening or for siblings of patients with CF. (See 'Diagnostic criteria' above.)
•CFTR-related metabolic syndrome (CRMS), also known as CF screen positive, inconclusive diagnosis (CFSPID), is a term that describes asymptomatic infants and children with an equivocal diagnosis following newborn screening for CF (table 2). It is a provisional diagnosis and requires follow-up monitoring and testing. (See 'CRMS/CFSPID' above.)
•Newborn screening – As newborn screening programs become more widespread, individuals with CF are increasingly identified before they become symptomatic (figure 1). It is important to recognize that some cases of CF will be missed by the newborn screen, with the rate varying depending on the methods used. Thus, it is important to consider CF in individuals with suggestive symptoms, even in individuals who have negative results of the newborn screen. (See 'Newborn screening' above.)
•Sweat chloride testing – Sweat chloride testing is the most important diagnostic test and should be performed to clarify a diagnosis of CF in infants with positive CF newborn screening results, in any patient with symptoms suggestive of CF, and in siblings of a patient with confirmed CF (algorithm 1). (See 'Sweat chloride' above.)
-Sweat chloride ≥60 mmol/L is abnormal. This is sufficient to confirm the diagnosis of CF, provided that it is confirmed by a second sweat test or DNA testing.
-Sweat chloride ≤29 mmol/L is normal. This is sufficient to rule out CF for most individuals. Further testing is indicated for patients with symptoms strongly suggesting CF.
-Sweat chloride 30 to 59 mmol/L is intermediate. These patients should have repeat sweat chloride testing and CFTR sequencing. (See 'Interpretation' above.)
•DNA analysis – DNA analysis should be performed for patients with intermediate or positive sweat chloride results and occasionally for those with normal sweat chloride if there is a strong clinical suspicion of CF (algorithm 1). This is usually done by CFTR sequencing. The purpose of this testing is to confirm the diagnosis and also to establish the patient's genotype, which may affect treatment choices. (See 'Molecular diagnosis' above.)
•Further testing – Patients in whom the diagnosis remains uncertain should be further evaluated at a CF center with specialized testing, including measurement of NPD and/or consideration of other diagnoses. (See 'Nasal potential difference measurements' above.)
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