Updated guidance on the management of children with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID)

Cystic fibrosis is the most prevalent inherited disease caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The impaired electrolyte homeostasis caused by the mutated or absent protein leads to symptoms in multiple organ systems. However, the pulmonary manifestation with chronic infections and eventually respiratory failure remains the most important threat. Until one decade ago, only symptomatic treatment was available. However, since 2012, different combinations of CFTR modulators are available for people with cystic fibrosis (pwCF) that carry different mutations. The advent of these drugs has impressively changed life expectancy and quality of life in people with cystic fibrosis and raised new challenges regarding long-term complications and tapering of conventional therapies.Conclusion: In this review, we provide an update on the latest developments around diagnostics, treatment, and prognosis of pwCF. What is Known:• Cystic fibrosis is an incurable and life-shortening disease asking for life-long symptomatic treatment.• Three combination CFTR modulating drugs has gained marked approval over the last 10 years. What is New:• The emerge of new (modulating) therapies contribute to the increasing life expectancy.• A high unmet need to develop new therapies for people with CF who cannot access or benefit from these drugs remains. This review gives an update on the current status.

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“…The check up at year 6 has been enhanced with the advice to perform a pulmonary function test and chest imaging. [27]…”

Section: Diagnosismentioning

confidence: 99%

A new era for people with cystic fibrosis

et al. 2021

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“…In this context, recent studies also demonstrated the potential usefulness of ICM in the diagnosis of atypical CF and CFTR related disease [ 53 , 54 ]. In the future, with the widespread implementation of CF newborn screening in many countries, ICM may also become a useful tool for the diagnostic workup of CF newborn screening positive infants with inconclusive diagnosis (CF-SPID) to determine disease liability and prognosis [ 52 , 55 , 56 , 57 , 58 ]. Collectively, these studies have established ICM as a sensitive biomarker of CFTR function in the intestinal epithelium.…”

Section: Icm As a Biomarker Of Cftr Function And Diagnostic Test For Cfmentioning

confidence: 99%

Potential of Intestinal Current Measurement for Personalized Treatment of Patients with Cystic Fibrosis

Graeber

Vitzthum

Mall

2021

JPM

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Refinement of personalized treatment of cystic fibrosis (CF) with emerging medicines targeting the CF basic defect will likely benefit from biomarkers sensitive to detect improvement of cystic fibrosis transmembrane conductance regulator (CFTR) function in individual patients. Intestinal current measurement (ICM) is a technique that enables quantitative assessment of CFTR chloride channel function in rectal tissues or other intestinal epithelia. ICM was originally developed to study the CF ion transport defect in the intestine and has been established as a sensitive biomarker of CFTR function and diagnostic test for CF. With the emergence of CFTR-directed therapeutics, ICM has become an important tool to estimate the level of rescue of CFTR function achieved by approved CFTR modulators, both at the level of CFTR genotype groups, as well as individual patients with CF. In combination with preclinical patient-derived cell culture models, ICM may aid the development of targeted therapies for patients with rare CFTR mutations. Here, we review the principles of ICM and examine how this CFTR biomarker may be used to support diagnostic testing and enhance personalized medicine for individual patients with common as well as rare CFTR mutations in the new era of medicines targeting the underlying cause of CF.

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“…While CRMS was not considered to be a metabolic disorder, the CRMS diagnostic label was agreed upon in part because it provided a "clear name to families" that was distinct from CF and allowed "for US healthcare delivery system follow-up and billing purposes" [25,67]. Furthermore, the guidelines published in 2009 indicated the specific International Classification of Disease (ICD) codes that physicians could use in conjunction with the CRMS diagnosis [25,68].…”

Section: Addressing Diagnostic Uncertainty With a New Diagnostic Labelmentioning

confidence: 99%

“…However, by 2015, the European Cystic Fibrosis Society Neonatal Screening Working Group organized a consensus process and came up with the term CF Screen Positive, Inconclusive Diagnosis (CFSPID) to designate infants with an unclear diagnosis following CF NBS [27,74]. Although the CRMS label was considered during discussions, those involved did not favor its use because they felt that the terms metabolic and syndrome were not appropriate descriptors for this group of asymptomatic infants because they did not have a clear disease and because of concerns that the CRMS label might result in the "overmedicalization of these children" [68]. Australian investigators had also expressed concerns about the CRMS label and recommended that it be dropped completely, pointing out that it "may not be so helpful to the parents whose child now has a very elaborately named condition, that might not turn out to be a condition at all" [75].…”

Section: Addressing Diagnostic Uncertainty With a New Diagnostic Labelmentioning

confidence: 99%

“…Shortly after CFSPID was proposed, an international group of investigators collaborated to integrate the CFSPID and CRMS labels to "allow for collection of data from populations around the world and increase our understanding of the epidemiology and outcomes of CRMS/CFSPID" [67]. The collaboration culminated in recommendations for how to characterize and monitor infants with an inconclusive diagnosis following CF NBS [26,67,68,77,78]. As the resulting 2017 consensus guidelines note, "the term CRMS is used in the US for healthcare delivery purposes and CFSPID is used in other countries, but these both describe an inconclusive diagnosis following NBS" [28].…”

Section: Addressing Diagnostic Uncertainty With a New Diagnostic Labelmentioning

confidence: 99%

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Addressing Uncertainty: The Emergence of the CRMS/CFSPID Diagnostic Category Following Newborn Screening for Cystic Fibrosis

LaBonte¹

2021

obm genet

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This article uses cystic fibrosis as a case study to examine how physicians and scientists have navigated uncertainty following newborn screening. Despite the many benefits of newborn screening, including earlier diagnosis, therapeutic intervention, and a reduced diagnostic odyssey, this public health approach also comes with challenges. For example, physicians began to document infants with indeterminate diagnoses - those with a positive screen who did not clearly fit into the cystic fibrosis or “normal” categories - by the early twenty first century. As a means of addressing this uncertainty and to facilitate long-term follow up of such infants, the U.S. Cystic Fibrosis Foundation recommended in 2009 that a new diagnostic term, CFTR-related metabolic syndrome (CRMS), be used. However, the CRMS label was not favored in Europe and a different term, cystic fibrosis screen positive, inconclusive diagnosis (CFSPID), was adopted in 2015 instead. Efforts to address the uncertainty associated with indeterminate diagnoses have been complicated, as stakeholders have held differing views about whether the screening algorithms should aim to maximize or minimize CRMS/CFSPID cases. Many who favor the identification of babies with CRMS/CFSPID note that they are at increased risk of developing symptoms and signs consistent with a cystic fibrosis diagnosis. In contrast, those who support algorithms that reduce CRMS/CFSPID cases point to iatrogenic harms associated with the medicalization of children who may remain healthy into adulthood. Furthermore, investigators have grappled with how best to ensure equity in newborn screening among different racialized groups while concomitantly attempting to minimize false positive results. These issues are applicable beyond the context of cystic fibrosis, especially as programs contemplate the incorporation or expanded use of next generation sequencing in algorithms for a wide range of diseases, and this history highlights how efforts to reduce uncertainty in one setting can lead to new and persistent sources of uncertainty in other areas.

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Updated guidance on the management of children with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID)

Cited by 95 publications

References 48 publications

A new era for people with cystic fibrosis

A new era for people with cystic fibrosis

Potential of Intestinal Current Measurement for Personalized Treatment of Patients with Cystic Fibrosis

Addressing Uncertainty: The Emergence of the CRMS/CFSPID Diagnostic Category Following Newborn Screening for Cystic Fibrosis

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