Cystic Fibrosis Diagnosis in Newborns, Children, and Adults

Abstract

The diagnosis of cystic fibrosis (CF) has traditionally relied on the presence of clinical features of the disease. Today, diagnosis through newborn screening (NBS) is becoming the standard of modern CF care. CF NBS programs can identify CF prior to clinical presentation, but for the advantages of an early diagnosis to accrue a scrupulous system must be in place to ensure all steps in the program are performing. As we move rapidly into the era of CF transmembrane conductance regulator (CFTR) protein modulators, the opportunity to start a presymptomatic infant, identified through CF NBS, on these agents offers the prospect of true disease-modifying interventions which could result in a paradigm shift in CF care.Conversely, the introduction of NBS has resulted in many children being asymptomatic at the time of diagnosis. Some screened newborns are classified as “CF Screening Positive, Inconclusive Diagnosis”, or “CFTR-related metabolic syndrome” when the diagnosis can neither be confirmed nor excluded. Appropriate assessment and follow-up should be arranged at specialist centers as a proportion of these infants and adults will eventually be diagnosed with CF.Symptoms and signs are particularly pertinent when considering a diagnosis of CF outside the context of NBS. In older patients with a late diagnosis, the spectrum of clinical presentation can be very variable with vigilant clinicians from multiple specialties suspecting the diagnosis in conditions such as recurrent pulmonary infections, male infertility, pancreatitis, nasal polyposis, and malabsorption.In addition to clinical symptoms or positive NBS results, sweat test and genetic analysis are cornerstones in the diagnosis of CF, but in some cases the diagnosis cannot be confirmed on genetic or sweat testing. Difficult diagnosis may be supported by in vivo or ex vivo electrophysiology measurements on respiratory or intestinal epithelia. This can be done by either measuring transepithelial nasal potential difference or intestinal current measurements.

Impact of Newborn Screening for Cystic Fibrosis on Clinical Outcomes of Pediatric Patients: 10 Years’ Experience in Lodz Voivodship.

“…According to the literature, the most bene ts associated with early identi cation of CF including include better growth and lung function, less intensive therapeutic burden and reduced cost of care. [11][12][13][14] Our observations show that early diagnosis and the introduction of appropriate treatment for asymptomatic CF patients resulted in a lower frequency of the pulmonary exacerbation and lower number of hospitalizations. It is very bene cial observation due to reports which emphasise that the repeated mildto-moderate pulmonary exacerbations especially in the rst years of life result in airway remodelling, while more severe hospitalised episodes could increase structural airway injury risk.…”

“…According to the Neonatal Screening Working Group new-born screening for CF provides an immediate diagnosis, before the onset of clinical symptoms. [11][12][13] In the beginning CF NBS raised doubts about ethical aspects with regard to possible bene ts and risks. After many years of experience CF NBS has been widely implemented and accepted.…”

“…It is very bene cial observation due to reports which emphasise that the repeated mildto-moderate pulmonary exacerbations especially in the rst years of life result in airway remodelling, while more severe hospitalised episodes could increase structural airway injury risk. [13][14][15][16] Data from Australia showed improved survival in future in patients with lower number of hospitalisations in the rst 3 years of life. [17] The occurrence of respiratory exacerbations are associated with an accelerated decline in lung function and reduced quality of life and survival.…”

Proteomics and Metabolomics for Cystic Fibrosis Research

“…The concentration of chloride in the sweat above 60 meq/L is a diagnostic criterium used from the first days of life, to be eventually confirmed by the presence of mutations in the CFTR gene. In addition to this, tests of functionality of the protein may be carried out, such as the measurement of the potential difference at the level of the nasal mucosa (nasal potential difference) [61] or the measurement of the intestinal current after a biopsy [62]. Several studies on different biofluids aim at identifying biomarkers able to come across the limits of normal screening protocols as well as discriminating between a highly heterogeneous genotype of CF cases.…”

The Role of Extended CFTR Gene Sequencing in Newborn Screening for Cystic Fibrosis

“…The definition of CRMS/CFSPID includes infants with a sweat chloride value between 30-59 mmol/L and zero or one CF-causing variant, or a sweat chloride value below 30 mmol/L and two CFTR variants, at least one of which has unclear phenotypic consequences [8,9]. Beyond technical and medical aspects, the choice of a NBS strategy is driven by the mutation spectrum in the screened population, the laboratory facilities, the health care system, the legal and economic aspects, and the acceptability by the population [10][11][12][13]. There is thus no universal model of NBS strategy.…”