cystic fibrosis case study ncbi

Disclaimer » Advertising

• HealthyChildren.org

Recommendations

Genetic testing, communication and psychosocial issues, no consensus, limitations and areas for future research, cystic fibrosis foundation evidence-based guideline for the management of crms/cfspid.

Contributed equally as co-senior authors.

FUNDING: This guideline was supported by the Cystic Fibrosis Foundation. The sponsor assisted with the application of the committee members and resources for weekly and monthly virtual meetings of the committee members.

CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no potential conflicts of interest relevant to this article to disclose.

• Split-Screen
• Article contents
• Figures & tables
• Supplementary Data
• Peer Review
• CME Quiz Close Quiz
• Open the PDF for in another window
• Get Permissions
• Cite Icon Cite
• Search Site

Deanna M. Green , Thomas Lahiri , Karen S. Raraigh , Fadel Ruiz , Jacquelyn Spano , Nicholas Antos , Lynn Bonitz , Lillian Christon , Myrtha Gregoire-Bottex , Jaime E. Hale , Elinor Langfelder-Schwind , Álvaro La Parra Perez , Karen Maguiness , John Massie , Erin McElroy-Barker , Meghan E. McGarry , Angelique Mercier , Anne Munck , Kathryn E. Oliver , Staci Self , Kathryn Singh , Michael Smiley , Steven Snodgrass , Audrey Tluczek , Pamela Tuley , Paula Lomas , Elise Wong , Sarah E. Hempstead , Albert Faro , Clement L. Ren; Cystic Fibrosis Foundation Evidence-Based Guideline for the Management of CRMS/CFSPID. Pediatrics 2024; e2023064657. 10.1542/peds.2023-064657

Download citation file:

• Ris (Zotero)
• Reference Manager

Video Abstract

A multidisciplinary committee developed evidence-based guidelines for the management of cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen-positive, inconclusive diagnosis (CRMS/CFSPID). A total of 24 patient, intervention, comparison, and outcome questions were generated based on surveys sent to people with CRMS/CFSPID and clinicians caring for these individuals, previous recommendations, and expert committee input. Four a priori working groups (genetic testing, monitoring, treatment, and psychosocial/communication issues) were used to provide structure to the committee. A systematic review of the evidence was conducted, and found numerous case series and cohort studies, but no randomized clinical trials. A total of 30 recommendations were graded using the US Preventive Services Task Force methodology. Recommendations that received ≥80% consensus among the entire committee were approved. The resulting recommendations were of moderate to low certainty for the majority of the statements because of the low quality of the evidence. Highlights of the recommendations include thorough evaluation with genetic sequencing, deletion/duplication analysis if <2 disease-causing variants were noted in newborn screening; repeat sweat testing until at least age 8 but limiting further laboratory testing, including microbiology, radiology, and pulmonary function testing; minimal use of medications, which when suggested, should lead to shared decision-making with families; and providing communication with emphasis on social determinants of health and shared decision-making to minimize barriers which may affect processing and understanding of this complex designation. Future research will be needed regarding medication use, antibiotic therapy, and the use of chest imaging for monitoring the development of lung disease.

Cystic fibrosis (CF) newborn screening (NBS) has been offered in many countries around the world and in every US state since 2010. 1 An unintended consequence of CF NBS is the detection of infants with an abnormal CF NBS result but inconclusive diagnostic testing, which has been termed CF transmembrane conductance regulator ( CFTR )-related metabolic syndrome (CRMS) in the United States and CF screen-positive, inconclusive diagnosis (CFSPID) in other parts of the world. 2 Many people with CRMS/CFSPID are healthy, but a small proportion (<10%) will be reclassified as CF because of an updated annotation of their CFTR variants as CF-causing or an increase in sweat chloride concentration (sweat [Cl - ]) to ≥60 mmol/L(2). Approximately 10% will also develop clinical features that are concerning for CF (eg, pulmonary disease, Pseudomonas aeruginosa [ Pa ] in a respiratory culture). 2  

In 2009, the Cystic Fibrosis Foundation (CFF) convened an expert panel to develop consensus recommendations for the management of infants with CRMS. 3 There have been multiple studies of CRMS/CFSPID outcomes and genetics 2 , 4 since then; thus, a diverse committee of CF providers and parents of people with CRMS/CFSPID was assembled in 2021 to develop an up-to-date, evidence-based guideline for the management and care of people with CRMS/CFSPID.

This guideline is intended to be used by both CF specialists and primary care providers (PCPs) who care for people with CRMS/CFSPID and their families. It should supplement the standard care provided in primary care. The guideline will not address how CRMS/CFSPID is diagnosed, nor the criteria for reclassifying people with CRMS/CFSPID as people with CF (pwCF) because these recommendations already exist; 2 , 5 however, it will address genetic testing to better refine the diagnosis. The European Cystic Fibrosis Society (ECFS) recently published a consensus guidance document concerning the management of children with CRMS/CFSPID. 6 The current guideline is evidence-based and is intended to complement the ECFS paper.

CFF intends for this guideline to summarize data and provide reasonable clinical recommendations to clinicians, patients, and other stakeholders. The application of these recommendations should not be mandated. Care decisions regarding individual patients should be made by using a combination of these recommendations, an associated benefit–risk assessment of the treatment options, the patient’s individual and unique circumstances, and the goals and preferences of the patients and families that the team serves as a part of shared decision-making (SDM) between the patient and clinician.

CFF sponsored the creation of the committee. The committee defined people with CRMS/CFSPID as people with an abnormal CF NBS result and (1) a sweat [Cl - ] of <30 mmol/l (normal) and 2 CFTR variants, at least 1 of which with unclear phenotypic consequences, or (2) sweat [Cl - ] of ≥30 to 59 mmol/L (intermediate value) and 1 or no CF-causing variants. 2 An online survey was sent to CF care centers (CFCC) and the families of people with CRMS/CFSPID to identify high-priority issues for both groups. Based on survey results, input from the committee, and areas of further research identified in previous guidelines, 24 questions were written in patient, intervention, comparison, outcome (PICO) format. 7 A systematic review was performed by using PubMed and the Cumulative Index to Nursing and Allied Health Literature databases. Literature review and evidence grading were performed by 4 working groups: genetic testing, monitoring, treatment, and psychosocial and communication issues. The groups generated recommendations that were graded by using the US Preventive Services Task Force (USPSTF) definitions ( Table 1 ). 8 The committee adhered to the USPSTF Procedure Manual 9 in generating and reviewing 31 specific recommendations. Statements that received ≥80% consensus among the committee were approved, resulting in 30 final recommendations ( Table 2 ) and 1 non-consensus statement ( Table 3 ). Details of the committee selection, PICO framework, search terms, and recommendation statements are available in the Supplemental Information and Supplementary Table 5 .

USPSTF Guideline Recommendations 8  

Consensus Recommendation Statements: 30 Statements That Made Consensus

Non-Consensus Recommendation Statement: 1 Statement That Did Not Make Consensus

Additional CFTR Genetic Testing

The CFF recommends that people with CRMS/CFSPID who have <2 disease-causing variants identified by NBS should undergo sequencing of the coding and flanking regions and deletion/duplication (del/dup) analysis of the coding and exon flanking regions of CFTR (Grade B).

Establishing the CFTR genotype of people with CRMS/CFSPID is important for diagnosis, monitoring, and genetic counseling and, should reclassification to CF occur, may also be useful for the approval of CFTR modulators. Genotyping requires a stepwise approach that is dependent on the state’s NBS algorithm. A glossary of genetic terms is available in Supplemental Table 6 . Further genetic analysis is not necessary when 2 CFTR variants identified by NBS are confirmed to be in trans (1 inherited from each parent). However, sequencing of the coding and flanking intronic regions of CFTR, with del/dup analysis to evaluate for large structural variants, such as exon deletions, is useful in the diagnostic workup. 10 It should be performed when people with CRMS/CFSPID have only 1 or no identified disease-causing CFTR variants from NBS.

2. The CFF recommends, for people with CRMS/CFSPID, selectively offering full-gene CFTR sequencing including intronic regions when the CFTR genotype remains incomplete after coding and flanking region sequencing and del/dup (Grade C).

CFTR sequencing that includes all intronic regions has identified putatively causal variants among individuals with CF, CFTR -related disorders, and positive CF NBS results. 18 , – 23 Tests that include many flanking nucleotides and several deep intronic variants are fairly comprehensive; additional testing of all other intronic regions may offer little additional value or sensitivity. Full intronic sequencing should be selectively performed in people with CRMS/CFSPID who demonstrate evidence of potential CFTR dysfunction (eg, sweat [Cl-] of 30–59 mmol/L), or individuals for whom the clinical suspicion of CF development is high and who possess only 1 previously identified causal variant after full sequence and del/dup is provided (see Supplemental Information for further discussion). Availability of full CFTR sequencing is currently limited; this service may become more widely available in the future.

CFTR Testing in Family Members

3. The CFF recommends CFTR genetic evaluation for parents of people with CRMS/CFSPID when phasing the CFTR variants (ie, in cis or trans ) would inform the diagnostic status of the individual by confirming the inheritance pattern (Grade A).

4. The CFF recommends offering CFTR genetic evaluation for siblings of people with CRMS/CFSPID (Grade B).

For people with CRMS/CFSPID who have 2 identified CFTR variants, determining if the variants reside within the same copy (in cis ) or different copies (in trans ) of CFTR is achieved through the genetic testing of at least 1 first-degree relative, which is referred to as “phasing.” CFTR variants in cis can lead to diagnosis of CF carrier instead of CRMS/CFSPID, 21 , 24 which bears health and reproductive implications for the individual and family members.

Evaluating the siblings of people with CRMS/CFSPID can identify at-risk individuals who may also benefit from clinical monitoring and follow-up. 25 , 26 This assessment should be offered to families and promotes SDM with emphasis on the risks and benefits to the individual sibling. 6 In many instances, this may be delayed until childbearing age and at a time the sibling may also share in the decision-making regarding the value of this genetic information.

Genetic Counseling

5. The CFF recommends, for families of people with CRMS/CFSPID, that health care professionals (HCPs) providing genetic counseling should have training or clinical expertise in CF and genetics. A licensed or certified genetic counselor (GC) should be accessible to families of people with CRMS/CFSPID for further support, including discussions regarding future reproductive decision-making (Grade B).

Published recommendations affirm that genetic counseling should be offered to the families of people with CRMS/CFSPID. 6 , 27 , 28 The genetic counseling provider, whether they are a licensed or certified GC or a CF clinician, should have a high level of expertise in both CF genetics and CRMS/CFSPID. 27 Some families feel more comfortable discussing these topics with providers outside the CFCC. 29 , 30 Having access to a trained GC to discuss genetic findings and complement team members in providing psychosocial support promotes understanding 3 , 6 and strengthens long-term retention of genetic knowledge. 31 Genetic counseling at regular intervals throughout the lifespan allows for timely, accurate, supportive, and nondirective information on recurrence risk and reproductive options. 29  

Frequency of Follow-Up

6. The CFF recommends, for people with CRMS/CFSPID, at least annual follow-up by a CF clinician and nurse, with an initial assessment to include a social worker, a mental health coordinator (MHC), and/or a genetic counseling provider. Continued follow-up by a social worker, MHC, and/or genetic counselor should be part of the care of CRMS/CFSPID, depending on the needs of that individual and family (Grade B).

The primary goal of monitoring people with CRMS/CFSPID is to detect those individuals who may be reclassified as CF and would benefit from care at a CFCC. Equally important is avoiding the overmedicalization of otherwise healthy individuals, which involves its own set of adverse consequences. Families should be informed about possible outcomes for people with CRMS/CFSPID and plans for future monitoring visits. Communication with PCPs is essential and should highlight reasons for more frequent reassessment by CFCC (eg, persistent cough, constipation, or inadequate weight gain). Routine follow-up should be provided by clinicians with expertise in CF and CFTR genetics to reexamine CFTR variants (eg, periodic assessment of the CFTR2 database) and changes in clinical status. Because most people with CRMS/CFSPID are healthy, evaluation by an entire multidisciplinary team is often unnecessary.

Sweat Chloride Testing (SCT)

7. The CFF recommends for people with CRMS/CFSPID to repeat SCT at 6 months of life and annually, at least until age 8 years (Grade B).

SCT is the mainstay for diagnosing CF and part of the diagnostic criteria for CRMS/CFSPID. One reason for reclassification of CRMS/CFSPID to CF is a sweat [Cl - ] of >60 mmol/L. The authors of multiple studies have reported sweat [Cl - ] elevation above this level after an initial sweat [Cl - ] of <60 mmol/L during the newborn period. 16 , 30 , 32 , – 39 However, evidence is lacking regarding changes in sweat [Cl - ] after 8 years of age, and SDM with parents should be used to determine if SCT should continue past this age. Careful consideration for continued SCT may be given to certain populations, including (1) individuals with initial sweat [Cl - ] of 40 to 59 mmol/L because they are up to 10 times more likely to have a sweat [Cl-] elevation of >59 mmol/L in later childhood 33 , 40 and (2) individuals with sweat [Cl - ] increasing at a high rate over time (>5 mmol/L per year). 16  

Respiratory Cultures

8. The CFF recommends, for people with CRMS/CFSPID, selectively offering CF respiratory cultures at each visit (at least until age 8 years) and as clinically indicated for respiratory symptoms (Grade C).

Airway infection with CF-associated microorganisms, specifically Pa , is considered a phenotypic feature supporting a CF diagnosis. Compared with the general population, people with CRMS/CFSPID exhibit a higher prevalence of Pa (10.7% to 78.6%), Stenotrophomonas maltophilia (4.9% to 10%), and Staphylococcus aureus (40% to 85%) in respiratory cultures. 30 , 41 , 42 Some studies have revealed that people with CRMS/CFSPID who reclassify to CF more likely have a positive culture result for Pa than those who do not reclassify (33% vs 10%), whereas other reports have revealed no difference. 30 , 35 However, a positive culture result alone does not warrant reclassification. Some families and physicians may not want to expose the individual to trauma associated with cultures. Respiratory culture data from people with CRMS/CFSPID >8 years of age are currently lacking. If persistent respiratory symptoms are present, obtaining respiratory cultures in people with CRMS/CFSPID may be warranted. Thus, the evidence supports that cultures obtained via throat swab or sputum should be selectively offered after SDM with the family.

Laboratory Testing

9. The CFF recommends, for people with CRMS/CFSPID, that measurement of fecal elastase (FE) should be performed at the initial assessment. Further testing of FE can be provided when clinically appropriate (Grade B).

10. The CFF recommends against routine laboratory evaluations, including fat-soluble vitamin testing, liver function testing, glucose monitoring, and blood counts for people with CRMS/CFSPID (Grade D).

Measuring FE at the initial assessment is important to evaluate for exocrine pancreatic function because pancreatic insufficiency is a clinical feature of CF. FE levels can fluctuate in the first year of life; therefore, a single abnormal FE level should be interpreted cautiously, and repeat testing may be warranted 43 if symptoms of steatorrhea or failure to thrive develop. Most people with CRMS/CFSPID exhibit normal growth and nutrition and are pancreatic sufficient; thus, the presence of pancreatic insufficiency would strongly support reclassification to CF. 35 , 44 , 45  

There is no evidence that laboratory results, such as electrolyte concentrations or liver function tests, are abnormal in people with CRMS/CFSPID. 35 Excessive testing leads to overmedicalization and increased cost of care. Therefore, laboratory tests should only be considered when clinically indicated.

Pulmonary Function Testing

11. The CFF recommends against routine pulmonary function testing (PFT; ie, spirometry, multiple-breath washout) for people with CRMS/CFSPID (Grade D).

Spirometry and multiple-breath washout are normal in people with CRMS/CFSPID 4 , 33 , 35 and do not affect reclassification to CF. PFTs should be considered if clinical concern for respiratory disease arises, and if abnormal, may support reclassification to CF.

Radiographic Imaging

12. The CFF recommends against routine chest radiographs for people with CRMS/CFSPID (Grade D).

Chest imaging is normal in people with CRMS/CFSPID within the first years of life 35 and does not inform reclassification to CF. Chest radiographs should be considered if clinical concerns arise.

Infection Prevention and Control

13. The CFF recommends, for people with CRMS/CFSPID, the implementation of standard CF infection prevention and control (IPC) guidelines in health care settings and situations in which there is a high likelihood of being in close contact with multiple pwCF or people with CRMS/CFSPID (Grade B).

The acquisition of Pa may guide reclassification to CF, and there is a risk that exposure to pathogens commonly associated with CF may negatively impact the individual. 46 This risk is most substantial in the health care setting in which close contact could occur among multiple pwCF or people with CRMS/CFSPID. IPC guidelines have been adopted by CF programs with minimal negative impact. 47 The implementation of IPC guidelines in non-health care settings, such as schools, may have significant negative psychological effects that outweigh potential benefits and are not recommended.

Infectious Disease Interventions

14. The CFF recommends, for people with CRMS/CFSPID, selectively offering inhaled antibiotics for the treatment of Pa based on a positive respiratory culture (Grade C).

15. The CFF recommends, for people with CRMS/CFSPID and an unexplained prolonged cough (>2 weeks), selectively offering the use of oral antibiotics (Grade C).

A higher prevalence of Pa is reported in respiratory cultures from people with CRMS/CFSPID compared with those collected from children without CF, 2 , 4 , 41 , 42 and treatment to eradicate incident Pa infection is recommended for pwCF. 48 However, the clinical impact of Pa in respiratory cultures from people with CRMS/CFSPID is unclear. Pa may clear spontaneously, (ie, independent of whether treatment is provided), 49 calling into question the value of Pa eradication therapy. The committee recommends selectively offering this treatment after a SDM process incorporating the potential benefits, risks, and treatment burden of inhaled antibiotic therapy in people with CRMS/CFSPID with positive respiratory culture for Pa . If the decision is to treat, then follow-up cultures are warranted to ensure Pa clearance.

Precedent is established regarding use of oral antibiotics for prolonged cough for individuals with respiratory conditions other than CF, including tracheobronchomalacia, protracted bacterial bronchitis, non-CF bronchiectasis and neuromuscular disease. 50 , – 54 The committee discussed this consideration while weighing the potential benefits and harms of antibiotic therapy. The use of any antibiotic for eradication or treatment may depend on clinical status of the individual, and the risks and benefits of treatment burden should be assessed for each family. For people with CRMS/CFSPID with a cough lasting >2 weeks, other etiologies of persistent cough, such as asthma, should be considered.

Nutritional Interventions

16. The CFF recommends, for people with CRMS/CFSPID with adequate growth, that nutritional management be provided under the direction of the PCP (Grade B).

17. The CFF recommends, for people with CRMS/CFSPID with a downward trajectory of weight-for-age percentile or z-score (eg, crossing percentiles), that screening and evaluation be provided by a dietitian with experience in the management of CRMS/CFSPID and CF (Grade B).

18. The CFF recommends against salt supplementation for people with CRMS/CFSPID (Grade D).

19. The CFF recommends against the use of fat-soluble vitamins for people with CRMS/CFSPID (Grade D).

No evidence exists to support the use of supplemental nutrition, caloric modifications, or CF-specific diets for people with CRMS/CFSPID who are exhibiting normal growth. 55 A downward growth trajectory, as measured by weight-for-age percentile or weight z-score, may be a sign of reclassification to CF. Children who demonstrate this pattern should undergo nutritional screening and appropriate intervention by dietitians with experience in CRMS/CFSPID and CF. Given that people with CRMS/CFSPID have intermediate or normal sweat [Cl - ], excessive salt loss is not expected, and potentially harmful consequences could be conferred by a high-salt diet. 56 , 57 No evidence suggests the need for supplementing fat-soluble vitamins to people with CRMS/CFSPID 35 because deficits in these vitamins have not been observed, and routine laboratory tests are not being monitored.

Pulmonary Interventions

20. The CFF recommends against the routine use of airway clearance therapy (ACT) for people with CRMS/CFSPID (Grade D).

21. The CFF recommends for people with CRMS/CFSPID experiencing new respiratory symptoms selectively offering the use of ACT (Grade C).

22. The CRMS/CFSPID guideline committee recommends against the use of CFTR modulators for people with CRMS/CFSPID (Grade D).

23. The CFF has determined that there is insufficient evidence to recommend for or against the use of medications usually used to treat CF respiratory symptoms for people with CRMS/CFSPID (Grade I).

Routine ACT and its effects on outcomes, such as bronchiectasis, are unclear for people with CRMS/CFSPID; hence, daily use is not recommended. ACT has been recommended for the management of acute respiratory symptoms for pediatric patients with other pulmonary conditions 58 , 59 ; thus, for people with CRMS/CFSPID and new respiratory symptoms, ACT may be considered. Initiation should be discussed with the family because ACT may add a significant burden. The use of cost-effective methods (such as manual percussion) should be attempted.

No studies have been reported in which the authors investigated the outcomes of CFTR modulator therapies among people with CRMS/CFSPID, and potential adverse effects are associated with these medications. 60 , – 62 If people with CRMS/CFSPID develop signs and symptoms warranting the use of CFTR modulators, reclassification to CF may be justified.

Medications that are commonly used for CF lung disease, 63 , 64 (ie, dornase alfa, hypertonic saline, and low-dose azithromycin) have not been evaluated in people with CRMS/CFSPID. The potential benefits of these medications for people with CRMS/CFSPID are unclear because the degree of CFTR dysfunction in CRMS/CFSPID may not necessarily result in significant changes in airway surface liquid. Weighed against the risks of medical complexity, treatment burden, and cost, there is insufficient evidence to either recommend for or against use of these medications. For people with CRMS/CFSPID with chronic respiratory symptoms that would require consideration of therapy, the reassessment of CF is warranted.

Communication With Families

24. The CFF recommends, for people with CRMS/CFSPID, that HCPs assess and consider social determinants of health (SDOH) that can influence the understanding and psychological impact of a CRMS/CFSPID diagnosis and tailor communications appropriately (Grade B).

25. The CFF recommends, for people with CRMS/CFSPID, that HCP tailor communication about CFTR variants based on SDM to minimize psychological, cognitive, and other barriers to processing and understanding genetic information (Grade B).

26. The CFF recommends, for people with CRMS/CFSPID, that clear, concise, consistent, and timely information about the uncertainty related to the CRMS/CFSPID diagnosis is provided using family-centered communication strategies (Grade B).

27. The CFF recommends, for people with CRMS/CFSPID and their families, that gradual, clear, and consistent, verbal and written, developmentally appropriate education about CRMS/CFSPID is provided at diagnosis, at follow-up visits, and at the time of reproductive decision-making (Grade B).

The psychological impact of the uncertainty associated with CRMS/CFSPD is challenging for parents and highlights the need for consistent and clear communication between families, patients, and HCP. 65 , 66 SDOH can influence a persons’ understanding of a diagnosis based on previous knowledge, emotional state, genetic and health literacy, and perceptions of test results. 66 , – 69 Screening for SDOH will identify social needs for which CFCC can provide links to further services. Parental learning preferences should be considered. Qualified medical language interpreters should be involved unless the provider is certified as a proficient interpreter in the primary language of the people with CRMS/CFSPID and their caregivers.

Perceived lack of knowledge of the person communicating NBS results has been linked to parental distress. 70 Clear, concise, and consistent information with plans for future follow-up is necessary for parents managing the uncertainty associated with the diagnosis of CRMS/CFSPID. 2 , 65 Accurate information, with reassurance and without conjecture, is critical for moderating parental response to this diagnosis. 66 , 71 Educational tools have been developed to assist HCP when communicating information to families the uncertainty of other diagnoses. 70 Additional information on this topic is available in the Supplemental Information .

Communication With Primary Care

28. The CFF recommends, for people with CRMS/CFSPID, that the PCPs and other HCPs involved in the care of individuals with CRMS/CFSPID receive accurate and up-to-date education about CRMS/CFSPID, its management, and the state’s NBS program (Grade B).

When communicating with parents and HCPs, it is important to provide information regarding further symptoms that may arise and when to refer to a CFCC. Because NBS algorithms vary by state, 1 CFCCs should serve as a resource with current information for PCPs to help educate and clarify any CFTR results, SCT, or other evaluations that pertain to CRMS/CFSPID. 3 , 6  

Screening for Depression and Anxiety

29. The CFF recommends that at least 1 primary caregiver of people with CRMS/CFSPID be offered screening for depression and anxiety annually (Grade B).

30. The CFF recommends, for people with CRMS/CFSPID aged 12 years and older still being followed by CFCC, that screening for depression and anxiety be provided annually (Grade B).

The International Committee on Mental Health in Cystic Fibrosis 72 and the USPSTF screening guidelines 73 , 74 recommend annual screening for depression and anxiety in people aged 12 years and older. To be consistent with guidelines, the committee recommends utilizing the Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 forms. A team member with expertise and training in mental health should be identified to implement screening, follow-up, and referral. 72 Although there is insufficient evidence to recommend routine screening for anxiety and depression in people with CRMS/CFSPID aged 7 to 11 years, this population should be clinically evaluated for these problems when significant symptoms or behavioral concerns are reported or if caregiver depression or anxiety scores are elevated.

Mothers of people with CRMS/CFSPID exhibit increased rates of anxiety, depression, and postpartum depression that are comparable to rates detected among mothers of pwCF. 75 News of the CRMS/CFSPID designation may create a state of cognitive uncertainty regarding the nature of the diagnosis and prognosis. This mental state contributes to clinically significant distress for parents and caregivers 76 , – 78 like that experienced by parents of pwCF. 66 Discussions should be family-centered and may include asking about the caregiver’s emotional and mental health concerns and SDOH, racism, poverty, and relational health. 73 , 79 , 80  

The committee was unable to reach a consensus of 80%, with 20 voting for recommendation (74%) and 7 voting against a recommendation for selectively offering chest computed tomography (CT) scans. There are few reports of chest CT imaging in people with CRMS/CFSPID, 35 , 49 , 81 , 82 and abnormal findings are rare. Many members of the committee felt that chest CTs are not routinely recommended for pwCF and should not be recommended for people with CRMS/CFSPID.

Although numerous studies of CRMS/CFSPID have been published since 2009, most encompass single-center analyses with relatively small cohorts. The CFF Patient Registry (CFFPR) contains many people with CRMS/CFSPID and has been used to study CRMS outcomes. However, there is no requirement for inclusion in the CFFPR, and many people with CRMS/CFSPID are not represented in this database. No randomized clinical trials of people with CRMS/CFSPID have been reported, and it is unlikely that such future studies will be performed, all of which affect the strength of the present recommendations. Enrolling more people with CRMS/CFSPID into CFFPR will be a primary way to develop larger multicenter cohort studies and better guide management.

Genetic testing technology is continually advancing. Tests with limited availability now (eg, compete sequencing of the intronic regions of CFTR ) may become more widely available in the future. Establishing the disease liability of VVCCs and variants of uncertain significance represents an unmet need that may help assess the risk of reclassifying CRMS/CFSPID to CF, as well as guide the selection of CFTR variants in NBS algorithms. Knowledge of state NBS algorithms and access to further genetic testing will be essential because these platforms continue to vary across the United States. 1 People with CFTR -related disorder have CFTR and SCT results similar to people with CRMS/CFSPID, 83 but the likelihood of people with CRMS/CFSPID developing into CFTR -related disorder is currently unknown. Pursuing this area of research is also an important area for future research.

Working closely with PCPs is a mainstay of care for people with CRMS/CFSPID. Table 4 is a suggestion for the continued monitoring and care of people with CRMS/CFSPID and can be employed at both specialty care and primary care. Determining an appropriate time to discharge from care at a specialized center will require SDM with the people with CRMS/CFSPID, family, specialty providers and PCPs. Guidance regarding when to refer back to specialty clinics (eg, change in respiratory symptoms) needs to be developed.

Monitoring and Care for the Person With CRMS/CFSPID

A, annually perform; C, consider; P, perform. —, not needed at this age.

a If still being followed at CFCC.

We present this evidence-based guideline for the management of CRMS. Most of the recommendations were grade C because of the limited data that are currently available. As more people with CRMS/CFSPID are followed for longer periods of time, reassessment of these recommendations will be required. Additionally, research is needed to assess clinical benefits of treating pulmonary symptoms with medications commonly used for CF lung disease, antibiotic therapy for Pa in respiratory cultures, and the use of PFTs or chest imaging for monitoring development of lung disease in people with CRMS/CFSPID.

Drs Green and Ren were co-chairs of the guideline committee, conceptualized the initial survey questions, outlined community concerns and topics to address, authorized and had final selection of committee members, participated in working group meeting and leadership meetings, drafted the initial manuscript, and critically reviewed and revised the manuscript; Drs Lahiri, Ruiz, and Spano and Ms Raraigh were the working group leads, reviewed data, conducted monthly meetings to revise statements, drafted initial sections of the manuscript, and critically reviewed and revised the manuscript; Drs Antos, Christon, Gregoire-Bottex, La Parra Perez, Massie, McGarry, Munck, Oliver, Smiley, and Snodgrass and Ms Bonitz, Ms Hale, Ms Langfelder-Schwind, Ms Maguiness, Ms McElroy-Barker, Ms Mercier, Ms Self, Ms Singh, Ms Tluczek, and Ms Tuley were assigned specific PICO questions to review and abstract data, participated in the final voting meeting for statement inclusion and grading, and critically reviewed and revised the manuscript; Ms Lomas, Ms Wong, Ms Hempstead, and Dr Faro critically reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

The guidelines and recommendations in this article are not American Academy of Pediatrics policy, and publication herein does not imply endorsement.

airway clearance therapy

cystic fibrosis

cystic fibrosis care centers

Cystic Fibrosis Foundation

CFF Patient Registry

cystic fibrosis screen-positive, inconclusive diagnosis

cystic fibrosis transmembrane conductance regulator

CFTR-related metabolic syndrome

computed tomography

deletion/duplication

European Cystic Fibrosis Society

fecal elastase

genetic counselor

health care professional

infection prevention and control

mental health coordinator

newborn screening

Pseudomonas aeruginosa

primary care provider

pulmonary function testing

patient, intervention, comparison, outcome

people with cystic fibrosis

shared decision-making

social determinants of health

sweat chloride concentration

US Preventive Services Task Force

variants of varying clinical consequence

Competing Interests

Supplementary data.

Advertising Disclaimer »

Citing articles via

Email alerts.

Affiliations

• Editorial Board
• Editorial Policies
• Journal Blogs
• Pediatrics On Call
• Online ISSN 1098-4275
• Print ISSN 0031-4005
• Pediatrics Open Science
• Hospital Pediatrics
• Pediatrics in Review
• AAP Grand Rounds
• Latest News
• Pediatric Care Online
• Red Book Online
• Pediatric Patient Education
• AAP Toolkits
• AAP Pediatric Coding Newsletter

First 1,000 Days Knowledge Center

Institutions/librarians, group practices, licensing/permissions, integrations, advertising.

• Privacy Statement | Accessibility Statement | Terms of Use | Support Center | Contact Us
• © Copyright American Academy of Pediatrics

This Feature Is Available To Subscribers Only

Sign In or Create an Account

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Published: 14 May 2015
• Cystic fibrosis
• Felix Ratjen 1 ,
• Scott C. Bell 2 ,
• Steven M. Rowe 3 ,
• Christopher H. Goss 4 ,
• Alexandra L. Quittner 5 &
• Andrew Bush 6  

Nature Reviews Disease Primers volume  1 , Article number:  15010 ( 2015 ) Cite this article

14k Accesses

351 Citations

61 Altmetric

Metrics details

• Genetic testing
• Metabolic disorders
• Respiratory tract diseases

Cystic fibrosis is an autosomal recessive, monogenetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene. The gene defect was first described 25 years ago and much progress has been made since then in our understanding of how CFTR mutations cause disease and how this can be addressed therapeutically. CFTR is a transmembrane protein that transports ions across the surface of epithelial cells. CFTR dysfunction affects many organs; however, lung disease is responsible for the vast majority of morbidity and mortality in patients with cystic fibrosis. Prenatal diagnostics, newborn screening and new treatment algorithms are changing the incidence and the prevalence of the disease. Until recently, the standard of care in cystic fibrosis treatment focused on preventing and treating complications of the disease; now, novel treatment strategies directly targeting the ion channel abnormality are becoming available and it will be important to evaluate how these treatments affect disease progression and the quality of life of patients. In this Primer, we summarize the current knowledge, and provide an outlook on how cystic fibrosis clinical care and research will be affected by new knowledge and therapeutic options in the near future. For an illustrated summary of this Primer, visit: http://go.nature.com/4VrefN

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 1 digital issues and online access to articles

92,52 € per year

only 92,52 € per issue

Rent or buy this article

Prices vary by article type

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Future therapies for cystic fibrosis

Lucy Allen, Lorna Allen, … Jane C. Davies

Beyond cystic fibrosis transmembrane conductance regulator therapy: a perspective on gene therapy and small molecule treatment for cystic fibrosis

Elena K. Schneider-Futschik

A Systematic Review of the Clinical Efficacy and Safety of CFTR Modulators in Cystic Fibrosis

Al-Rahim R. Habib, Majid Kajbafzadeh, … Bradley S. Quon

Weiler, C. A. & Drumm, M. L. Genetic influences on cystic fibrosis lung disease severity. Front. Pharmacol. 4 , 40 (2013).

Article   PubMed   PubMed Central   Google Scholar  

Jarvi, K. et al . Cystic fibrosis transmembrane conductance regulator and obstructive azoospermia. Lancet 345 , 1578 (1995).

Article   CAS   PubMed   Google Scholar  

Gonska, T. et al . Role of cystic fibrosis transmembrane conductance regulator in patients with chronic sinopulmonary disease. Chest 142 , 996–1004 (2012).

Wilschanski, M. et al . Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Am. J. Respir. Crit. Care Med. 174 , 787–794 (2006).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Riordan, J. R. et al . Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245 , 1066–1073 (1989).

Rommens, J. M. et al . Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245 , 1059–1065 (1989).

Ratjen, F. & Grasemann, H. New therapies in cystic fibrosis. Curr. Pharm. Des. 18 , 614–627 (2012).

O'Sullivan, B. P. & Freedman, S. D. Cystic fibrosis. Lancet 373 , 1891–1904 (2009).

Article   PubMed   Google Scholar  

Walters, S., M. A . in Hodson and Geddes' Cystic Fibrosis 3rd edn (eds Hodson, M. E., Geddes D. M., Bush, A. ) 21–45 (Edward Arnold Ltd, 2007).

Google Scholar  

Farrell, P. M. The prevalence of cystic fibrosis in the European Union. J. Cyst. Fibros. 7 , 450–453 (2008).

Festini, F. et al . Incidence of cystic fibrosis in the Albanian population. Pediatr. Pulmonol. 43 , 1124–1129 (2008).

Festini, F., Taccetti, G., Cioni, M. L., Repetto, T. & De Martino, M. High incidence of cystic fibrosis in children born in Italy to Albanian immigrants. Thorax 58 , 93 (2003).

Dupuis, A., Hamilton, D., Cole, D. E. & Corey, M. Cystic fibrosis birth rates in Canada: a decreasing trend since the onset of genetic testing. J. Pediatr. 147 , 312–315 (2005).

Kulich, M., Rosenfeld, M., Goss, C. H. & Wilmott, R. Improved survival among young patients with cystic fibrosis. J. Pediatr. 142 , 631–636 (2003).

MacKenzie, T. et al . Longevity of patients with cystic fibrosis in 2000 to 2010 and beyond: survival analysis of the cystic fibrosis foundation patient registry. Ann. Intern. Med. 161 , 233–241 (2014).

Cystic Fibrosis Foundation Cystic Fibrosis Foundation Patient Registry 2012 annual data report. (Cystic Fibrosis Foundation, 2013).

Dodge, J. A., Lewis, P. A., Stanton, M. & Wilsher, J. Cystic fibrosis mortality and survival in the UK: 1947–2003. Eur. Respir. J. 29 , 522–526 (2007). References 15 and 17 show the improvements in survival in the US and the UK cystic fibrosis populations, respectively, over the past decade.

Cystic Fibrosis Canada. Canadian cystic fibrosis patient data registry report 2010. (Cystic Fibrosis Canada, 2010).

Kerem, E. et al . Factors associated with FEV1 decline in cystic fibrosis: analysis of the ECFS patient registry. Eur. Respir. J. 43 , 125–133 (2014).

Rodman, D. M. et al . Late diagnosis defines a unique population of long-term survivors of cystic fibrosis. Am. J. Respir. Crit. Care Med. 171 , 621–626 (2005).

Nick, J. A. et al . Effects of gender and age at diagnosis on disease progression in long-term survivors of cystic fibrosis. Am. J. Respir. Crit. Care Med. 182 , 614–626 (2010).

Simmonds, N. J. et al . Cystic fibrosis and survival to 40 years: a study of cystic fibrosis transmembrane conductance regulator function. Eur. Respir. J. 37 , 1076–1082 (2011).

George, P. M. et al . Improved survival at low lung function in cystic fibrosis: cohort study from 1990 to 2007. BMJ 342 , d1008 (2011).

Accurso, F. J. et al . Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N. Engl. J. Med. 363 , 1991–2003 (2010).

Ramsey, B. W. et al . A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N. Engl. J. Med. 365 , 1663–1672 (2011). This article shows the efficacy of CFTR modulation by the potentiator ivacaftor in patients with the G551D mutation.

Kerem, B. et al . Identification of the cystic fibrosis gene: genetic analysis. Science 245 , 1073–1080 (1989).

Higgins, C. F. ABC transporters: from microorganisms to man. Annu. Rev. Cell Biol. 8 , 67–113 (1992).

Klein, I., Sarkadi, B. & Varadi, A. An inventory of the human ABC proteins. Biochim. Biophys. Acta 1461 , 237–262 (1999).

Collins, F. S. Cystic fibrosis: molecular biology and therapeutic implications. Science 256 , 774–779 (1992).

Serohijos, A. W. et al . Phenylalanine-508 mediates a cytoplasmic-membrane domain contact in the CFTR 3D structure crucial to assembly and channel function. Proc. Natl Acad. Sci. USA 105 , 3256–3261 (2008).

Drumm, M. L. et al . Genetic modifiers of lung disease in cystic fibrosis. N. Engl. J. Med. 353 , 1443–1453 (2005).

Chillon, M. et al . Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens. N. Engl. J. Med. 332 , 1475–1480 (1995).

Sharer, N. et al . Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N. Engl. J. Med. 339 , 645–652 (1998).

Cohn, J. A. et al . Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N. Engl. J. Med. 339 , 653–658 (1998).

Sosnay, P. R. et al . Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat. Genet. 45 , 1160–1167 (2013).

Welsh, M. J. & Smith, A. E. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell 73 , 1251–1254 (1993).

Okiyoneda, T. et al . Peripheral protein quality control removes unfolded CFTR from the plasma membrane. Science 329 , 805–810 (2010).

Mendoza, J. L. et al . Requirements for efficient correction of DeltaF508 CFTR revealed by analyses of evolved sequences. Cell 148 , 164–174 (2012).

Rabeh, W. M. et al . Correction of both NBD1 energetics and domain interface is required to restore ΔF508 CFTR folding and function. Cell 148 , 150–163 (2012). References 38 and 39 delineate the importance of two distinct molecular defects conferred by the F508del. CFTR mutation, including their effect of correcting CFTR misfolding to restore CFTR expression. These papers show that to fully restore mutated CFTR to the cell surface, both NBD1 stability and interdomain assembly must be addressed.

Green, D. M. et al . Heritability of respiratory infection with Pseudomonas aeruginosa in cystic fibrosis. J. Pediatr. 161 , 290–295 e1 (2012).

Garred, P. et al . Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis. J. Clin. Invest. 104 , 431–437 (1999).

Sun, L. et al . Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis. Nat. Genet. 44 , 562–569 (2012).

Blackman, S. M. et al . Genetic modifiers of cystic fibrosis-related diabetes. Diabetes 62 , 3627–3635 (2013).

Dorfman, R. et al . Modifier gene study of meconium ileus in cystic fibrosis: statistical considerations and gene mapping results. Hum. Genet. 126 , 763–778 (2009).

Romi, H. et al . Meconium ileus caused by mutations in GUCY2C , encoding the CFTR-activating guanylate cyclase 2C. Am. J. Hum. Genet. 90 , 893–899 (2012).

Li, W. et al . Unraveling the complex genetic model for cystic fibrosis: pleiotropic effects of modifier genes on early cystic fibrosis-related morbidities. Hum. Genet. 133 , 151–161 (2014).

Wright, F. A. et al . Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. Nat. Genet. 43 , 539–546 (2011).

Collaco, J. M., Blackman, S. M., McGready, J., Naughton, K. M. & Cutting, G. R. Quantification of the relative contribution of environmental and genetic factors to variation in cystic fibrosis lung function. J. Pediatr. 157 , 802–807 e1–3 (2010).

Vanscoy, L. L. et al . Heritability of lung disease severity in cystic fibrosis. Am. J. Respir. Crit. Care Med. 175 , 1036–1043 (2007).

Kolbe, E. W. et al . CLCA4 variants determine the manifestation of the cystic fibrosis basic defect in the intestine. Eur. J. Hum. Genet. 21 , 691–694 (2013).

Bremer, L. A. et al . Interaction between a novel TGFB1 haplotype and CFTR genotype is associated with improved lung function in cystic fibrosis. Hum. Mol. Genet. 17 , 2228–2237 (2008).

Yarden, J. et al . Association of tumour necrosis factor alpha variants with the CF pulmonary phenotype. Thorax 60 , 320–325 (2005).

Goss, C. H., Newsom, S. A., Schildcrout, J. S., Sheppard, L. & Kaufman, J. D. Effect of ambient air pollution on pulmonary exacerbations and lung function in cystic fibrosis. Am. J. Respir. Crit. Care Med. 169 , 816–821 (2004).

Collaco, J. M. et al . Interactions between secondhand smoke and genes that affect cystic fibrosis lung disease. JAMA 299 , 417–424 (2008).

Martin, B. et al . Comparison of the US and Australian cystic fibrosis registries: the impact of newborn screening. Pediatrics 129 , e348–e355 (2012).

Boyle, M. P., Sabadosa, K. A., Quinton, H. B., Marshall, B. C. & Schechter, M. S. Key findings of the US Cystic Fibrosis Foundation's clinical practice benchmarking project. BMJ Qual. Saf. 23 (Suppl. 1), i15–i22 (2014). This article reports the key outcomes of the quality improvement programme of cystic fibrosis care in the United States and shows the assessment of patterns of practice in the top-performing (20%) treatment centres, and provides insight into the features of practice that could lead to optimization of patient outcomes.

Ooi, C. Y. & Durie, P. R. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J. Cyst. Fibros. 11 , 355–362 (2012).

Ratjen, F. & Doring, G. Cystic fibrosis. Lancet 361 , 681–689 (2003).

Rowe, S. M., Miller, S. & Sorscher, E. J. Cystic fibrosis. N. Engl. J. Med. 352 , 1992–2001 (2005).

Boucher, R. C. Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. Annu. Rev. Med. 58 , 157–170 (2007).

Adebamiro, A., Cheng, Y., Rao, U. S., Danahay, H. & Bridges, R. J. A segment of γ-ENaC mediates elastase activation of Na + transport. J. Gen. Physiol. 130 , 611–629 (2007).

Caldwell, R. A., Boucher, R. C. & Stutts, M. J. Neutrophil elastase activates near-silent epithelial Na + channels and increases airway epithelial Na + transport. Am. J. Physiol. Lung Cell. Mol. Physiol. 288 , L813–819 (2005).

Passero, C. J. et al . TMPRSS4-dependent activation of the epithelial sodium channel requires cleavage of the γ-subunit distal to the furin cleavage site. Am. J. Physiol. Renal Physiol. 302 , F1–8 (2012).

Matsui, H. et al . Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell 95 , 1005–1015 (1998).

Button, B. et al . A periciliary brush promotes the lung health by separating the mucus layer from airway epithelia. Science 337 , 937–941 (2012).

Chen, J. H. et al . Loss of anion transport without increased sodium absorption characterizes newborn porcine cystic fibrosis airway epithelia. Cell 143 , 911–923 (2010).

Tuggle, K. L. et al . Characterization of defects in ion transport and tissue development in cystic fibrosis transmembrane conductance regulator (CFTR)-knockout rats. PLoS ONE 9 , e91253 (2014).

Itani, O. A. et al . Human cystic fibrosis airway epithelia have reduced Cl − conductance but not increased Na + conductance. Proc. Natl Acad. Sci. USA 108 , 10260–10265 (2011).

Birket, S. E. et al . A functional anatomic defect of the cystic fibrosis airway. Am. J. Respir. Crit. Care Med. 190 , 421–432 (2014).

Hoegger, M. J. et al . Cystic fibrosis. Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis. Science 345 , 818–822 (2014).

Corcoran, T. E. et al . Absorptive clearance of DTPA as an aerosol-based biomarker in the cystic fibrosis airway. Eur. Respir. J. 35 , 781–786 (2010).

Schutte, A. et al . Microbial-induced meprin beta cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus. Proc. Natl Acad. Sci. USA 111 , 12396–12401 (2014).

Henderson, A. G. et al . Cystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressure. J. Clin. Invest. 124 , 3047–3060 (2014).

Quinton, P. M. Cystic fibrosis: impaired bicarbonate secretion and mucoviscidosis. Lancet 372 , 415–417 (2008).

Garcia, M. A., Yang, N. & Quinton, P. M. Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator-dependent bicarbonate secretion. J. Clin. Invest. 119 , 2613–2622 (2009).

Gustafsson, J. K. et al . Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype. J. Exp. Med. 209 , 1263–1272 (2012). References 70, 71 and 76 demonstrate that a defect in mucociliary clearance emanates from abnormalities of mucus in cystic fibrosis, including its adhesive properties, shown in mouse models in which the intestines are bicarbonate-dependent, porcine airway gland ducts submerged in saline and the human airway surface, even in the setting of adequate periciliary layer depth.

Keiser, N. W. et al . Defective innate immunity and hyper-inflammation in newborn CFTR-knockout ferret lungs. Am. J. Respir. Cell. Mol. Biol. 15 Oct 2014 [epub ahead of print].

Rogers, C. S. et al . Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science 321 , 1837–1841 (2008).

Kunzelmann, K. & Mehta, A. CFTR: a hub for kinases and crosstalk of cAMP and Ca 2+ . FEBS J. 280 , 4417–4429 (2013).

Garnett, J. P. et al . Novel role for pendrin in orchestrating bicarbonate secretion in cystic fibrosis transmembrane conductance regulator (CFTR)-expressing airway serous cells. J. Biol. Chem. 286 , 41069–41082 (2011).

Pezzulo, A. A. et al . Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Nature 487 , 109–113 (2012).

Pohl, K. et al . A neutrophil intrinsic impairment affecting Rab27a and degranulation in cystic fibrosis is corrected by CFTR potentiator therapy. Blood 124 , 999–1009 (2014).

Bruscia, E. M. et al . Macrophages directly contribute to the exaggerated inflammatory response in cystic fibrosis transmembrane conductance regulator −/− mice. Am. J. Respir. Cell. Mol. Biol. 40 , 295–304 (2009).

Wang, X. et al . Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 127 , 803–815 (2006).

Bedrossian, C., Greenberg, S., Singer, D., Hansen, J. & Rosenberg, H. The lung in cystic fibrosis: a quantitative study including prevalence of pathologic findings among different age groups. Hum. Pathol. 7 , 195–204 (1976).

Livraghi-Butrico, A. et al . Mucus clearance, MyD88-dependent and MyD88-independent immunity modulate lung susceptibility to spontaneous bacterial infection and inflammation. Mucosal Immunol. 5 , 397–408 (2012).

Hybiske, K. et al . Effects of cystic fibrosis transmembrane conductance regulator and Delta F508CFTR on inflammatory response, ER stress, and Ca 2+ of airway epithelia. Am. J. Physiol. Lung Cell. Mol. Physiol. 293 , L1250–L1260 (2007).

Mott, L. S. et al . Progression of early structural lung disease in young children with cystic fibrosis assessed using CT. Thorax 67 , 509–516 (2011).

Sly, P. D. et al . Risk factors for bronchiectasis in children with cystic fibrosis. N. Engl. J. Med. 368 , 1963–1970 (2013). This article highlights that neutrophil elastase activity in bronchoalveolar lavage fluid in early life of children with cystic fibrosis undergoing bronchoscopy is associated with early bronchiectasis. This finding shows the importance of early detection of lung infection and inflammation, and the importance of its treatment.

Gehrig, S. et al . Lack of neutrophil elastase reduces inflammation, mucus hypersecretion, and emphysema, but not mucus obstruction, in mice with cystic fibrosis-like lung disease. Am. J. Respir. Crit. Care Med. 189 , 1082–1092 (2014).

Vandivier, R. W. et al . Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis. J. Clin. Invest. 109 , 661–670 (2002).

Berger, M., Sorensen, R. U., Tosi, M. F., Dearborn, D. G. & Doring, G. Complement receptor expression on neutrophils at an inflammatory site, the Pseudomonas -infected lung in cystic fibrosis. J. Clin. Invest. 84 , 1302–1313 (1989).

Day, B. J., van Heeckeren, A. M., Min, E. & Velsor, L. W. Role for cystic fibrosis transmembrane conductance regulator protein in a glutathione response to bronchopulmonary pseudomonas infection. Infect. Immun. 72 , 2045–2051 (2004).

Roum, J. H., Buhl, R., McElvaney, N. G., Borok, Z. & Crystal, R. G. Systemic deficiency of glutathione in cystic fibrosis. J. Appl. Physiol. 75 , 2419–2424 (1993).

Knowles, M. R. & Boucher, R. C. Mucus clearance as a primary innate defense mechanism for mammalian airways. J. Clin. Invest. 109 , 571–577 (2002).

Emerson, J., Rosenfeld, M., McNamara, S., Ramsey, B. & Gibson, R. L. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr. Pulmonol. 34 , 91–100 (2002).

Nixon, G. M. et al . Clinical outcome after early Pseudomonas aeruginosa infection in cystic fibrosis. J. Pediatr. 138 , 699–704 (2001).

Gangell, C. et al . Inflammatory responses to individual microorganisms in the lungs of children with cystic fibrosis. Clin. Infect. Dis. 53 , 425–432 (2011).

van Ewijk, B. E. et al . Prevalence and impact of respiratory viral infections in young children with cystic fibrosis: prospective cohort study. Pediatrics 122 , 1171–1176 (2008).

Wat, D. et al . The role of respiratory viruses in cystic fibrosis. J. Cyst. Fibros. 7 , 320–328 (2008).

Wark, P. A. et al . Viral infections trigger exacerbations of cystic fibrosis in adults and children. Eur. Respir. J. 40 , 510–512 (2012).

Amin, R., Dupuis, A., Aaron, S. D. & Ratjen, F. The effect of chronic infection with Aspergillus fumigatus on lung function and hospitalization in patients with cystic fibrosis. Chest 137 , 171–176 (2010).

Dasenbrook, E. C. et al . Association between respiratory tract methicillin-resistant Staphylococcus aureus and survival in cystic fibrosis. JAMA 303 , 2386–2392 (2010).

Govan, J. R., Brown, A. R. & Jones, A. M. Evolving epidemiology of Pseudomonas aeruginosa and the Burkholderia cepacia complex in cystic fibrosis lung infection. Future Microbiol. 2 , 153–164 (2007).

Ledson, M. J., Gallagher, M. J., Jackson, M., Hart, C. A. & Walshaw, M. J. Outcome of Burkholderia cepacia colonisation in an adult cystic fibrosis centre. Thorax 57 , 142–145 (2002).

Aaron, S. D. et al . Infection with transmissible strains of Pseudomonas aeruginosa and clinical outcomes in adults with cystic fibrosis. JAMA 304 , 2145–2153 (2010).

Armstrong, D. S. et al . Detection of a widespread clone of Pseudomonas aeruginosa in a pediatric cystic fibrosis clinic. Am. J. Respir. Crit. Care Med. 166 , 983–987 (2002).

McCallum, S. J. et al . Superinfection with a transmissible strain of Pseudomonas aeruginosa in adults with cystic fibrosis chronically colonised by P. aeruginosa . Lancet 358 , 558–560 (2001).

Cramer, N. et al . Molecular epidemiology of chronic Pseudomonas aeruginosa airway infections in cystic fibrosis. PLoS ONE 7 , e50731 (2012).

Kidd, T. J. et al . Pseudomonas aeruginosa exhibits frequent recombination, but only a limited association between genotype and ecological setting. PLoS ONE 7 , e44199 (2012).

Wiehlmann, L. et al . Effective prevention of Pseudomonas aeruginosa cross-infection at a cystic fibrosis centre — results of a 10-year prospective study. Int. J. Med. Microbiol. 302 , 69–77 (2012).

Griffiths, A. L. et al . Effects of segregation on an epidemic Pseudomonas aeruginosa strain in a cystic fibrosis clinic. Am. J. Respir. Crit. Care Med. 171 , 1020–1025 (2005).

Adjemian, J., Olivier, K. N. & Prevots, D. R. Nontuberculous mycobacteria among patients with cystic fibrosis in the United States: screening practices and environmental risk. Am. J. Respir. Crit. Care Med. 190 , 581–586 (2014).

Qvist, T. et al . Epidemiology of nontuberculous mycobacteria among patients with cystic fibrosis in Scandinavia. J. Cyst. Fibros. 14 , 46–52 (2014).

Bryant, J. M. et al . Whole-genome sequencing to identify transmission of Mycobacterium abscessus between patients with cystic fibrosis: a retrospective cohort study. Lancet 381 , 1551–1560 (2013).

Rogers, G. B. et al . Bacterial diversity in cases of lung infection in cystic fibrosis patients: 16S ribosomal DNA (rDNA) length heterogeneity PCR and 16S rDNA terminal restriction fragment length polymorphism profiling. J. Clin. Microbiol. 41 , 3548–3558 (2003).

Tunney, M. M. et al . Detection of anaerobic bacteria in high numbers in sputum from patients with cystic fibrosis. Am. J. Respir. Crit. Care Med. 177 , 995–1001 (2008).

LiPuma, J. J. Expanding our understanding of respiratory microbiota in cystic fibrosis. Ann. Am. Thorac. Soc. 11 , 1084–1085 (2014).

Worlitzsch, D. et al . Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. J. Clin. Invest. 109 , 317–325 (2002).

Bragonzi, A. et al . Pseudomonas aeruginosa microevolution during cystic fibrosis lung infection establishes clones with adapted virulence. Am. J. Respir. Crit. Care Med. 180 , 138–145 (2009).

Marvig, R. L., Sommer, L. M., Molin, S. & Johansen, H. K. Convergent evolution and adaptation of Pseudomonas aeruginosa within patients with cystic fibrosis. Nat. Genet. 47 , 57–64 (2015).

Young, R. L. et al . Neutrophil extracellular trap (NET)-mediated killing of Pseudomonas aeruginosa : evidence of acquired resistance within the CF airway, independent of CFTR. PLoS ONE 6 , e23637 (2011).

Regamey, N. et al . Distinct patterns of inflammation in the airway lumen and bronchial mucosa of children with cystic fibrosis. Thorax 67 , 164–170 (2012).

Tan, H. L. et al . The Th17 pathway in cystic fibrosis lung disease. Am. J. Respir. Crit. Care Med. 184 , 252–258 (2011).

Hector, A. et al . Regulatory T cell impairment in cystic fibrosis patients with chronic Pseudomonas infection. Am. J. Respir. Crit. Care Med. 191 , 914–923 (2015).

Ooi, C. Y. et al . Does extensive genotyping and nasal potential difference testing clarify the diagnosis of cystic fibrosis among patients with single-organ manifestations of cystic fibrosis? Thorax 69 , 254–260 (2014). This manuscript looks at the use of ancillary testing in the diagnosis of cystic fibrosis. Despite increasing sophistication of ion transport measurements and genetic testing, the diagnosis frequently remains in doubt, underscoring the importance of clinical acumen in these indeterminate cases.

Ooi, C. Y. et al . Comparing the American and European diagnostic guidelines for cystic fibrosis: same disease, different language? Thorax 67 , 618–624 (2012). The article discusses the nomenclature of and the approach to infants with an equivocal newborn screening test. This is a very difficult area of uncertainty for paediatricians and families, and this consensus statement, whether the nomenclature is thought to be correct or not, offers important guidance.

Stewart, B., Zabner, J., Shuber, A. P., Welsh, M. J. & McCray, P. B. Jr. Normal sweat chloride values do not exclude the diagnosis of cystic fibrosis. Am. J. Respir. Crit. Care Med. 151 , 899–903 (1995).

Knowles, M., Gatzy, J. & Boucher, R. Increased bioelectric potential difference across respiratory epithelia in cystic fibrosis. N. Engl. J. Med. 305 , 1489–1495 (1981).

Ooi, C. Y. et al . Does integration of various ion channel measurements improve diagnostic performance in cystic fibrosis? Ann. Am. Thorac Soc. 11 , 562–570 (2014).

Vermeulen, F., Proesmans, M., Boon, M. & De Boeck, K. Improved repeatability of nasal potential difference with a larger surface catheter. J. Cyst. Fibros. [online] , (2014).

Veeze, H. J., Sinaasappel, M., Bijman, J., Bouquet, J. & de Jonge, H. R. Ion transport abnormalities in rectal suction biopsies from children with cystic fibrosis. Gastroenterology 101 , 398–403 (1991).

Cohen-Cymberknoh, M. et al . Evaluation of the intestinal current measurement method as a diagnostic test for cystic fibrosis. Pediatr. Pulmonol. 48 , 229–235 (2013).

Dekkers, J. F. et al . A functional CFTR assay using primary cystic fibrosis intestinal organoids. Nat. Med. 19 , 939–945 (2013).

Quinton, P. et al . β-adrenergic sweat secretion as a diagnostic test for cystic fibrosis. Am. J. Respir. Crit. Care Med. 186 , 732–739 (2012).

Lebecque, P. et al . Mutations of the cystic fibrosis gene and intermediate sweat chloride levels in children. Am. J. Respir. Crit. Care Med. 165 , 757–761 (2002).

Bush, A. & Wallis, C. Time to think again: cystic fibrosis is not an ‘all or none’ disease. Pediatr. Pulmonol. 30 , 139–144 (2000).

Sims, E. J. et al . Economic implications of newborn screening for cystic fibrosis: a cost of illness retrospective cohort study. Lancet 369 , 1187–1195 (2007).

Farrell, P. M. et al . Nutritional benefits of neonatal screening for cystic fibrosis. Wisconsin Cyst. Fibrosis Neonatal Screen. Study Group. N. Engl. J. Med. 337 , 963–969 (1997). This article is a major report on the only randomized controlled trial of screening. Screening led to improved nutritional outcomes but no respiratory improvements. This finding probably reflects suboptimal care in one clinic, making the important point that if cystic fibrosis newborn screening is instituted, the best standards of care for the screen-positive babies must be available.

Article   CAS   Google Scholar  

Wilcken, B. & Gaskin, K. More evidence to favour newborn screening for cystic fibrosis. Lancet 369 , 1146–1147 (2007).

Balfour-Lynn, I. M. Newborn screening for cystic fibrosis: evidence for benefit. Arch. Dis. Child 93 , 7–10 (2008).

Wagener, J. S., Zemanick, E. T. & Sontag, M. K. Newborn screening for cystic fibrosis. Curr. Opin. Pediatr. 24 , 329–335 (2012).

Ranganathan, S. C. et al . Airway function in infants newly diagnosed with cystic fibrosis. Lancet 358 , 1964–1965 (2001).

Ranganathan, S. C. et al . The evolution of airway function in early childhood following clinical diagnosis of cystic fibrosis. Am. J. Respir. Crit. Care Med. 169 , 928–933 (2004).

Southern, K. W. et al . A survey of newborn screening for cystic fibrosis in Europe. J. Cyst. Fibros. 6 , 57–65 (2007).

Vernooij- van Langen, A. M. et al . Novel strategies in newborn screening for cystic fibrosis: a prospective controlled study. Thorax 67 , 289–295 (2012).

Article   Google Scholar  

Southern, K. W. Determining the optimal newborn screening protocol for cystic fibrosis. Thorax 67 , 281–282 (2012).

Roussey, M. et al . Neonatal screening of cystic fibrosis: diagnostic problems with CFTR mild mutations. J. Inherit Metab. Dis. 30 , 613 (2007).

Scotet, V. et al . Immunoreactive trypsin/DNA newborn screening for cystic fibrosis: should the R117H variant be included in CFTR mutation panels? Pediatrics 118 , e1523–e1529 (2006).

O'Sullivan, B. P., Zwerdling, R. G., Dorkin, H. L., Comeau, A. M. & Parad, R. Early pulmonary manifestation of cystic fibrosis in children with the ΔF508/R117H-7T genotype. Pediatrics 118 , 1260–1265 (2006).

Peckham, D., Conway, S. P., Morton, A., Jones, A. & Webb, K. Delayed diagnosis of cystic fibrosis associated with R117H on a background of 7T polythymidine tract at intron 8. J. Cyst. Fibros. 5 , 63–65 (2006).

de Nooijer, R. A. et al . Assessment of CFTR function in homozygous R117H-7T subjects. J. Cyst. Fibros. 10 , 326–332 (2011).

Cystic Fibrosis, F. et al . Cystic Fibrosis Foundation practice guidelines for the management of infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome during the first two years of life and beyond. J. Pediatr. 155 , S106–S116 (2009).

Mayell, S. J. et al . A European consensus for the evaluation and management of infants with an equivocal diagnosis following newborn screening for cystic fibrosis. J. Cyst. Fibros. 8 , 71–78 (2009).

Ren, C. L., Desai, H., Platt, M. & Dixon, M. Clinical outcomes in infants with cystic fibrosis transmembrane conductance regulator (CFTR) related metabolic syndrome. Pediatr. Pulmonol. 46 , 1079–1084 (2011).

Wielputz, M. O. et al . Magnetic resonance imaging detects changes in structure and perfusion, and response to therapy in early cystic fibrosis lung disease. Am. J. Respir. Crit. Care Med. 189 , 956–965 (2014).

Aurora, P. et al . Multiple breath inert gas washout as a measure of ventilation distribution in children with cystic fibrosis. Thorax 59 , 1068–1073 (2004).

Aurora, P. et al . Multiple-breath washout as a marker of lung disease in preschool children with cystic fibrosis. Am. J. Respir. Crit. Care Med. 171 , 249–256 (2005).

Kraemer, R., Blum, A., Schibler, A., Ammann, R. A. & Gallati, S. Ventilation inhomogeneities in relation to standard lung function in patients with cystic fibrosis. Am. J. Respir. Crit. Care Med. 171 , 371–378 (2005).

Lum, S. et al . Early detection of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests. Thorax 62 , 341–347 (2007).

Hoo, A. F. et al . Lung function is abnormal in 3-month-old infants with cystic fibrosis diagnosed by newborn screening. Thorax 67 , 874–881 (2012).

Sly, P. D. et al . Lung disease at diagnosis in infants with cystic fibrosis detected by newborn screening. Am. J. Respir. Crit. Care Med. 180 , 146–152 (2009).

Pillarisetti, N. et al . Infection, inflammation, and lung function decline in infants with cystic fibrosis. Am. J. Respir. Crit. Care Med. 184 , 75–81 (2011).

Nguyen, T. T. et al . Evolution of lung function during the first year of life in newborn screened cystic fibrosis infants. Thorax 69 , 910–917 (2013).

Brennan, L. C. et al . S7 Evolution of lung function during the first two years of life in infants with cystic fibrosis diagnosed by newborn screening. Thorax 68 , A6–A7 (2013).

Amin, R. et al . The effect of dornase alfa on ventilation inhomogeneity in patients with cystic fibrosis. Eur. Respir. J. 37 , 806–812 (2011).

Amin, R. et al . Hypertonic saline improves the LCI in paediatric CF patients with normal lung function. Thorax 65 , 379–383 (2010).

Vermeulen, F., Proesmans, M., Boon, M., Havermans, T. & De Boeck, K. Lung clearance index predicts pulmonary exacerbations in young patients with cystic fibrosis. Thorax 69 , 39–45 (2014).

Maisonneuve, P., Marshall, B. C., Knapp, E. A. & Lowenfels, A. B. Cancer risk in cystic fibrosis: a 20-year nationwide study from the United States. J. Natl Cancer Inst. 105 , 122–129 (2013).

Thia, L. P. et al . Is chest CT useful in newborn screened infants with cystic fibrosis at 1 year of age? Thorax 69 , 320–327 (2014).

Gustafsson, P. M., De Jong, P. A., Tiddens, H. A. & Lindblad, A. Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis. Thorax 63 , 129–134 (2008).

Owens, C. M. et al . Lung Clearance Index and HRCT are complementary markers of lung abnormalities in young children with CF. Thorax 66 , 481–488 (2011).

Stafler, P., Davies, J. C., Balfour-Lynn, I. M., Rosenthal, M. & Bush, A. Bronchoscopy in cystic fibrosis infants diagnosed by newborn screening. Pediatr. Pulmonol. 46 , 696–700 (2011).

Wainwright, C. E. et al . Effect of bronchoalveolar lavage-directed therapy on Pseudomonas aeruginosa infection and structural lung injury in children with cystic fibrosis: a randomized trial. JAMA 306 , 163–171 (2011).

CAS   PubMed   Google Scholar  

King, V. V. Upper respiratory disease, sinusitis, and polyposis. Clin. Rev. Allergy 9 , 143–157 (1991).

Henriksson, G. et al . Nasal polyps in cystic fibrosis: clinical endoscopic study with nasal lavage fluid analysis. Chest 121 , 40–47 (2002).

Hansen, S. K. et al . Evolution and diversification of Pseudomonas aeruginosa in the paranasal sinuses of cystic fibrosis children have implications for chronic lung infection. ISME J. 6 , 31–45 (2012).

Rubinstein, S., Moss, R. & Lewiston, N. Constipation and meconium ileus equivalent in patients with cystic fibrosis. Pediatrics 78 , 473–479 (1986).

Blondeau, K. et al . Gastro-oesophageal reflux and aspiration of gastric contents in adult patients with cystic fibrosis. Gut 57 , 1049–1055 (2008).

Ledder, O., Haller, W., Couper, R. T., Lewindon, P. & Oliver, M. Cystic fibrosis: an update for clinicians. Part 2: hepatobiliary and pancreatic manifestations. J. Gastroenterol. Hepatol. 29 , 1954–1962 (2014).

Borowitz, D. et al . Gastrointestinal outcomes and confounders in cystic fibrosis. J. Pediatr. Gastroenterol. Nutr. 41 , 273–285 (2005).

Lewindon, P. J., Robb, T. A., Moore, D. J., Davidson, G. P. & Martin, A. J. Bowel dysfunction in cystic fibrosis: importance of breath testing. J. Paediatr. Child Health 34 , 79–82 (1998).

Konstan, M. W. et al . Growth and nutritional indexes in early life predict pulmonary function in cystic fibrosis. J. Pediatr. 142 , 624–630 (2003).

Sharma, R. et al . Wasting as an independent predictor of mortality in patients with cystic fibrosis. Thorax 56 , 746–750 (2001).

Corbett, K. et al . Cystic fibrosis-associated liver disease: a population-based study. J. Pediatr. 145 , 327–332 (2004).

Rowland, M. et al . Outcome in cystic fibrosis liver disease. Am. J. Gastroenterol. 106 , 104–109 (2011).

Moran, A. et al . Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care 33 , 2697–2708 (2010).

Lewis, C. et al . Diabetes-related mortality in adults with cystic fibrosis. Role of genotype and sex. Am. J. Respir. Crit. Care Med. 191 , 194–200 (2015).

Neinstein, L. S., Stewart, D., Wang, C. I. & Johnson, I. Menstrual dysfunction in cystic fibrosis. J. Adolesc. Health Care 4 , 153–157 (1983).

Stern, M., Wiedemann, B., Wenzlaff, P. & German Cystic Fibrosis Quality Assessment, G. From registry to quality management: the German Cystic Fibrosis Quality Assessment project 1995–2006. Eur. Respir. J. 31 , 29–35 (2008).

Marshall, B. C. & Nelson, E. C. Accelerating implementation of biomedical research advances: critical elements of a successful 10 year Cystic Fibrosis Foundation healthcare delivery improvement initiative. BMJ Qual. Saf. 23 (Suppl. 1), i95–i103 (2014).

McCormick, J. et al . Comparative demographics of the European cystic fibrosis population: a cross-sectional database analysis. Lancet 375 , 1007–1013 (2010).

Colombo, C. & Littlewood, J. The implementation of standards of care in Europe: state of the art. J. Cyst. Fibros. 10 (Suppl. 2), S7–S15 (2011).

Stern, M., Niemann, N., Wiedemann, B., Wenzlaff, P. & German, C. G. Benchmarking improves quality in cystic fibrosis care: a pilot project involving 12 centres. Int. J. Qual. Health Care 23 , 349–356 (2011).

Schechter, M. S. Benchmarking to improve the quality of cystic fibrosis care. Curr. Opin. Pulm. Med. 18 , 596–601 (2012).

Conway, S. et al . European Cystic Fibrosis Society standards of care: framework for the Cystic Fibrosis Centre. J. Cyst. Fibros. 13 , S3–S22 (2014).

European Cystic Fibrosis Society. ECFS Patient Registry annual data report 2010. (European Cystic Fibrosis Society, 2010).

Cystic Fibrosis Trust. UK CF Registry annual report 2011. (Cystic Fibrosis Trust, 2013).

Goss, C. H. et al . Children and young adults with CF in the USA have better lung function compared with the UK. Thorax 70 , 229–236 (2014).

Cystic Fibrosis Australia. 15th Annual Report from the Cystic Fibrosis Data Registry. (Cystic Fibrosis Australia, 2013).

Stern, M. et al . European Cystic Fibrosis Society standards of care: quality management in cystic fibrosis. J. Cyst. Fibros. 13 , S43–S59 (2014).

Quittner, A. L. et al . Pulmonary medication adherence and health-care use in cystic fibrosis. Chest 146 , 142–151 (2014).

Abbott, J., Dodd, M. & Webb, A. K. Health perceptions and treatment adherence in adults with cystic fibrosis. Thorax 51 , 1233–1238 (1996).

Conway, S. P., Pond, M. N., Hamnett, T. & Watson, A. Compliance with treatment in adult patients with cystic fibrosis. Thorax 51 , 29–33 (1996).

Plant, B. J., Goss, C. H., Plant, W. D. & Bell, S. C. Management of comorbidities in older patients with cystic fibrosis. Lancet Respir. Med. 1 , 164–174 (2013).

Grasemann, H. & Ratjen, F. Early lung disease in cystic fibrosis. Lancet Respir. Med. 1 , 148–157 (2013).

Flume, P. A. et al . Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am. J. Respir. Crit. Care Med. 180 , 802–808 (2009).

Smyth, A. R. et al . European Cystic Fibrosis Society Standards of Care: Best Practice guidelines. J. Cyst. Fibros. 13 , S23–S42 (2014).

Okumura, M. J. et al . Improving transition from paediatric to adult cystic fibrosis care: programme implementation and evaluation. BMJ Qual. Saf. 23 (Suppl. 1), i64–i72 (2014).

Lester, M. K. & Flume, P. A. Airway-clearance therapy guidelines and implementation. Respir. Care 54 , 733–753 (2009).

McIlwaine, M. P. et al . Long-term multicentre randomised controlled study of high frequency chest wall oscillation versus positive expiratory pressure mask in cystic fibrosis. Thorax 68 , 746–751 (2013).

Schneiderman, J. E. et al . Longitudinal relationship between physical activity and lung health in patients with cystic fibrosis. Eur. Respir. J. 43 , 817–823 (2014).

Cox, N. S., Alison, J. A. & Holland, A. E. Interventions for promoting physical activity in people with cystic fibrosis. Cochrane Database Syst. Rev. 12 , CD009448 (2013).

Fuchs, H. J. et al . Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. N. Engl. J. Med. 331 , 637–642 (1994).

Jones, A. P. & Wallis, C. E. Recombinant human deoxyribonuclease for cystic fibrosis. Cochrane Database Syst. Rev. 3 , CD001127 (2003).

Shah, P. I. et al . Recombinant human DNase I in cystic fibrosis patients with severe pulmonary disease: a short-term, double-blind study followed by six months open-label treatment. Eur. Respir. J. 8 , 954–958 (1995).

Quan, J. M. et al . A two-year randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities. J. Pediatr. 139 , 813–820 (2001).

Flume, P. A. et al . Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am. J. Respir. Crit. Care Med. 176 , 957–969 (2007). References 197 and 218 describe current standards of care of implementing a cystic fibrosis centre, and for the management of patients with chronic maintenance therapies, respectively.

Elkins, M. R. et al . A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N. Engl. J. Med. 354 , 229–240 (2006).

Rosenfeld, M. et al . Inhaled hypertonic saline in infants and children younger than 6 years with cystic fibrosis: the ISIS randomized controlled trial. JAMA 307 , 2269–2277 (2012).

Subbarao, P. et al . Lung clearance index as an outcome measure for clinical trials in young children with cystic fibrosis. A pilot study using inhaled hypertonic saline. Am. J. Respir. Crit. Care Med. 188 , 456–460 (2013).

Bilton, D. et al . Inhaled dry powder mannitol in cystic fibrosis: an efficacy and safety study. Eur. Respir. J. 38 , 1071–1080 (2011).

Aitken, M. L. et al . Long-term inhaled dry powder mannitol in cystic fibrosis: an international randomized study. Am. J. Respir. Crit. Care Med. 185 , 645–652 (2012).

Ramsey, B. W. et al . Efficacy of aerosolized tobramycin in patients with cystic fibrosis. N. Engl. J. Med. 328 , 1740–1746 (1993).

Ramsey, B. W. et al . Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. N. Engl. J. Med. 340 , 23–30 (1999).

Konstan, M. W. et al . Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: The EAGER trial. J. Cyst. Fibros. 10 , 54–61 (2011).

McCoy, K. S. et al . Inhaled aztreonam lysine for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am. J. Respir. Crit. Care Med. 178 , 921–928 (2008).

Retsch-Bogart, G. Z. et al . A phase 2 study of aztreonam lysine for inhalation to treat patients with cystic fibrosis and Pseudomonas aeruginosa infection. Pediatr. Pulmonol. 43 , 47–58 (2008).

Doring, G., Flume, P., Heijerman, H., Elborn, J. S. & Consensus Study, G. Treatment of lung infection in patients with cystic fibrosis: current and future strategies. J. Cyst. Fibros. 11 , 461–479 (2012).

Tullis, D. E. et al . Inhaled aztreonam for chronic Burkholderia infection in cystic fibrosis: a placebo-controlled trial. J. Cyst. Fibros. 13 , 296–305 (2014).

Wolter, J. et al . Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Thorax 57 , 212–216 (2002).

Saiman, L. et al . Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa : a randomized controlled trial. JAMA 290 , 1749–1756 (2003).

Saiman, L. et al . Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa : a randomized controlled trial. JAMA 303 , 1707–1715 (2010).

Clement, A. et al . Long term effects of azithromycin in patients with cystic fibrosis: A double blind, placebo controlled trial. Thorax 61 , 895–902 (2006).

Konstan, M. W., Byard, P. J., Hoppel, C. L. & Davis, P. B. Effect of high-dose ibuprofen in patients with cystic fibrosis. N. Engl. J. Med. 332 , 848–854 (1995).

Lands, L. C. & Stanojevic, S. Oral non-steroidal anti-inflammatory drug therapy for lung disease in cystic fibrosis. Cochrane Database Syst, Rev. 6 , CD001505 (2013).

Auerbach, H. S., Williams, M., Kirkpatrick, J. A. & Colten, H. R. Alternate-day prednisone reduces morbidity and improves pulmonary function in cystic fibrosis. Lancet 2 , 686–688 (1985).

Eigen, H., Rosenstein, B. J., FitzSimmons, S. & Schidlow, D. V. A multicenter study of alternate-day prednisone therapy in patients with cystic fibrosis. J. Pediatr. 126 , 515–523 (1995).

Balfour-Lynn, I. M. & Welch, K. Inhaled corticosteroids for cystic fibrosis. Cochrane Database Syst. Rev. 11 , CD001915 (2009).

Balfour-Lynn, I. M. et al . Multicenter randomized controlled trial of withdrawal of inhaled corticosteroids in cystic fibrosis. Am. J. Respir. Crit. Care Med. 173 , 1356–1362 (2006).

Konstan, M. W. et al . A randomized double blind, placebo controlled phase 2 trial of BIIL 284 BS (an LTB4 receptor antagonist) for the treatment of lung disease in children and adults with cystic fibrosis. J. Cyst. Fibros. 13 , 148–155 (2014).

Hirche, T. O. et al . Practical guidelines: lung transplantation in patients with cystic fibrosis. Pulm. Med. 2014 , 621342 (2014).

Madden, B. P. et al . Noninvasive ventilation in cystic fibrosis patients with acute or chronic respiratory failure. Eur. Respir. J. 19 , 310–313 (2002).

Gill, D. R. & Hyde, S. C. Delivery of genes into the CF airway. Thorax 69 , 962–964 (2014).

Crystal, R. G. et al . Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis. Nat. Genet. 8 , 42–51 (1994).

Harvey, B. G., Hackett, N. R., Ely, S. & Crystal, R. G. Host responses and persistence of vector genome following intrabronchial administration of an E1 − E3 − , adenovirus gene transfer vector to normal individuals. Mol. Ther. 3 , 206–215 (2001).

Knowles, M. R. et al . A controlled study of adenoviral-vector-mediated gene transfer in the nasal epithelium of patients with cystic fibrosis. N. Engl. J. Med. 333 , 823–831 (1995).

Moss, R. B. et al . Repeated adeno-associated virus serotype 2 aerosol-mediated cystic fibrosis transmembrane regulator gene transfer to the lungs of patients with cystic fibrosis: a multicenter, double-blind, placebo-controlled trial. Chest 125 , 509–521 (2004).

Moss, R. B. et al . Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: a randomized placebo-controlled phase 2B trial. Hum. Gene Ther. 18 , 726–732 (2007).

Griesenbach, U. et al . Assessment of F/HN-pseudotyped lentivirus as a clinically relevant vector for lung gene therapy. Am. J. Respir. Crit. Care Med. 186 , 846–856 (2012).

Alton, E. W. et al . A randomised, double-blind, placebo-controlled phase IIB clinical trial of repeated application of gene therapy in patients with cystic fibrosis. Thorax 68 , 1075–1077 (2013).

Bangel-Ruland, N. et al . Cystic fibrosis transmembrane conductance regulator-mRNA delivery: a novel alternative for cystic fibrosis gene therapy. J. Gene Med. 15 , 414–426 (2013).

Wilschanski, M. et al . Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. N. Engl. J. Med. 349 , 1433–1441 (2003).

Linde, L. et al . Nonsense-mediated mRNA decay affects nonsense transcript levels and governs response of cystic fibrosis patients to gentamicin. J. Clin. Invest. 117 , 683–692 (2007).

Kerem, E. et al . Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Respir. Med. 2 , 539–547 (2014).

Study of ataluren (PTC124 ® ) in cystic fibrosis [online] , (2014).

Van Goor, F. et al . Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc. Natl Acad. Sci. USA 106 , 18825–18830 (2009).

Rowe, S. M. et al . Clinical mechanism of the cystic fibrosis transmembrane conductance regulator potentiator ivacaftor in G551D-mediated cystic fibrosis. Am. J. Respir. Crit. Care Med. 190 , 175–184 (2014).

De Boeck, K. et al . Efficacy and safety of ivacaftor in patients with cystic fibrosis and a non-G551D gating mutation. J. Cyst. Fibros. 13 , 674–680 (2014).

Sloane, P. A. et al . A pharmacologic approach to acquired cystic fibrosis transmembrane conductance regulator dysfunction in smoking related lung disease. PLoS ONE 7 , e39809 (2012).

Flume, P. A. et al . Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest 142 , 718–724 (2012).

Boyle, M. P. et al . A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial 2 , 527–538 (2014).

Van Goor, F. et al . Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc. Natl Acad. Sci. USA 108 , 18843–18848 (2011).

Veit, G. et al . Some gating potentiators, including VX-770, diminish ΔF508–CFTR functional expression. Sci. Transl. Med. 6 , 246ra97 (2014).

Cholon, D. M. et al . Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis. Sci. Transl. Med. 6 , 246ra96 (2014).

Okiyoneda, T. et al . Mechanism-based corrector combination restores DeltaF508-CFTR folding and function. Nat. Chem. Biol. 9 , 444–454 (2013).

Accurso, F. J. et al . Denufosol tetrasodium in patients with cystic fibrosis and normal to mildly impaired lung function. Am. J. Respir. Crit. Care Med. 183 , 627–634 (2011).

Ratjen, F. et al . Long term effects of denufosol tetrasodium in patients with cystic fibrosis. J. Cyst. Fibros. 11 , 539–549 (2012).

Burrows, E. F., Southern, K. W. & Noone, P. G. Sodium channel blockers for cystic fibrosis. Cochrane Database Syst, Rev. 4 , CD005087 (2014).

Quittner, A. L., Alpern, A. N. & Kimberg, C. I. in Kendig and Chernick's Disorders of the Respiratory Tract in Children . 8th edn (eds Wilmott, R. W., Boat, T. F., Bush, A., Chernick, V., Deterding, R. R. & Ratjen, F. ) 251–260 (Elsevier (Saunders), 2012).

Book   Google Scholar  

Goss, C. H., Edwards, T. C., Ramsey, B. W., Aitken, M. L. & Patrick, D. L. Patient-reported respiratory symptoms in cystic fibrosis. J. Cyst. Fibros. 8 , 245–252 (2009).

Schmidt, A. M. et al . Exercise and quality of life in patients with cystic fibrosis: A 12-week intervention study. Physiother Theory Pract. 27 , 548–556 (2011).

Schechter, M. S. et al . Long-term effects of pregnancy and motherhood on disease outcomes of women with cystic fibrosis. Ann. Am. Thorac Soc. 10 , 213–219 (2013).

Sawicki, G. S. et al . Longitudinal assessment of health-related quality of life in an observational cohort of patients with cystic fibrosis. Pediatr. Pulmonol. 46 , 36–44 (2011).

Snyder, C. F. et al . Implementing patient-reported outcomes assessment in clinical practice: a review of the options and considerations. Qual. Life Res. 21 , 1305–1314 (2012).

Sawicki, G. S., Sellers, D. E. & Robinson, W. M. High treatment burden in adults with cystic fibrosis: challenges to disease self-management. J. Cyst. Fibros. 8 , 91–96 (2009).

Quittner, A. L. Measurement of quality of life in cystic fibrosis. Curr. Opin. Pulm. Med. 4 , 326–331 (1998).

Goss, C. H. & Quittner, A. L. Patient-reported outcomes in cystic fibrosis. Proc. Am. Thorac. Soc. 4 , 378–386 (2007).

Quittner, A. L. et al . Erratum to: Psychometric evaluation of the Cystic Fibrosis Questionnaire-Revised in a national, US sample. Qual. Life Res. 21 , 1279–1290 (2012).

Donaldson, S. H. et al . Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N. Engl. J. Med. 354 , 241–250 (2006).

Sawicki, G. S. et al . Treatment complexity in cystic fibrosis: trends over time and associations with site-specific outcomes. J. Cyst. Fibros. 12 , 461–467 (2013). References 277 and 281 show the treatment burden and the complexity in patients with cystic fibrosis, respectively.

Quittner, A. L. et al . Impact of socioeconomic status, race, and ethnicity on quality of life in patients with cystic fibrosis in the United States. Chest 137 , 642–650 (2010).

Quittner, A. L. et al . Prevalence of depression and anxiety in patients with cystic fibrosis and parent caregivers: results of The International Depression Epidemiological Study across nine countries. Thorax 69 , 1090–1097 (2014).

Smith, B. A., Modi, A. C., Quittner, A. L. & Wood, B. L. Depressive symptoms in children with cystic fibrosis and parents and its effects on adherence to airway clearance. Pediatr. Pulmonol. 45 , 756–763 (2010).

Riekert, K. A., Bartlett, S. J., Boyle, M. P., Krishnan, J. A. & Rand, C. S. The association between depression, lung function, and health-related quality of life among adults with cystic fibrosis. Chest 132 , 231–237 (2007).

Goldbeck, L. et al . Prevalence of symptoms of anxiety and depression in German patients with cystic fibrosis. Chest 138 , 929–936 (2010).

Snell, C., Fernandes, S., Bujoreanu, I. S. & Garcia, G. Depression, illness severity, and healthcare utilization in cystic fibrosis. Pediatr. Pulmonol. 49 , 1177–1181 (2014).

Wong, A. P. et al . Directed differentiation of human pluripotent stem cells into mature airway epithelia expressing functional CFTR protein. Nat. Biotech. 30 , 876–882 (2012). References 135 and 288 describe model systems to assess response to CFTR modulators in vitro by either using intestinal organoids or skin-derived pluripotent stem cells transformed into airway epithelial cells, respectively.

Download references

Author information

Authors and affiliations.

Division of Respiratory Medicine, Department of Paediatrics, The Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto, M5G 1X8, Canada

Felix Ratjen

Department of Thoracic Medicine, Queensland Children's Medical Research Institute, Brisbane, Queensland, Australia

Scott C. Bell

Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA

Steven M. Rowe

Division of Pulmonary and Critical Care Medicine, University of Washington Medical Center, Seattle, Washington, USA

Christopher H. Goss

Department of Psychology, University of Miami, Miami, Florida, USA

Alexandra L. Quittner

Paediatrics Section, Imperial College, Paediatric Respirology, National Heart and Lung Institute, and the Royal Brompton Harefield NHS Foundation Trust, London, UK

Andrew Bush

You can also search for this author in PubMed   Google Scholar

Contributions

Introduction (F.R.); Epidemiology (C.H.G.), Mechanisms/pathophysiology (S.M.R. and S.C.B.); Diagnosis, screening and prevention (A.B., F.R. and S.M.R.); Management (S.C.B. and F.R.); Quality of life (A.L.Q.); Outlook (F.R. and A.B.); overview of the Primer (F.R.).

Corresponding author

Correspondence to Felix Ratjen .

Ethics declarations

Competing interests.

S.M.R. has received grants and/or non-financial support from: Cystic Fibrosis Foundation Therapeutics, the US National Institutes of Health (NIH), Vertex Pharmaceuticals, PTC Therapeutics, Novartis, Forest Research Institute, Bayer Healthcare and Galapagos. C.H.G. has received grant funding and/or honoraria from: the NIH (grants P30 DK089507, R01HL103965, R01AI101307 and UM1HL119073), Food and Drug Administration (grant R01FD003704), the Cystic Fibrosis Foundation, Vertex Pharmaceuticals, Transave Inc., L. Hoffmann-La Roche Ltd, Johns Hopkins University, the European Cystic Fibrosis Society, Medscape and Gilead Sciences. He has also participated in Advisory Boards for KaloBios Pharmaceuticals and Transave Inc. A.L.Q. has received grants and/or consulting income from: NIH (grant R01 DC04797), European Union Health Commission (BESTCILIA), National Health and Medical Research Council of Australia, Cystic Fibrosis Foundation Clinical Research Grant, Novartis, Abbott Pharmaceuticals, Vertex Pharmaceuticals and Gilead Sciences. F.R. has received grants and/or consulting fees from: the Canadian Institutes of Health Research, National Heart, Lung, and Blood Institute, the Cystic Fibrosis Foundation, Genentech, Vertex Pharmaceuticals, Novartis, Gilead Sciences, Boehringer Ingelheim and Roche. S.C.B. has received grants, personal fees, speaker's fees and/or non-financial support from the National Health and Medical Research Council of Australia, the Cystic Fibrosis Foundation, the Office of Health and Medical Research, Queensland Health, the Queensland Children's Foundation, Vertex Pharmaceuticals, Novartis and Gilead. He has served on advisory boards for Vertex Pharmaceuticals, Novartis and Rempex and as a site principal investigator in several clinical trials sponsored by Vertex Pharmaceuticals. A.B. is supported by the UK National Institute of Health Research Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield National Health Service Foundation Trust and Imperial College London.

PowerPoint slides

Powerpoint slide for fig. 1, powerpoint slide for fig. 2, powerpoint slide for fig. 3, powerpoint slide for fig. 4, powerpoint slide for fig. 5, powerpoint slide for fig. 6, rights and permissions.

Reprints and permissions

About this article

Cite this article.

Ratjen, F., Bell, S., Rowe, S. et al. Cystic fibrosis. Nat Rev Dis Primers 1 , 15010 (2015). https://doi.org/10.1038/nrdp.2015.10

Download citation

Published : 14 May 2015

DOI : https://doi.org/10.1038/nrdp.2015.10

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

This article is cited by

Solvent effects in anion recognition.

• Sophie C. Patrick
• Paul D. Beer
• Jason J. Davis

Nature Reviews Chemistry (2024)

Dual-color live imaging unveils stepwise organization of multiple basal body arrays by cytoskeletons

• Gen Shiratsuchi
• Satoshi Konishi
• Sachiko Tsukita

EMBO Reports (2024)

Longitudinal microbial and molecular dynamics in the cystic fibrosis lung after Elexacaftor–Tezacaftor–Ivacaftor therapy

• Christian Martin
• Douglas V. Guzior
• Robert A. Quinn

Respiratory Research (2023)

Lung development and regeneration: newly defined cell types and progenitor status

• Xiaogao Meng
• Guizhong Cui
• Guangdun Peng

Cell Regeneration (2023)

Fractional Exhalation Nitric Oxide (FeNO) changes in cystic fibrosis patients induced by compound honey syrup: a pretest–posttest clinical trial

• Hanieh Tahermohammadi
• Shima Derikvandi

BMC Pulmonary Medicine (2023)

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

• Open access
• Published: 12 April 2024

The prevalence of developmental defects of enamel in people with cystic fibrosis: a systematic review

• Fiona O’Leary 1 , 2 ,
• Niamh Coffey 1 ,
• Martina Hayes 3 ,
• Francis Burke 1 ,
• Mairéad Harding 1 &
• Barry Plant 4  

BMC Oral Health volume  24 , Article number:  446 ( 2024 ) Cite this article

Metrics details

Oral health impacts systemic health, individual well-being, and quality of life. It is important to identify conditions that may exacerbate oral disease to aid public health and policy development and promote targeted patient treatment strategies. Developmental defects can increase an individual’s risk of dental caries, hypersensitivity, premature tooth wear, erosion, and poor aesthetics. As part of an ongoing study assessing oral health in adults with cystic fibrosis at Cork University Dental School and Hospital, a systematic review of available literature was conducted to assess the prevalence of enamel defects in people with cystic fibrosis.

To critically evaluate the literature to determine if the prevalence of developmental defects of enamel is higher in people with cystic fibrosis (PwCF).

Data Sources: Three online databases were searched Embase, Scopus, and Web of Science Core Collection. Studies that examined an association between cystic fibrosis and developmental defects of enamel were included in this systematic review.

The initial search identified 116 publications from the following databases Embase, Web of Science Core Collection, and Scopus. Eleven studies were included for qualitative analysis. Nine studies concluded that PwCF had a higher prevalence of enamel defects than control people and one study found no difference in cystic fibrosis (CF) status. All studies had a risk of bias that may influence study results and their interpretation.

Conclusions

The results of the systematic review show a consistent pattern that PwCF have a higher prevalence of DDE than people without CF. Genetic dysfunction, chronic systemic infections, and long-term antibiotic use are possible aetiological causes. This review highlights the need for future studies to investigate if DDEs are caused by the underlying CFTR mutation or as a consequence of disease manifestations and/or management.

Peer Review reports

Introduction

Developmental defects of enamel (DDE) are disturbances in the quality and/or quantity of enamel which present as enamel hypoplasia and/or enamel hypomineralisation. Enamel hypoplasia is a quantitative defect of enamel presenting clinically as surface pits and groves, enamel absence, and microdontia. Enamel hypomineralisation is a qualitative defect of mineral content resulting in the discolouration of teeth. Enamel defects may affect a single tooth or multiple or groups of teeth [ 1 ]. Individuals with DDE may be at a greater risk of oral pathologies such as dental caries, hypersensitivity, and premature tooth wear [ 2 ]. DDE also poses a considerable aesthetic concern for patients [ 3 ]. Additional dental concerns associated with the presence of DDEs include dental behavioural problems such as dental fear and anxiety [ 1 ].

DDEs are caused by diverse interacting genetic and environmental factors. There is a higher prevalence of DDEs in individuals with genetic conditions such as amelogenesis imperfecta and ectodermal dysplasia [ 4 ] and systemic conditions such as coeliac disease. People with cystic fibrosis (CF) have also been identified as having a higher prevalence of enamel defects. CF is an autosomal recessive condition caused by a mutation of the cystic fibrosis transmembrane conductance regulator gene (CFTR). Pulmonary manifestations of the disease are most widely recognised; however, multiple organ systems are affected by the condition. The exact aetiology of DDEs within this population is not fully understood, reports from animal studies indicate that the dysfunctional CFTR gene may be responsible. Other possible aetiologies include recurrent systemic infection, long- term antibiotic use, and nutritional malabsorption similar to that seen in coeliac disease.

Oral health in CF populations is under-researched possibly as a consequence of historic premature mortality, however, people with cystic fibrosis (PwCF) are now living longer. This is a consequence of multifaceted developments in the management of the disease particularly the introduction of gene modulator therapies. These target the underlying genetic mutation and were introduced in 2012. Previous studies have identified the oral cavity as a reservoir for bacteria capable of colonising the pulmonary system [ 5 ]. It is imperative to identify if people with this condition are at a greater risk of developing oral disease so that preventative programmes and targeted patient care can be developed. These are some of the catalysts for conducting research into the oral health in the CF population. There are currently no guidelines for the provision of dental care for PwCF. Therefore, it is timely to review the existing evidence regarding oral manifestations of CF specifically enamel defects. This can identify gaps in research and aid in future research design. The objective of this systematic review was to identify if PwCF have a higher prevalence of DDE than people without CF. A systematic review of the current literature was conducted. The following research question was formulated using the PICO framework; Is the prevalence of developmental defects of enamel higher in people with cystic fibrosis compared to people without cystic fibrosis?

Materials and methods

Eligibility criteria.

Studies were screened according to the following inclusion and exclusion criteria. The inclusion criteria were formed based on the parameters of the review PICO (study population: people with cystic fibrosis, intervention: developmental defects of enamel). Articles published between 1960 and 2023 permitted a larger search scale and allowed the authors to determine if any time trends in the prevalence of DDEs existed. Only primary literature sources were used, hence review articles were excluded.

Inclusion criteria

Studies involving human subjects.

Studies that were of cohort, cross-sectional or case-control design.

Study subjects had a positive diagnosis of cystic fibrosis.

Studies published from 1960 to 2023.

Developmental defects of enamel reported for deciduous and/or permanent teeth.

Exclusion criteria

Studies involving animal subjects.

Review articles.

Information sources

The searches were conducted in the following electronic databases: Embase, Web of Science Core Collection, and Scopus. The bibliographies of relevant publications were manually screened to identify additional publications not found in the electronic databases.

Search strategy and selection criteria

The following search terms “cystic fibrosis” AND “enamel defect”, “cystic fibrosis” AND “dental hard tissue”, “cystic fibrosis” AND “developmental enamel defect”, “cystic fibrosis” AND “dental hypoplasia”, “cystic fibrosis” AND “dental hypomineralisation” were used. Identical methods were used to search for all relevant publications in all three databases. The final search was conducted on the 13th of December 2023. An example of a search strategy is included in Appendix 1 .

Two investigators (FO’L & NC) screened titles and abstracts to determine eligibility. Full articles were obtained for identified titles and those that met eligibility were included in the review. Investigators (FO’L & NC) worked independently, and any differences in opinion were reviewed by a third investigator (MH).

The following data were extracted by two investigators (FO’L & NC) from studies meeting the eligibility criteria: year of study, type of study, participant ages, sample size, prevalence of enamel defects, statistical methods, and study conclusions.

Study selection

The search resulted in 116 publications from Embase, Web of Science Core Collection, and Scopus. Following title and abstract screening, 11 publications were included for full-text screening. Two publications referred to the same study so were therefore considered as one. Ten studies were included for qualitative analysis (Fig.  1 ).

Flow chart indicating the number of records identified and included for qualitative analysis on developmental defects of enamel in people with cystic fibrosis

Study characteristics

Of the ten studies included, three were conducted in the USA [ 6 , 7 , 8 ], five in Europe [ 9 , 10 , 11 , 12 , 13 ], one in Brazil [ 14 ],and one in Turkey [ 15 ]. A total of 476 people with CF were studied. The earliest study included was published in 1976 6 , with the most recent study published in 2019 12 .

Eight studies included children and adolescents with CF up to the age of eighteen 6,8–11,13−15 . One study included both children and adults with CF over the age of eighteen [ 7 ]. One study limited study participants to adults with CF over the age of eighteen [ 12 ].

Several different clinical indices were used to categorize enamel defects. Four studies used the modified developmental defects of enamel (mDDE) index [ 8 , 10 , 11 , 12 ], and one study used the DDE index [ 14 ]. The study conducted by Narang [ 9 ] categorized enamel defects based on WHO criteria. Primosch [ 7 ] measured defects using criteria developed by Russel [ 16 ], whereas Peker used criteria developed by Weerheijm [ 17 ]. The study conducted by Jagels and Sweeney [ 6 ] measured enamel defects as a percentage of teeth showing hypomineralisation.

Eight studies included control groups [ 6 , 7 , 9 , 10 , 11 , 12 , 14 , 15 ], and only two studies did not [ 8 , 13 ]. Six studies included age and gender-matched ‘healthy’ individuals in the control group [ 7 , 10 , 11 , 12 , 14 , 15 ], one study included non-CF siblings in the control group [ 6 ], and another study included control subjects with chronic respiratory conditions [ 9 ]. This data is summarised in Table  1 .

Four studies reported a statistically significant increase in the prevalence of DDE in PwCF compared to non-CF control groups [ 8 , 10 , 11 , 12 ]. The study by Narang [ 9 ] reported a statistically significant difference in the prevalence of DDE in the CF control group aged 6–9 years only. Two studies reported a non-significant increase in the prevalence of DDE between CF a non-CF control groups [ 14 , 15 ]. Primosch [ 7 ] found that DDE were more common in people with CF compared to healthy individuals. Two studies by Jagels and Sweeney [ 6 ] and Collard [ 13 ] reported no difference in the prevalence of enamel defects between PwCF and non-CF people/ national averages. These results are summarised in Table  2 .

Risk of Bias

The risk of bias was assessed using several headings. These were adapted from previous reviews in this subject field by Chi et al. [ 18 ] and Coffey et al. [ 19 ]. This assessment was conducted by two investigators working independently (FO’L & NC). Any conflict was reviewed by a third investigator (MH). Studies meeting all seven criteria were classified as being at low risk of bias. Studies meeting three to five criteria were classified as medium risk of bias. Studies meeting less than three criteria were classified as being at high risk of bias. Seven studies were classified as being at medium risk of bias, and three as a high risk [ 6 , 7 , 13 ]. Eight studies included a control group [ 6 , 7 , 9 , 10 , 11 , 12 , 14 , 15 ]. Only one study provided an explanation for the study group [ 6 ]. The study by Jagels and Sweeney included non-CF siblings [ 6 ] in the control group. The study by Narang included individuals with chronic respiratory illness as control subjects [ 9 ]. The inclusion of such control groups may influence results as siblings may be carriers of the CFTR mutation, and people with respiratory illness may have a similar therapeutic history to PwCF. A limitation common to all studies was the absence of examiner blinding. The authors appreciate this may be difficult to achieve owing to the complex medical history of PwCF. Five studies were conducted by one examiner and did not provide sufficient information regarding examiner reliability [ 6 , 7 , 9 , 14 , 15 ]. Seven studies adopted standard defect measures (e.g., DDE, mDDE) [ 8 , 9 , 10 , 11 , 13 , 14 ], while three studies did not (Table  3 ) [ 6 , 7 , 15 ].

The objective of this review was to identify if PwCF had a higher prevalence of enamel defects compared to people without. The results of the review indicate that while there is not a unanimous agreement across all studies, there is a consistent pattern that the prevalence of enamel defects is higher in PwCF. Eight studies reported an increased prevalence of enamel defects in CF groups compared to non-CF control groups. Five of these studies reported a statistically significant increase [ 8 , 9 , 10 , 11 , 12 ], although the study by Narang et al. found this difference was limited to children aged between 6 and 9 years only [ 9 ]. The differences in enamel defect status in the additional three studies were not statistically significant [ 7 , 14 , 15 ]. Two studies reported no difference in the prevalence of enamel defects between groups [ 6 , 13 ]. One of these studies by Jagels & Sweeney used siblings of individuals with CF as control participants. These individuals may carrier one of the CFTR mutations which may influence results. Interpretation of the study outcomes should be done with caution as all studies reviewed had design and/or methodological limitations that placed them at a medium or high risk of bias. The risk of bias and small sample sizes may reduce the validity and reliability of the study findings.

There are several limitations of the data included in this review. Studies used different measurement indices for enamel defects. Some studies measured defects at an individual level (percentage of individuals with enamel defects), while other studies measured at a tooth level (percentage of teeth with enamel defects). The absence of a standardised measurement criteria makes the comparability of studies challenging. Six studies were conducted by a single examiner. Therefore, we cannot exclude the possibility of examiner bias in these studies. Four studies [ 8 , 11 , 12 ] were conducted by multiple examiners which is a study strength however, only three provided information regarding examiner training and reliability. For ease of reproducibility and comparability, future studies should include details of examiners training and calibration using a WHO-approved or standardised measurement index.

Another limitation common to all studies was the recruitment of small sample sizes, with children and adolescents accounting for the majority of study participants. To increase study recruitment and sample sizes, future studies should use a multicentre approach. The majority of studies were conducted before the introduction of gene modulators such as Kaftrio® and Orizaba® in 2012 and can now be deemed historic. Only three studies [ 8 , 15 , 20 ] were conducted after the introduction of these medications. Gene modulators improve CFTR function, reduce pulmonary exacerbations and systemic manifestations of the disease [ 21 ]. However, PwCF included in these three studies would not have had the benefit of gene modulators during tooth development since mineralisation of permanent teeth occurs during the first three years of life. Children as young as four months old are now being offered gene modulator therapy. DDE in PwCF have been attributed to metabolic disturbances, long-term antibiotic, surgical intervention, and pancreatic enzyme use [ 11 , 7 , 8 ]. It is therefore reasonable to assume that with fewer disease manifestations and exacerbations requiring antibiotics, and surgical intervention as a result of improved CFTR function there may be a reduction in the number of enamel defects in children with CF.

This review was conducted to identify gaps in the area of oral health in PwCF. A strength was a clearly defined and reproducible search criteria which was conducted by two investigators independently (FO’L & NC). The inclusion of two investigators aims to reduce the risk of reviewer bias. The investigators included articles published between 1960 and 2023, publications were not confined to the English language which permitted a larger search scale. While the authors manually screened bibliographies there is a possibility that not all eligible publications were included which is a limitation of the study.

The objective of the systematic review was met. A general trend that PwCF have more enamel defects than people without was identified. While the strength of the evidence to support this was moderate at best, if one considers the concepts of biological plausibility, accepted medical knowledge, and consistent result patterns the strength of the evidence is greatly improved. The presence of DDEs increases the risk of preventable oral diseases such as dental caries and erosion occurring, both can negatively impact an individual’s quality of life and masticatory function. Therefore, dental practitioners should be mindful of this so that early identification and appropriate treatment can be provided to the patient. Prevention and early intervention may afford PwCF the opportunity and tools to maintain their dentition into old age. The review has highlighted a need for future longitudinal studies taking a multi-centre approach assessing the effect that gene modulator therapies have on the incidence of DDE.

Data availability

The datasets used and/or analysed during the current study are included within this paper and available from online database Embase, Scopus, Web of Science Core Collection.

Jälevik B, Szigyarto-Matei A, Robertson A. The prevalence of developmental defects of enamel, a prospective cohort study of adolescents in western Sweden: a barn I TAnadvarden (BITA, children in dental care) study. Eur Archives Pediatr Dentistry. 2018;19(3):187–95. https://doi.org/10.1007/s40368-018-0347-7 .

Article   Google Scholar  

Robles MJ, Ruiz M, Bravo-Perez M, González E, Peñalver MA. Prevalence of enamel defects in primary and permanent teeth in a group of schoolchildren from Granada (Spain). Med Oral Patol Oral Cir Bucal . Mar 1. 2013;18(2):e187-93. https://doi.org/10.4317/medoral.18580 .

Sadana G, Gupta T, Rai HK. Effect of esthetic defects in Anterior Teeth on the emotional and Social Well-being of children: a Survey. Int J Clin Pediatr Dentistry. 2019;12(3):229–32. https://doi.org/10.5005/jp-journals-10005-1628 .

Seow WK. Developmental defects of enamel and dentine: challenges for basic science research and clinical management. Aust Dent J. 2014;59(SUPPL 1):143–54. https://doi.org/10.1111/adj.12104 .

Article   PubMed   Google Scholar  

Gomes-Filho IS, Passos JS, Da Cruz SS. Respiratory disease and the role of oral bacteria. Journal of Oral Microbiology . 2010;2(2010) https://doi.org/10.3402/jom.v2i0.5811 .

Jagels AE, Sweeney EA. Oral health of patients with cystic fibrosis and their siblings. J Dent Res. 1976;55(6):991–6. https://doi.org/10.1177/00220345760550065101 .

Article   CAS   PubMed   Google Scholar  

Primosch RE. Tetracycline discoloration, enamel defects, and dental caries in patients with cystic fibrosis. Oral Surgery, Oral Medicine, Oral Pathology . 1980/10/01/1980;50(4):301–308. https://doi.org/10.1016/0030-4220(80)90411-9 .

Abu-Zahra R, Antos NJ, Kump T, Angelopoulou MV. Oral health of cystic fibrosis patients at a north American center: a pilot study. Med Oral Patol Oral Cir Bucal May. 2019;1(3):e379–84. https://doi.org/10.4317/medoral.22756 .

Narang A, Maguire A, Nunn JH, Bush A. Oral health and related factors in cystic fibrosis and other chronic respiratory disorders. Arch Dis Child. 2003;88:702–7.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Ferrazzano GF, Orlando S, Sangianantoni G, Cantile T, Ingenito A. Dental and periodontal health status in children affected by cystic fibrosis in a southern Italian region. Eur J Paediatr Dent Jun. 2009;10(2):65–8.

CAS   Google Scholar  

Ferrazzano GF, Sangianantoni G, Cantile T, Amato I, Orlando S, Ingenito A. Dental enamel defects in Italian children with cystic fibrosis: an observational study. Community Dent Health. 2012;29(1):106–9.

CAS   PubMed   Google Scholar  

Pawlaczyk-Kamieńska T, Borysewicz-Lewicka M, Śniatała R, Batura-Gabryel H. Clinical evaluation of the dental hard tissues in an adult population with cystic fibrosis. Pol Archives Intern Med. 2019.

Collard M, Azzopardi KA, Hall SJ, Jones V, Thia LP. Oral health in children with cystic fibrosis. Conference Abstract. Journal of Cystic Fibrosis . 2016;15:S87-S88.

Azevedo TDPL, Feijó GCS, Bezerra ACB. Presence of developmental defects of enamel in cystic fibrosis patients. J Dentistry Child (Chicago Ill). 73(3):159–63.

Peker S, Mete S, Gokdemir Y, Karadag B, Kargul B. Related factors of dental caries and molar incisor hypomineralisation in a group of children with cystic fibrosis. Eur Archives Pediatr Dentistry. 2014;15:275–80.

Article   CAS   Google Scholar  

RUSSELL AL, THE DIFFERENTIAL DIAGNOSIS OF FLUORIDE, AND NONFLUORIDE ENAMEL OPACITIES. J Public Health Dent. 1961;21(4):143–6. https://doi.org/10.1111/j.1752-7325.1961.tb00373.x .

Weerheijm KL, Mejàre I. Molar incisor hypomineralization: a questionnaire inventory of its occurrence in member countries of the European Academy of Paediatric Dentistry (EAPD). Int J Paediatr Dent Nov. 2003;13(6):411–6. https://doi.org/10.1046/j.1365-263x.2003.00498.x .

Chi DL. Dental caries prevalence in children and adolescents with cystic fibrosis: a qualitative systematic review and recommendations for future research. Int J Paediatr Dent Sep. 2013;23(5):376–86. https://doi.org/10.1111/ipd.12042 .

Coffey N, O’ Leary F, Burke F, Roberts A, Hayes M. Periodontal and oral health status of people with Cystic Fibrosis: a systematic review. Journal of dentistry . 2020 12 (Epub 2020 Oct 2020;103:103509. https://doi.org/10.1016/j.jdent.2020.103509 .

Pawlaczyk–Kamieńska T, Borysewicz–Lewicka M, Śniatała R, Batura–Gabryel H. Clinical evaluation of dental hard tissues in an adult population with cystic fibrosis. Article. Pol Archives Intern Med. 2019;129(10):725–7. https://doi.org/10.20452/pamw.14918 .

Martin C, Guzior DV, Gonzalez CT et al. Longitudinal microbial and molecular dynamics in the cystic fibrosis lung after Elexacaftor–Tezacaftor–Ivacaftor therapy. Respir Res . 2023/12/16 2023;24(1):317. https://doi.org/10.1186/s12931-023-02630-z .

Download references

Acknowledgements

The authors would like to acknowledge Cystic Fibrosis Ireland, the College of Medicine and Health Interdisciplinary Seed Awards [CiSA], and the Health Research Board of Ireland [CSF-2020-003], who provided funding for this paper and ongoing research into the area of Oral Health in Adults with Cystic Fibrosis.

Cystic Fibrosis Ireland, the College of Medicine and Health interdisciplinary Seed Awards [CiSA], and the Health Research Board of Ireland [CSF-2020-003] provided funding for this paper.

Author information

Authors and affiliations.

Cork University Dental School & Hospital, Wilton, Cork, Ireland

Fiona O’Leary, Niamh Coffey, Francis Burke & Mairéad Harding

University College Cork, Wilton, Cork, Ireland

Fiona O’Leary

Dublin Dental University Hospital, Trinity College Dublin, Dublin, Ireland

Martina Hayes

University College Cork, Cork, Ireland

Barry Plant

You can also search for this author in PubMed   Google Scholar

Contributions

O Leary, F contributed to conception and design, to acquisition, drafted the manuscript, critically revised manuscript and agrees to be accountable for all aspects of work ensuring integrity and accuracy.Coffey, N contributed to acquisition and interpretation, critically revised manuscript and gave final approval.Hayes, M contributed to concept and design, critically revised the manuscript and gave final approval Burke, F contributed to design, critically revised the manuscript and gave final approval.Harding, M critically revised the manuscript and provided images for the manuscript and gave final approval Plant, B contributed to design and concept and gave final approval All authors reviewed the manuscript.

Corresponding author

Correspondence to Fiona O’Leary .

Ethics declarations

Ethics approval and consent to participate.

Not Applicable.

Consent for publication

Competing interests.

The authors declare no competing interests.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

O’Leary, F., Coffey, N., Hayes, M. et al. The prevalence of developmental defects of enamel in people with cystic fibrosis: a systematic review. BMC Oral Health 24 , 446 (2024). https://doi.org/10.1186/s12903-024-04227-4

Download citation

Received : 18 July 2023

Accepted : 04 April 2024

Published : 12 April 2024

DOI : https://doi.org/10.1186/s12903-024-04227-4

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Cystic fibrosis
• Developmental Defects of Enamel
• Oral health
• Public Health Policy
• Policy Development
• Prevention.

BMC Oral Health

ISSN: 1472-6831

• Submission enquiries: [email protected]
• General enquiries: [email protected]

Queen's University Belfast

• Semester dates
• Ask a question
• Staff Directory
• Undergraduate
• Postgraduate
• International Students
• Students from Great Britain
• Fees & Funding
• Open Learning
• Short Courses
• Accommodation
• Life in Belfast
• Open Days & Campus Tours
• The Graduate School
• Queen's Sport
• Your Student Guide
• Research Themes
• Global Research
• Research Areas
• Research Excellence Framework
• Research Strategy
• Research Impact
• Research Opportunities
• Postdoctoral Development Centre
• Governance, Ethics and Integrity
• Sustainability Research
• Research Contacts
• Applying to Queen's
• English Language Requirements
• Tuition Fees
• International Scholarships
• INTO Queen's
• Exchange and Study Abroad
• Find Your Country / Region
• Middle East and North Africa
• South East Asia
• Sub Saharan Africa
• Commercialisation
• Case Studies
• Knowledge Transfer Partnerships
• IP & Innovation
• Business Support
• Business Engagement
• Chief Executives' Club
• Queen's Business School
• William J Clinton Leadership Institute
• MBA programme
• Campus & Facilities
• Sustainability
• Social Charter
• Public Engagement
• Leadership and Structure
• Strategy 2030
• Faculties & Schools
• Professional Services
• University Department List
• Rankings and Reputation
• Our Research
• Research portal
• Global Research Institutes
• Governance, ethics and integrity
• Support for researchers
• News and Media
• Research contacts

Transforming the lives of people with Cystic Fibrosis

Researchers from Queen’s have transformed the lives of people with Cystic Fibrosis by leading on the clinical development of treatments that address the underlying genetic disorder.

Research Challenge

80,000 people live with cystic fibrosis globally.

Cystic Fibrosis is a progressive, life-limiting genetic disease that causes severe respiratory and digestive problems as well as other complications such as infections and diabetes.

There are over 80,000 people living with Cystic Fibrosis globally, including 10,500 in the UK accounting for 9,500 hospital admissions and over 100,000 bed days per year .

The condition is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene which is responsible for the regulation of salt and water levels in the body. The mutations can lead to the build-up of thick mucus in the lungs, digestive tract and other parts of the body causing persistent chest infections, resulting in lung damage and an early death.

Our Approach

Pioneering a drug development programme.

Queen’s University’s Cystic Fibrosis research team is recognised as world leading, having worked for over 12 years supporting the development of drugs that improve the function of CTFR.

Prior to their work, treatments for Cystic Fibrosis had been focused on symptom control. However, during the last decade, Queen’s University Belfast has been at the forefront of major advancements in drugs targeting the underlying genetic deficit .

This work included the development of clinical trial protocols, and inclusion of key outcome measures such as; lung function (FEV1), pulmonary exacerbation rate, and Quality of Life (QoL) tools for use in clinical trials of new therapeutics.

Extensive clinical trial experience coupled with a Clinical Trial Network infrastructure established by Queen’s and the Belfast Health and Social Care Trust, resulted in Queen’s playing a pivotal role in a drug development programme working alongside Vertex Pharmaceuticals to deliver trials for single, double and triple therapies in Cystic Fibrosis .

Working with industry, clinical trial networks and contract research organisations and colleagues at other Higher Education Institutes such as Imperial College, Queen’s University has developed expertise in the delivery of clinical trials of single and multiple combination therapies .

Their expertise in Cystic Fibrosis, and with respect to clinical trials has hugely contributed to the outstanding progress in treating this severe, life shortening disease across more than a decade of dedicated help and knowledge. - Vice-President of Medical Affairs, Vertex Pharmaceuticals

What impact did it make?

Transforming the lives of people with cystic fibrosis.

These transformative therapies improve lung health and have underpinned the regulatory approval and marketing of 4 breakthrough Cystic Fibrosis therapies . 

The most recent trials successfully demonstrated that a combination of drugs can treat up to 90% of people with Cystic Fibrosis by addressing the underlying cause of their disease. This new “triple therapy” results in a significant improvement in lung function and quality of life and reduces the frequency of chest infections.   

Both the Food and Drug Administration and the European Medicines Agency approved Trikafta (US)/Kaftrio (EU) for use in 2020. The drug was hailed as a  “landmark approval” by the FDA having an expedited approval process including Priority Review, Fast Track, Breakthrough Therapy, and orphan drug designation. 

The importance of these CFTR modulators has also been recognised by experts in the international CF community. The National Institutes of Health Director who, with colleagues, discovered the CFTR mutation in 1989 spoke about the importance of the Trikafta phase 3 trial results:

“…it has been 30 years that we've been hoping and dreaming for a day like this, where you could look at data and just absolutely - your jaw drops because it is so impressive and so good. Now we are at the point with this triple therapy where 90% of people with cystic fibrosis are going to have substantial and amazing benefit from the drug therapy...”  

The Queen’s research team has been instrumental in developing and strengthening international Cystic Fibrosis research initiatives.  Professor Stuart Elborn  was instrumental in establishing the  of which  Dr Damien Downey  is now Director. It has grown to encompass 58 research centres across 17 countries, caring for over 21,000 adult and paediatric patients, which is approximately 20% of the global population of patients with Cystic Fibrosis.

Impact related to the UN Sustainable Development Goals

Learn more about Queen’s University’s commitment to nurturing a culture of sustainability and achieving the Sustainable Development Goals (SDGs) through research and education.

80,000 people with Cystic Fibrosis

There are over 80,000 people living with Cystic Fibrosis globally, including 10,500 in the UK - accounting for 9,500 hospital admissions and over 100,000 bed days per year.

Treating up to 90% of people

The most recent trials successfully demonstrated that a combination of drugs can treat up to 90% of people with Cystic Fibrosis by addressing the underlying cause of their disease.

• Impacted Countries
• Impacted Regions
• North America

Explore more

What is cystic fibrosis, exactly, school/institute.

• Faculty of Medicine, Health and Life Sciences
• School of Medicine, Dentistry and Biomedical Sciences
• Wellcome-Wolfson Institute for Experimental Medicine

Related Research

A New Approach to Weaning Critically Ill Patients from Mechanical Ventilation across the UK

A Vision For Healthy Urban Design: Non-Communicable Disease (NCD) prevention

Adverse Childhood Experiences in South Africa

Development of a Biopsychosocial Translational Research Programme

Diabetic Retinopathy: From Screening To Treatment: A sustainable model for diabetic retinopathy in the Philippines

‘Groundbreaking’: Cystic fibrosis drug is safe and effective in newborns, new research shows

Ivacaftor - sold under trade name kalydeko - previously available to babies aged four months or older.

Siblings Kara (5) and Isaac Moss (2), who participated in a landmark study which supports use of a ground-breaking cystic fibrosis drug in infants from four weeks of age.

A “groundbreaking” drug which targets the underlying cause of cystic fibrosis has been shown to be safe and effective in newborns aged four weeks and above.

Until now, Ivacaftor - sold under the trade name Kalydeko - has been available to those aged four months or older.

Ivacaftor is the first drug designed to treat the underlying cause of cystic fibrosis and was originally approved for adults before subsequently being extended to younger age groups.

Ireland has the highest incidence of the inherited disease in the world due to its high prevalence of Celtic genes which are more susceptible to mutations that cause the progressive disease.

A sense of foreboding descends on Liveline. Then Joe Duffy takes an unexpected turn

Electric vehicles: is now the time for Irish drivers to buy?

La Rochelle have learned how to press all of Leinster’s buttons

Caledonian Road by Andrew O’Hagan: enjoyable but groans under the weight of its own ambition

The new research carried out by RCSI University of Medicine and Health Sciences and Children’s Health Ireland has been described as a “huge moment” for the condition.

Co-author of the study and Associate Professor of Paediatrics at RCSI and Consultant in Respiratory Medicine at CHI Paul McNally described it as a “huge moment in cystic fibrosis” as it means treatment can be started immediately after diagnosis, once it is approved by the European Medicines Agency.

[  Mothers with cystic fibrosis: ‘We’ve lives we never thought we could as no one thought we’d still be alive’  ]

Though it is known that drugs like Kalydeko improve cystic fibrosis, the “big question” is if they slow down or prevent decline when started earlier in life, he said.

A longer-term study which is tracking the impact and efficacy of earlier intervention among 550 children from Ireland and the UK has recently begun.

However, some early findings in children are promising including a lack of respiratory symptoms and restoration of pancreatic function.

“There’s a lot of stuff that we don’t understand but what we do know I suppose is these drugs hold really amazing promise and what we need is more research,” he said.

With new effective treatments, Prof McNally said the CF adult population across the world is constantly climbing.

“We’re hopefully looking at future generations of children who will have much, much milder disease than previous generations because they started on drugs much earlier,” he said.

About 1,400 children and adults in Ireland live with the condition and more than 30 new cases are diagnosed each year, most commonly at about four weeks of age through the newborn screening programme.

Two-year-old Isaac Moss from Ashbourne, Co Meath was the first baby in the world to be diagnosed with cystic fibrosis from birth through the programme, after which he was enrolled directly onto the trial. His five-year-old sister Kara was part of an earlier phase of the study that paved the approval of the drug in older infants and led to the latest trial.

Their mother Debbie said Kara’s diagnosis through screening was a “huge shock” at the time, and although her husband Wayne has a cousin with cystic fibrosis, none of their nieces or nephews had it.

“Initially, we were devastated, we didn’t know much about CF so we didn’t know what it meant for Kara and what it meant for her life,” she said adding that Kara’s diagnosis meant a one in four risk of their second child having it.

However, Kara had enrolled on a trial of Kalydeko - which is taken twice a day - at nine months of age.

“Because of our experience with Kara and because she was doing so well we were happy to have a second child knowing that the child could be affected.

“We were hopeful that it would be just as successful as it was for Kara and thankfully it has been,” she said.

Because Kara and Isaac have started at such a young age, “they’re the same as any other child,” she said.

“We feel lucky that they have the gene types that respond well to these particular drugs and it gives a lot of hope for the kids’ lives,” she said.

• Listen to our Inside Politics podcast for the best political chat and analysis
• Sign up for push alerts and have the best news, analysis and comment delivered directly to your phone
• Find The Irish Times on WhatsApp and stay up to date

IN THIS SECTION

Hospital waiting lists may take up to a decade to clear, consultants warn, ‘groundbreaking’ cystic fibrosis drug safe and effective in newborns, new research shows, menopause support must tread a fine line between awareness and stigma, tony holohan takes up adjunct professor role at trinity’s school of medicine, john magnier’s coolmore pays €8.925m for 591 acres in tipperary, sinn féin is watching the polls and beginning to panic, says stephen donnelly, pets from ukraine cost the state up to €1 million a month, ole gunnar solskjaer now in frame to be next republic of ireland manager, latest stories, the irish times view on the european court of human rights decision on climate change: key messages for ireland, micheál martin repeats position fianna fáil will not go into government with sinn féin, leinster vs la rochelle: kick-off time, tv details and team news ahead of champions cup clash, muslim cleric announces candidacy for european elections in june, the irish times view on postponing the next referendum: avoiding a potential banana skin.

• Terms & Conditions
• Privacy Policy
• Cookie Information
• Cookie Settings
• Community Standards

• Open supplemental data
• Reference Manager
• Simple TEXT file

People also looked at

Original research article, pancreatic enzymes digest obstructive meconium from cystic fibrosis pig intestines.

• 1 Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA, United States
• 2 Department of Pediatrics, East Tennessee State University, Johnson City, TN, United States
• 3 Department of Pediatrics, University of Iowa, Iowa City, IA, United States
• 4 Department of Internal Medicine, University of Iowa, Iowa City, IA, United States
• 5 Department of Pathology, University of Iowa, Iowa City, IA, United States

Introduction: Meconium ileus (MI) is a life-threatening obstruction of the intestines affecting ∼15% of newborns with cystic fibrosis (CF). Current medical treatments for MI often fail, requiring surgical intervention. MI typically occurs in newborns with pancreatic insufficiency from CF. Meconium contains mucin glycoprotein, a potential substrate for pancreatic enzymes or mucolytics. Our study aim was to determine whether pancreatic enzymes in combination with mucolytic treatments dissolve obstructive meconium using the CF pig model.

Methods: We collected meconium from CF pigs at birth and submerged it in solutions with and without pancreatic enzymes, including normal saline, 7% hypertonic saline, and the reducing agents N-acetylcysteine (NAC) and dithiothreitol (DTT). We digested meconium at 37 °C with agitation, and measured meconium pigment release by spectrophotometry and residual meconium solids by filtration.

Results and discussion: In CF pigs, meconium appeared as a solid pigmented mass obstructing the ileum. Meconium microscopically contained mucus glycoprotein, cellular debris, and bile pigments. Meconium fragments released pigments with maximal absorption at 405 nm after submersion in saline over approximately 8 h. Pancreatic enzymes significantly increased pigment release and decreased residual meconium solids. DTT did not improve meconium digestion and the acidic reducing agent NAC worsened digestion. Pancreatic enzymes digested CF meconium best at neutral pH in isotonic saline. We conclude that pancreatic enzymes digest obstructive meconium from CF pigs, while hydrating or reducing agents alone were less effective. This work suggests a potential role for pancreatic enzymes in relieving obstruction due to MI in newborns with CF.

Introduction

Newborn babies with cystic fibrosis (CF) are at risk of developing meconium ileus (MI), a life-threatening obstruction of the intestines that occurs in approximately 15%–20% of newborns with CF ( 1 – 3 ). Most newborns with CF who suffer from MI have CFTR mutations with relatively low residual CFTR function, and the vast majority are pancreatic insufficient. In CF pigs, MI can be prevented by expressing CFTR in intestinal cells ( 4 ). Similarly, CFTR modulator drug treatment in utero , which would increase CFTR function in both the intestines and pancreas, protects against MI in the ferret model of CF ( 5 ). However, except for rare cases ( 6 ), using CFTR modulators to prevent MI in newborn babies with CF remains problematic. Many cases of MI from CF are unexpected, owing to a lack of prenatal genetic diagnosis. While some fetal ultrasound findings may suggest MI, the sensitivity and specificity of this method is inadequate to predict MI ( 1 , 2 ). Thus, newborns with CF can present with symptoms of abdominal distension, bilious vomiting, and shock, which indicate life-threatening MI. Furthermore, many newborns with MI may be ineligible for CFTR modulator therapy due to their genotype.

To relieve MI, many centers use therapeutic enemas which typically include radiographic contrast media to visualize the extent of obstruction and reduce the obstruction. Some protocols include hyperosmolar solutions or reducing agents such as N-acetylcysteine (NAC) to disrupt chemical bonds in meconium. While some have reported successful medical treatment of MI with enemas, the treatment solutions used have not been studied in randomized controlled trials. As most cases of MI ultimately require surgery ( 2 , 7 ), it is likely that current medical treatments for MI are ineffective.

Surgery is the definitive intervention for MI, but it has associated risks. Newborns with MI can suffer immediate or delayed postoperative complications ( 1 , 8 ). Babies with MI have prolonged hospitalization in the neonatal intensive care unit ( 9 ), and some develop short bowel syndrome from the loss of extensive segments of small intestine ( 9 ). These children will ultimately depend upon parenteral nutrition through a central line ( 10 ). Short bowel syndrome combined with pancreatic insufficiency contribute to growth failure in children with CF, and infants requiring parenteral nutrition can suffer from central line-associated bloodstream infections ( 11 ). Other late surgical complications include intestinal obstruction due to post-surgical adhesions ( 12 , 13 ). Thus, there is an unmet need to improve medical treatments for MI. Ideally, these treatments would be genotype-agnostic and reduce the risk of long-term surgical complications.

The goal of this study was to determine whether common treatments for MI are effective in breaking down obstructive meconium. We studied newborn pigs with complete loss of CFTR by homozygous deletion of exon 10 (referred to as CFTR −/− ) or severe loss of CFTR function by F508del knock-in mutations ( CFTR Δ F508/ Δ F508 ) that consistently develop MI with a severe intestinal obstruction that would require surgery for survival ( 14 , 15 ). We hypothesized that reagents that disrupt the chemical bonds of meconium would disintegrate it over time. Further, as most babies with CF and CF pigs are pancreatic insufficient, the pancreatic enzymes that may normally digest meconium would be deficient. Therefore, we hypothesized that exogenous pancreatic enzyme supplementation could improve digestion of obstructive meconium from CF pigs.

Animal care and procedures were approved by the Animal Care and Use Committees at the University of Iowa (IACUC approved protocol number # 0081121). We obtained male and female CFTR −/− and CFTR ΔF508/ΔF508 piglets from Exemplar Genetics. Individual pigs used in this study are listed in Supplementary Table S1 . We euthanized piglets with pentobarbital sodium-phenytoin sodium (Euthasol, Virbac, Fort Worth, TX). At necropsy, we examined the gut to identify the site of obstruction. We excluded piglets that had evidence of intestinal perforation or peritonitis. We removed the intestines from the abdominal cavity and opened the intestines at the site of obstruction to collect meconium from the dilated segment proximal (orad) of the obstruction. We stored meconium at 4 °C in isotonic saline until the time of experimentation.

Histopathology

Archived formalin-fixed and paraffin embedded CF pig intestinal tissues ( n  = 5 newborn CF pigs) were identified, and proximal and distal segments of MI obstructions were morphologically examined. Additionally, we preserved proximal segments of MI obstruction ( n  = 3 CF pigs) in 10% neutral buffered formalin for ∼5–7 days. Fixed intestinal segments were paraffin embedded and stained with diastase pretreated Periodic Acid Schiff (dPAS) to visualize glycoproteins vs. appropriate controls ( 16 ).

Chemical reagents

Normal saline was obtained from Baxter. Powdered pancreatic enzymes (Epizyme Product # NDC 068720-023-12) were obtained from VET Brands International. Each teaspoon (2.8 g) of powdered Epizyme preparation contains lipase (71,400 USP Units), protease (388,000 USP Units) and amylase (460,000 USP Units). Other chemical reagents were obtained from Fisher Scientific.

Meconium digestion

We used a razor to cut CF meconium into small pieces (∼5–10 mm) and weighed them. The typical weight for these pieces was 3–5 g. We placed the weighed meconium pieces in vented 14 ml Falcon tubes and submerged the meconium in 3 ml of test solutions, including normal saline, 7% NaCl, 1 M NAC (as free acid) in water, or 1 M DTT in water. We assumed there would be a stoichiometric relationship between NAC or DTT with the protein disulfide bonds in the meconium. Therefore, we selected high concentrations of NAC and DTT so that these reducing agents would not be limiting reagents. To test the effect of pancreatic enzymes, we added 10 mg/ml of Epizyme powdered pancreatic enzymes to some of the test solutions. We incubated the submerged CF meconium at 37 °C for 16 h. Because mechanical forces could contribute to digestion in normal physiology, we agitated the solutions in an orbital shaker at 250 RPM (New Brunswick Scientific Excella E25).

Meconium pigment release

After meconium digestion, we allowed meconium solids to sediment on the benchtop for 30 min. We measured the release of colored pigments from the meconium by sampling 200  µ l of the supernatant and transferring it to a clear 96 well plate (Corning). We obtained the absorbance spectrum of the supernatant for each sample using a SpectraMax i3x plate reader (Molecular Devices) recording wavelengths between 300 and 700 nm at 5 nm intervals. We used the corresponding test solutions as blanks for each sample. Because the peak in meconium pigment absorbance was near 405 nm, we used A 405 to compare pigment release between different conditions. We used 10 pigs to compare test solutions (5 males, 5 females, all CFTR −/− ).

Residual meconium solids

After sampling the supernatant, we measured undigested residual meconium solids by decanting the meconium and test solution onto pre-weighed Whatman #1 filters (GE Healthcare Life Sciences) placed in a Büchner funnel under vacuum. To remove residual salts and other soluble materials, we rinsed the filters with 50 ml of deionized water. We air-dried the filters and measured the dry weight of residual meconium on an analytical balance. We divided the dry weight of the residual filtered meconium by the original weight of the meconium piece prior to treatment to obtain the percentage of residual weight for each treatment group. We photographed residual meconium on each filter paper. The same 10 pigs were used to compare residual solids after treatment with test solutions.

pH dependence of meconium digestion

We modified our protocol to determine the optimal pH for dissolving obstructive meconium. We prepared a stock solution of 130 mM NaCl buffered with 10 mM 2-N-morpholinoethanesulfonic acid (MES), 10 mM N-(2-hydroxyethyl)piperazine-N′-2-ethanesulfonic acid (HEPES), and 10 mM tromethamine (Tris). We then divided this stock solution into 5 equal aliquots and added either NaOH or HCl to adjust the solution to the desired pH (4.50, 5.50, 6.50, 7.50, or 8.50). We tested the pH dependence of meconium digestion using 6 additional CF pigs (3 males, 3 females, 5 CFTR −/− and 1 CFTR ΔF508/ΔF508 ) that were independent of the studies above, using the same methods.

Pancreatic enzyme dose response for meconium digestion

We tested pancreatic enzyme concentrations ranging from 1 mg/ml to 10 mg/ml mixed using the pH 7.50 buffer described above. We used 6 additional newborn CF pigs (3 male, 3 female, independent of the studies above, 5 CFTR −/− and 1 CFTR ΔF508/ΔF508 ) for these studies with the same methods.

Kinetics of meconium digestion

We studied the time-response of enzymatic digestion of CF meconium using 4 mg/ml of pancreatic enzymes in normal saline buffered with the pH 7.50 buffer. We obtained meconium from an additional 6 newborn CFTR −/− pigs for this study (5 male, 1 female). Meconium solids were submerged either in pH of 7.50 normal saline and incubated at 37  °C with or without 4 mg/ml of pancreatic enzymes. We sampled the supernatant from each condition at two-hour intervals for 16 h. Each sample was measured vs. the corresponding blank solution.

Statistical analysis

We used GraphPad Prism version 9 for statistical testing. To examine the effects of treatment solution and pancreatic enzymes, we used 2-way repeated measured ANOVA, matching samples taken from the same animal. For post-hoc analysis, we used Holm-Sidak's multiple comparisons test comparing other treatment solutions vs. 0.9% NaCl and enzyme treated samples vs. no enzyme controls.

Morphology of meconium ileus in CF pigs

As previously reported, MI in CF pigs results in morphologically distinct intestinal segments ( 17 ). We observed that distal segments (i.e., farther from the oral cavity) were of small caliber ( Figure 1A ), while the proximal region was dilated by accumulated intestinal material and gas. The interface of these two regions has been described as the obstruction interface. This interface usually localized in the distal small intestine to proximal spiral colon in CF pigs.

Figure 1 . ( A ) Meconium obstruction in CF pig intestine. The proximate segment of the MI obstruction is dilated with CF meconium. The distal segment of the MI obstruction is characterized by small hypoplastic spiral colon filled by abnormal mucus The proximal small bowel is dilated by gas and liquid. ( B ) Meconium from the proximal segment of MI obstruction in CF pigs was cut into smaller pieces (5–10 mm) for digestion studies. Note that the meconium remains a congealed tubular mass even after cutting.

CF and WT pig meconium

We examined the meconium from newborn non-CF and CF pigs at necropsy. Because meconium from non-CF pigs was scant and typically had already passed by the time we performed necropsy, we focused on CF pig meconium. In CF pigs, we were able to identify the MI obstruction. We transected the proximal segment to expose its luminal contents. Here the meconium was congealed and retained the tubular appearance of the intestinal lumen ( Figure 1B ).

Morphologic composition of meconium ileus in CF pigs

We obtained paraffin-embedded blocks from archival samples ( n  = 5 pigs) to microscopically examine the intestine proximal ( Figures 2A–C ) and distal ( Figures 2D–F ) of the obstruction. The proximal segments of MI were variably dilated by accumulated intestinal contents that compressed the adjacent mucosa ( Figure 2A ). The luminal contents included dPAS + mucus glycoproteins as well as nascent meconium arising from the intestinal epithelium. Higher powered images revealed that glycoprotein strands of meconium were tethered to mucus cells ( Figure 2B ). In addition to the glycoprotein, there was dPAS- material in the lumen that was composed of sloughed cellular debris and biliary pigments ( Figure 2C ). The small caliber distal segments of MI were composed mostly of dPAS + mucus strands with some minor cellular debris. Distal intestinal segments had dPAS + mucus glycoproteins ( Figure 2D ) that arose from intestinal crypts and goblet cells ( Figures 2E,F ). Both proximal and distal segments of MI had dPAS + mucus exhibiting adherence to the wall, but the presence of bile pigments in the proximal segment made this region more useful in for assays evaluating the dissolution of meconium.

Figure 2 . Spiral colon in newborn cystic fibrosis (CF) pigs with proximal ( A–C ) and distal ( D–F ) segments of meconium ileus obstruction. ( A ) Proximal segments of meconium ileus obstruction were composed of dPAS + mucus (*) and nascent meconium ( M ) that filled the lumen and compressed the adjacent mucosa. ( B ) dPAS + mucus was seen tethered to mucous cells (arrows, inset). ( C ) Additionally, nascent meconium contained pigmented globules consistent with bile (arrows) and sloughed cellular debris (*). ( D ) Distal segments of meconium ileus obstruction in CF pigs were composed primarily of dPAS + mucus. ( E,F ). Distal segments had dPAS + mucus that was tethered to the wall by mucous strands (arrowheads) originating from mucous cells in in the colonic crypts (arrows, E ) and surface epithelium (arrows). Staining in all images with dPAS stain. Scale bar = 871  µ m ( A,D ) and 87  µ m ( B–F ).

Incubating meconium in aqueous solutions releases colored pigments

We tested whether treatment solutions including saline, hypertonic saline, or sulfhydryl reducing agents like DTT and NAC would degrade congealed meconium originating from CF pigs. We took pieces of meconium from proximal segments of the MI obstruction, cut them into smaller fragments, and submerged them in treatment solutions. Because increased temperature or mechanical forces such as peristalsis could expedite meconium digestion, we agitated these solutions in an orbital shaker set to 225 RPM at 37 °C for 16 h. As the meconium digested, the release of biliary pigments darkened the supernatant ( Figure 3 ). We observed that adding pancreatic enzymes increased the release of meconium pigments. Unexpectedly, we found that including 1 M NAC in solution blunted the release of meconium pigments regardless of pancreatic enzyme condition. With NAC, we found large undigested pieces of meconium remained at the bottom of the test tube.

Figure 3 . Representative photographs of meconium digestion after 16 h in different test solutions, including 0.9% NaCl without pancreatic enzymes and four test solutions containing 10 mg/ml of pancreatic enzymes. Large undigested pieces of meconium are visible in the test tubes containing 0.9% NaCl without enzymes and in the tube containing 1M NAC with pancreatic enzymes (arrows). Less residual solid meconium is visible in the tube containing pancreatic enzymes in 0.9% NaCl and in the tube containing pancreatic enzymes with 1M DTT. The contrasting results between the neutral reducing agent DTT and the acidic NAC suggests that the acidity of NAC may inhibit digestion by pancreatic enzymes.

Meconium pigment release was greatest in samples treated with pancreatic enzymes and normal saline

We quantified the release of meconium pigments into the supernatant by spectrophotometry. Because different solutions could alter the absorbance spectrum of the meconium pigments, we determined the absorbance of the supernatant between 300 and 700 nm. For each of the treatment solutions, there was a wide peak in absorbance near 405 nm ( Figure 4A ) when compared to their corresponding blank solutions. The absorbance spectrum indicates higher absorption of blue light and is consistent with the green/brown color of meconium.

Figure 4 . Release of pigments following digestion of CF meconium is greatest in samples treated with normal saline and pancreatic enzymes. ( A ) Absorbance spectrum of meconium pigments in supernatant following digestion in different test solutions. In each condition, the peak absorbance was near 405 nm. Pigment release was greatest when the meconium was submerged in normal saline with pancreatic enzymes. Symbols represent mean and standard error of the mean for N  = 10 replicates. ( B ) Data show meconium pigment release, measured as A 405 , after treatment with different test solutions indicated on the x-axis. Samples with no added enzyme are grouped at left and pancreatic enzyme treated samples are grouped at right. Lines indicate median and interquartile range for each group. In the absence of pancreatic enzymes, samples treated with 0.9% NaCl had the greatest release of meconium pigment. A 2-way repeated measures ANOVA found significant effects of solution type (p  < 0.0001), pancreatic enzyme ( p  < 0.0001) and the interaction between solution and pancreatic enzyme ( p  < 0.0001). Asterisks indicate post-hoc comparisons between groups using Holm-Sidak's multiple comparisons test. ( C ) The data are grouped by solution to show the effect of pancreatic enzyme treatment for each solution type. Each symbol indicates a different animal, lines connect samples taken from the same animal. The graph at right shows pigment release in any of the test solutions depicted as a function of pancreatic enzymes. Lines indicate median and interquartile range. Meconium pigment release increased with pancreatic enzymes in all treatment solutions except 1 M NAC. Asterisks indicate post-hoc comparisons between groups are shown using Holm-Sidak's multiple comparisons test, comparing each treatment solution vs. 0.9% NaCl. * p  < 0.05, ** p  < 0.01, *** p  < 0.001, **** p  < 0.0001.

As all samples had peak absorbance at 405 nm, we used this wavelength to compare the digestion by different solutions ( Figure 4B ). In the absence of pancreatic enzymes, treatment with normal saline resulted in the highest release of meconium pigments. There were no significant differences between any of the other solutions. This suggested that reducing agents and hypertonic saline were worse than the normal saline control in degrading meconium.

When pancreatic enzymes were added to the treatment solutions, we observed an increased absorbance of the supernatant in most of the solutions, consistent with increased meconium digestion ( Figure 4C ). The pancreatic enzyme effect was greatest with normal saline, followed by DTT. We observed that 1 M unbuffered NAC minimally digested meconium despite co-incubating the samples with pancreatic enzymes. The attenuation of the pancreatic enzyme digestion with NAC was not observed with DTT, suggesting that the effects of NAC on digesting meconium were unrelated to its property as a reducing agent. To test whether pH explained the inhibitory effect, we titrated NAC-containing solutions to pH 7.00 using sodium hydroxide and compared data to non-titrated NAC-containing solutions. NAC solutions with pH 7.00 digested meconium, suggesting that NAC free acid solutions inhibited pancreatic enzymes because of their acidity, Supplementary Figure S1 . However, as we observed with NaCl, high solute concentrations of NAC also had poorer meconium digestion.

Pancreatic enzymes digested meconium into small pieces with low residual weight

To relieve the obstruction caused by CF meconium, it may be necessary to break the meconium plug into smaller pieces that can pass through a narrowed intestinal lumen. We tested whether digestive solutions in the presence or absence of pancreatic enzymes could break the meconium into pieces small enough to pass through a filter. After incubating meconium in test solutions and collecting the supernatant, we poured the sediment onto pre-weighed #1 Whatman filter papers and collected residual solids by vacuum filtration. We washed filters with 50 ml of deionized water to remove any excess salt, then air-dried the filter papers. Once dry, we weighed filters on an analytical balance to calculate the residual meconium weight.

In the absence of pancreatic enzymes, we found that residual meconium weight was lowest in samples treated with 0.9% NaCl compared to the other solutions ( Figure 5A ). DTT and non-titrated NAC did not increase meconium degradation as measured by residual weight. This result was consistent with our observation that meconium digestion, as measured by pigment release, was best in normal saline compared with the other test solutions.

Figure 5 . Treatment of CF meconium with pancreatic enzymes decreased residual meconium solids. ( A ) Data indicate the percentage of residual weight for meconium pieces following digestion in different test solutions and vacuum filtration. Samples with no added enzyme are grouped at left and pancreatic enzyme treated samples are grouped at right. Lines indicate median and interquartile range for each group. In the presence or absence of pancreatic enzymes, samples treated with 0.9% NaCl had the lowest residual weight. A 2-way repeated measures ANOVA found significant effects of solution type ( p  < 0.0001), pancreatic enzyme ( p  = 0.0005) and the interaction between solution and pancreatic enzyme ( p  = 0.03). p values for post-hoc comparisons between groups using Holm-Sidak's multiple comparisons test are given. ( B ) The data are grouped by solution to show the effect of pancreatic enzyme treatment on residual weight for each solution type. Each symbol indicates a different animal, lines connect samples taken from the same animal. The graph at right shows residual weight of meconium after treatment with any of the test solutions in the presence or absence of pancreatic enzymes. Lines indicate median and interquartile range. Asterisks indicate post-hoc comparisons between groups are shown using Holm-Sidak's multiple comparisons test, comparing each treatment solution vs. 0.9% NaCl. * p  < 0.05, ** p  < 0.01, *** p  < 0.001, **** p  < 0.0001. ( C ) Representative photographs of residual meconium on the filter papers after digestion. In samples treated with NAC, there were large undigested pieces of meconium, whereas in other treatments, the residual meconium was reduced to fine pieces.

Pancreatic enzymes generally decreased the residual weight of meconium, though there were differences in the effect of pancreatic enzymes between solutions ( Figure 5B ). We found that pancreatic enzymes in normal saline yielded the lowest residual weight, with meconium solids decreased to approximately 10% of their original weight. Samples treated with pancreatic enzymes in the presence of 7% NaCl or 1 M DTT reduced the meconium solids to approximately 20% of their original weight, whereas pancreatic enzymes in 1M unbuffered NAC were minimally effective. These results were consistent with our studies of meconium pigment release; treatments that caused greater pigment release also decreased the weight of residual meconium.

We observed and photographed the filter papers to inspect how the meconium pieces were degraded ( Figure 5C ). In the specimens of meconium that were treated with normal saline and pancreatic enzymes, the meconium was degraded into fine granular particles. By contrast, the specimens treated with 1 M non-titrated NAC in the presence or absence of pancreatic enzymes had coarse pieces of residual non-filterable solid.

Optimizing conditions for enzymatic degradation of CF meconium

Our results illustrate that pancreatic enzymes increase CF meconium digestion as measured by pigment release and weight of residual meconium solids. Because we observed differences in enzymatic digestion between 1 M NAC (an acidic reducing agent) compared to 1 M NAC titrated to pH 7.00 and 1 M DTT (a neutral reducing agent), we suspected that pH could affect enzymatic digestion. Because normal saline appeared more effective than either reducing agent or hypertonic saline, we studied the effect of pH on enzymatic digestion using an isotonic saline solution.

We prepared pancreatic enzymes in Good's buffers with pH ranging from 4.50–8.50, added pieces of meconium, and incubated for 16 h with agitation. After filtration, we compared the weight of residual solids. The lowest residual meconium was observed in the samples treated with pancreatic enzymes at pH 7.50 ( Figure 6A ). A small decrease in digestion occurring at pH 8.50 suggests that pH 7.50 is near the optimal pH for digestion of meconium by pancreatic enzymes.

Figure 6 . Optimal conditions for enzymatic digestion of CF meconium. ( A ) Residual meconium weight of CF meconium after pancreatic enzyme digestion varies with the pH of the test solution. The pH of the solution was established using Good's buffers with pH ranging from 4.5–8.5 and with 130 mM NaCl. Symbols represent mean and standard error of the mean for n  = 5–6 replicates per group. There were no statistically significant differences between groups by 1-way ANOVA. The lowest observed residual meconium was at pH 7.5. ( B ) Residual weight of CF meconium following treatment with pancreatic enzymes in a dose range in 130 mM NaCl at pH 7.5. Symbols represent mean and standard error of the mean for N  = 6 replicates per group. All doses of pancreatic enzyme were had significantly less residual meconium compared to buffer control (1-way ANOVA overall p  = 0.002, p  < 0.05 for all pairwise comparisons between enzyme doses and buffer control). ( C ) Time course of meconium digestion, as measured by meconium pigment release at A 405 . We observed a time-dependent increase in the release of meconium pigments, which plateaued at 6 h of digestion. Symbols represent mean and standard error of the mean for N  = 6 replicates. A 2-way repeated measures ANOVA found significant effects of enzyme treatment ( p  = 0.0003), time ( p  < 0.0001), and interaction ( p  < 0.0001). Holm-Sidak post-hoc comparisons of enzyme-treated samples vs. control showed increased A 405 in enzyme-treated samples at all timepoints ≥ 4 h ( p  < 0.01). Holm-Sidak post-hoc comparisons of time points in enzyme-treated samples showed no significant differences at timepoints ≥ 6 h.

The amount of pancreatic enzyme could also influence the digestion of CF meconium. We tested digestion of CF meconium using pancreatic enzymes in doses ranging between 2 and 10 mg/ml and compared these to the saline buffer control at pH 7.50. We measured the residual weight after treating pieces of meconium. All doses had lower residual weight compared to the buffer control. The dose response was plateaued beyond 4 mg/ml ( Figure 6B ).

Autodigestion by pancreatic enzymes could limit their duration of action, and it is unclear how long meconium needs to be treated for complete digestion. Therefore, we studied pancreatic enzymes in a time course to determine how long they continue to digest meconium. We selected 4 mg/ml pancreatic enzymes in the saline buffer at pH 7.5 for our treatment condition. We elected to use pigment release for this portion of the study as we needed to repeatedly sample from the digestion reactions. We found that pancreatic enzymes caused an increase in meconium pigment release within 4 h compared to buffer control ( Figure 6C ). By 6 h, there were no further significant increases in meconium pigment release. This suggests that digestion slows down after approximately 6 h.

Currently, MI is medically managed by administering therapeutic solutions rectally, but a standard protocol for treatment does not exist ( 18 ). Preferred treatment varies between institutions depending on physician preference and experience. Thus, many different enema solutions are used around the world including normal saline, iso-osmolar contrast materials (Omnipaque, Cysto-Conray II), hyperosmolar contrast material (Gastrografin), and NAC ( 1 , 7 , 19 ). Regardless of the treatment chosen, at least half of MI cases do not respond to these enemas. In those cases, surgical intervention is required to relieve the obstruction.

This suggested that existing strategies for treating MI are not effective, possibly because they do not sufficiently degrade obstructive meconium. We found that NAC, a commonly used mucolytic enema agent that works by reducing disulfide bonds ( 20 ), caused minimal breakdown of the meconium when administered as a free acid. Neutral-buffered NAC degraded meconium better than NAC as a free acid but did not improve meconium breakdown vs. saline or pancreatic enzymes. The neutral reducing agent DTT, which has two thiol groups, also did not fully degrade obstructive meconium when given in the absence of pancreatic enzymes and had no advantage over normal saline.

Most patients with CF have exocrine pancreatic insufficiency and some cases of MI that develop in the absence of CF suggest a role for the pancreas in the pathophysiology of MI ( 23 – 25 ). Bishop and Koop described the potential role of pancreatic enzymes in MI in 1957, but since then we found no further studies examining their utility in treating MI ( 21 ). There is strong mechanistic rationale for using pancreatic enzymes; meconium contains glycoproteins, a typical substrate of pancreatic enzymes. We tested a pancreatic enzyme formulation approved by the FDA for treating exocrine pancreatic insufficiency in animals. This formulation digested meconium best at neutral pH and without high salt or reducing agent.

While the CF pig has been useful to study MI ( 17 ), the pathophysiology of MI remains incompletely understood. Possible pathophysiologic mechanisms for MI include a lack of CFTR function in the intestinal epithelial cells causing (a) abnormal pH or HCO 3 − concentration in the intestinal lumen, (b) decreased hydration of the meconium making it more solid than in the non-CF intestine, (c) abnormal mucin cross-linking, (d) CFTR-dependent smooth muscle dysfunction causing intestinal dysmotility, or (e) CFTR-dependent intestinal growth anomalies leading to atresia, malrotation, or other structural abnormalities. It is possible that a combination of these factors contribute to physical obstruction of the distal small intestine ( 1 , 3 , 17 , 22 – 27 ). Our data suggest that the lack of pancreatic enzyme activity could contribute to MI.

Study advantages

Though mice lacking CFTR have been used as a model for the CF gastrointestinal tract and pancreas, they lack MI development but instead develop a distal intestinal obstruction syndrome-like phenotype postnatally without dietary modifications ( 28 – 30 ). An advantage of our study was that we used CF pigs, which uniformly develop MI similar to that seen in humans with 100% penetrance along with the associated organ dysfunction, making them an excellent model for our study ( 4 , 14 , 15 ). Additionally, we consistently collected CF pig meconium from the proximal segment of the MI obstruction to better quantify our assays and treatments using the biliary pigments that accumulated there. Using CF pigs also gave regular access to a reproducible source of meconium for testing, which would not have been possible with clinical samples or in other animal models.

Study limitations

Our experiments were performed ex vivo and may not reflect efficacy in vivo . We have not demonstrated the effect of individual components of the pancreatic enzyme mixture. However, we specifically chose to use a mixed pancreatic enzyme formulation because FDA-approved enzyme treatments are available for pancreatic insufficiency. We collected samples for testing exclusively from the distended portions proximal to the obstruction. therefore, it is possible that obstructions in other segments have different digestion characteristics.

The dosing of pancreatic enzymes required to relieve intestinal obstruction in vivo will require further investigation. At our lowest concentration of 4 mg/ml, the mixture included approximately 100 lipase units/ml and 550 protease units/ml. The typical dosing of pancreatic enzymes for infants receiving a 120 ml feeding is 2,000–4,000 lipase units, with the high end of 33 lipase units/ml ( 31 ). Meconium may be more difficult to digest, as shown by the higher concentrations in our studies.

Finally, our experiments relied on a mechanical shaker to agitate the meconium and assure adequate mixing. It is not known whether there are adequate smooth muscle contractions in the CF intestines to physically decompose meconium. Therefore, the mechanical requirements for breaking down meconium need further exploration in future studies.

Conclusions

Our results show that isotonic solutions are more effective than hypertonic solutions for the digestion of CF pig meconium, a finding that may inform the use of isotonic enema solutions and potentially decrease complications such as dehydration, hypovolemic shock, and even death that can be associated with hypertonic enemas. Our study also shows no significant effects of reducing agents on digestion of CF meconium. Determining whether current therapies are effective or not may help inform the management of MI in newborns with CF, sparing them from exposure to ineffective and potentially toxic treatments. Finally, our study suggests a role for exocrine pancreatic function in the development of MI.

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary Material , further inquiries can be directed to the corresponding authors.

Ethics statement

The animal study was approved by University of Iowa Office of the Institutional Animal Care and Use Committee. The study was conducted in accordance with the local legislation and institutional requirements.

Author contributions

GGN: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Resources, Visualization, Writing – original draft, Writing – review & editing. SGS: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Writing – review & editing. CFZ: Data curation, Investigation, Methodology, Visualization, Writing – review & editing. JJH: Investigation, Writing – review and editing. LSP: Investigation, Methodology, Resources, Writing – review & editing. DKM: Data curation, Formal Analysis, Investigation, Methodology, Resources, Visualization, Writing – review & editing. IMT: Conceptualization, Investigation, Methodology, Visualization, Writing – review & editing. DAS: Conceptualization, Funding acquisition, Resources, Supervision, Writing – review & editing. AJF: Conceptualization, Data curation, Funding acquisition, Methodology, Resources, Supervision, Visualization, Writing – original draft, Writing – review & editing.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article.

Cystic Fibrosis Foundation Clinical Fellowship Grants GANAGA20B0 (GGN) and 003607B122 – Gonzalez (SGS). University of Iowa Children’s Hospital/ Stead Family Department of Pediatrics and Children’s Miracle Network Research Grant Program (GGN). University of Iowa Stead Family Department of Pediatrics Start Up Funds (AJF). CFF Research and Development Program (STOLTZ19R0). NHLBI K08 HL136927 (AJF). NIH Program Project Grants HL091842 and HL051670 (DAS). NIH DK054759.

Acknowledgments

We thank Michael Welsh and Joseph Zabner for their guidance. We thank the University of Iowa Cystic Fibrosis Center for research support.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fped.2024.1387171/full#supplementary-material

1. Sathe M, Houwen R. Meconium ileus in cystic fibrosis. J Cyst Fibros . (2017) 16(Suppl 2):S32–9. doi: 10.1016/j.jcf.2017.06.007

PubMed Abstract | Crossref Full Text | Google Scholar

2. Jessula S, Van Den Hof M, Mateos-Corral D, Mills J, Davies D, Romao RL. Predictors for surgical intervention and surgical outcomes in neonates with cystic fibrosis. J Pediatr Surg . (2018) 53(11):2150–4. doi: 10.1016/j.jpedsurg.2018.05.016

3. Blackman SM, Deering-Brose R, McWilliams R, Naughton K, Coleman B, Lai T, et al. Relative contribution of genetic and nongenetic modifiers to intestinal obstruction in cystic fibrosis. Gastroenterology . (2006) 131(4):1030–9. doi: 10.1053/j.gastro.2006.07.016

4. Stoltz DA, Rokhlina T, Ernst SE, Pezzulo AA, Ostedgaard LS, Karp PH, et al. Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs. J Clin Invest . (2013) 123(6):2685–93. doi: 10.1172/JCI68867

5. Sun X, Yi Y, Yan Z, Rosen BH, Liang B, Winter MC, et al. In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis. Sci Transl Med . (2019) 11(485):eaau7531. doi: 10.1126/scitranslmed.aau7531

6. Szentpetery S, Foil K, Hendrix S, Gray S, Mingora C, Head B, et al. A case report of CFTR modulator administration via carrier mother to treat meconium ileus in a F508del homozygous fetus. J Cyst Fibros . (2022) 21(4):721–4. doi: 10.1016/j.jcf.2022.04.005

7. Copeland DR, St Peter SD, Sharp SW, Islam S, Cuenca A, Tolleson JS, et al. Diminishing role of contrast enema in simple meconium ileus. J Pediatr Surg . (2009) 44(11):2130–2. doi: 10.1016/j.jpedsurg.2009.06.005

8. Murshed R, Spitz L, Kiely E, Drake D. Meconium ileus: a ten-year review of thirty-six patients. Eur J Pediatr Sur . (1997) 7(5):275–7. doi: 10.1055/s-2008-1071170

Crossref Full Text | Google Scholar

9. Farrelly PJ, Charlesworth C, Lee S, Southern KW, Baillie CT. Gastrointestinal surgery in cystic fibrosis: a 20-year review. J Pediatr Surg . (2014) 49(2):280–3. doi: 10.1016/j.jpedsurg.2013.11.038

10. Ekema G, Milianti S, Boroni G. Total parenteral nutrition in patients with short bowel syndrome. Minerva Pediatr . (2009) 61(3):283–91.19461572

PubMed Abstract | Google Scholar

11. Bell T, O'Grady NP. Prevention of central line-associated bloodstream infections. Infect Dis Clin North Am . (2017) 31(3):551–9. doi: 10.1016/j.idc.2017.05.007

12. Jawaheer J, Khalil B, Plummer T, Bianchi A, Morecroft J, Rakoczy G, et al. Primary resection and anastomosis for complicated meconium ileus: a safe procedure? Pediatr Surg Int . (2007) 23(11):1091–3. doi: 10.1007/s00383-007-2020-9

13. Karimi A, Gorter RR, Sleeboom C, Kneepkens CM, Heij HA. Issues in the management of simple and complex meconium ileus. Pediatr Surg Int . (2011) 27(9):963–8. doi: 10.1007/s00383-011-2906-4

14. Rogers CS, Stoltz DA, Meyerholz DK, Ostedgaard LS, Rokhlina T, Taft PJ, et al. Dsisruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science . (2008) 321(5897):1837–41. doi: 10.1126/science.1163600

15. Ostedgaard LS, Meyerholz DK, Chen JH, Pezzulo AA, Karp PH, Rokhlina T, et al. The ΔF508 mutation causes CFTR misprocessing and cystic fibrosis-like disease in pigs. Sci Transl Med . (2011) 3(74):74r a 24. doi: 10.1126/scitranslmed.3001868

16. Meyerholz DK, Beck AP, Goeken JA, Leidinger MR, Ofori-Amanfo GK, Brown HC, et al. Glycogen depletion can increase the specificity of mucin detection in airway tissues. BMC Res Notes . (2018) 11(1):763. doi: 10.1186/s13104-018-3855-y

17. Meyerholz DK, Stoltz DA, Pezzulo AA, Welsh MJ. Pathology of gastrointestinal organs in a porcine model of cystic fibrosis. Am J Pathol . (2010) 176(3):1377–89. doi: 10.2353/ajpath.2010.090849

18. Schauble AL, Bisaccia EK, Lee G, Nasr SZ. N-acetylcysteine for management of distal intestinal obstruction syndrome. J Pediatr Pharmacol Ther . (2019) 24(5):390–7. doi: 10.5863/1551-6776-24.5.390

19. Burke MS, Ragi JM, Karamanoukian HL, Kotter M, Brisseau GF, Borowitz DS, et al. New strategies in nonoperative management of meconium ileus. J Pediatr Surg . (2002) 37(5):760–4. doi: 10.1053/jpsu.2002.32272

20. Fischer AJ, Pino-Argumedo MI, Hilkin BM, Shanrock CR, Gansemer ND, Chaly AL, et al. Mucus strands from submucosal glands initiate mucociliary transport of large particles. JCI Insight . (2019) 4(1):e124863. doi: 10.1172/jci.insight.124863

21. Bishop HC, Koop CE. Management of meconium ileus; resection, Roux-en-Y anastomosis and ileostomy irrigation with pancreatic enzymes. Ann Surg . (1957) 145(3):410–4. doi: 10.1097/00000658-195703000-00017

22. Cook DP, Adam RJ, Zarei K, Deonovic B, Stroik MR, Gansemer ND, et al. CF airway smooth muscle transcriptome reveals a role for PYK2. JCI Insight . (2017) 2(17):e95332. doi: 10.1172/jci.insight.95332

23. Cook DP, Rector MV, Bouzek DC, Michalski AS, Gansemer ND, Reznikov LR, et al. Cystic fibrosis transmembrane conductance regulator in sarcoplasmic reticulum of airway smooth muscle. Implications for airway contractility. Am J Respir Crit Care Med . (2016) 193(4):417–26. doi: 10.1164/rccm.201508-1562OC

24. Ermund A, Meiss LN, Gustafsson JK, Hansson GC. Hyper-osmolarity and calcium chelation: effects on cystic fibrosis mucus. Eur J Pharmacol . (2015) 764:109–17. doi: 10.1016/j.ejphar.2015.06.051

25. Sun L, Rommens JM, Corvol H, Li W, Li X, Chiang TA, et al. Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis. Nat Genet . (2012) 44(5):562–9. doi: 10.1038/ng.2221

26. Gelfond D, Heltshe S, Ma C, Rowe SM, Frederick C, Uluer A, et al. Impact of CFTR modulation on intestinal pH, motility, and clinical outcomes in patients with cystic fibrosis and the G551D mutation. Clin Transl Gastroenterol . (2017) 8(3):e81. doi: 10.1038/ctg.2017.10

27. McHugh DR, Cotton CU, Moss FJ, Vitko M, Valerio DM, Kelley TJ, et al. Linaclotide improves gastrointestinal transit in cystic fibrosis mice by inhibiting sodium/hydrogen exchanger 3. Am J Physiol Gastrointest Liver Physiol . (2018) 315(5):G868–78. doi: 10.1152/ajpgi.00261.2017

28. Tuggle KL, Birket SE, Cui X, Hong J, Warren J, Reid L, et al. Characterization of defects in ion transport and tissue development in cystic fibrosis transmembrane conductance regulator (CFTR)-knockout rats. PLoS One . (2014) 9(3):e91253. doi: 10.1371/journal.pone.0091253

29. Grubb BR, Boucher RC. Pathophysiology of gene-targeted mouse models for cystic fibrosis. Physiol Rev . (1999) 79(1 Suppl):S193–214. doi: 10.1152/physrev.1999.79.1.S193

30. Case RM. Is the rat pancreas an appropriate model of the human pancreas? Pancreatology . (2006) 6(3):180–90. doi: 10.1159/000091849

31. Borowitz DS, Grant RJ, Durie PR. The consensus committee. Use of pancreatic enzyme supplements for patients with cystic fibrosis in the context of fibrosing colonopathy. J Pediatr . (1995) 127:681–84. doi: 10.1016/S0022-3476(95)70153-2

Keywords: meconium, cystic fibrosis, meconium ileus, pancreatic enzymes, mucus, mucolytic, reducing agents, contrast enemas

Citation: Gangadharan Nambiar G, Gonzalez Szachowicz S, Zirbes CF, Hill JJ, Powers LS, Meyerholz DK, Thornell IM, Stoltz DA and Fischer AJ (2024) Pancreatic enzymes digest obstructive meconium from cystic fibrosis pig intestines. Front. Pediatr. 12:1387171. doi: 10.3389/fped.2024.1387171

Received: 16 February 2024; Accepted: 21 March 2024; Published: 11 April 2024.

Reviewed by:

© 2024 Gangadharan Nambiar, Gonzalez Szachowicz, Zirbes, Hill, Powers, Meyerholz, Thornell, Stoltz and Fischer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Gopinathan Gangadharan Nambiar [email protected] Anthony J. Fischer [email protected]

This article is part of the Research Topic

Gastrointestinal and Hepatic Involvement in Cystic Fibrosis in the era of CFTR Modulator Therapies

Landmark study involving babies in Ireland supports use of Cystic Fibrosis drug in infants from four weeks of age

A Cystic Fibrosis drug targeting the basic defect that causes the condition has been shown to be safe and effective in newborns aged four weeks and above, new research involving RCSI University of Medicine and Health Sciences and Children's Health Ireland has found.

The finding is described as a 'huge moment' for Cystic Fibrosis by one of the lead researchers. The study included the first baby in the world with Cystic Fibrosis to be diagnosed from birth and enrolled directly onto a trial of this sort.

The drug, Ivacaftor (Kalydeko), is the first drug designed to treat the basic defect in Cystic Fibrosis. It was originally approved for adults, then sequentially over several years for older and younger children. Currently, it is approved for babies aged four months and older, however, this new research suggests that it is safe and effective for babies as young as four weeks of age.

Cystic Fibrosis experts predict that the earlier treatments can begin, the more likely that progression of the condition can be slowed down or halted in children, and this is the focus of several international research studies led by RCSI and Children's Health Ireland. The findings of this study could pave the way for eligible newborns to start treatment on the medicine at the time of diagnosis (typically at newborn screening) rather than having to wait until they are four months old.

"This is a huge moment in Cystic Fibrosis," said Paul McNally, Associate Professor of Paediatrics at RCSI and Consultant in Respiratory Medicine at CHI. McNally is one of the authors of the new study, which was published in the Journal of Cystic Fibrosis .

"Over the years Ivacaftor, or Kalydeko, has been put through clinical trials in younger and younger children. Now, through this study, it has been shown to be safe and effective all the way down to four weeks of age," he said. "This is an important development because almost all children are diagnosed through newborn screening at around this time. The availability of a treatment that targets the underlying cause of the disease in newborns and can be started immediately at diagnosis will provide a huge sense of reassurance and hope for families."

Cystic Fibrosis is an inherited disease that mainly affects the lungs and digestive system. Ireland has the highest incidence of the condition in the world: approximately 1,400 children and adults in Ireland live with the condition and more than 30 new cases of

Cystic Fibrosis are diagnosed here each year, typically around 4 weeks of age through the newborn screening programme.

In recent years, new medicines have emerged that target the basic defect that causes Cystic Fibrosis. Ivacaftor (Kalydeko) is one such treatment. It targets a genetic change seen in around 4% of people with Cystic Fibrosis worldwide, and around 10% in Ireland.

Siblings Kara (aged 5) and Isaac Moss (aged 2) both participated in the study through Children's Health Ireland. Kara was part of an earlier phase of the study that paved the approval of the drug in older infants and led to the latest trial that Isaac took part in.

Isaac was the first baby with Cystic Fibrosis in the world to be diagnosed from birth and enrolled directly onto a trial of these ground-breaking treatments.

"Both Kara and Isaac are doing really well and remarkably are not experiencing any of the typical symptoms of Cystic Fibrosis at the moment," said their mother Debbie.

"Research studies like this one are so important to ensuring that children get access to the right treatments as early as possible. With the right medications, they can enjoy a healthy childhood and look forward to a brighter future"

Ivacaftor is manufactured by pharmaceutical company Vertex Pharmaceuticals, who are currently applying to the European Medicines Agency for an extension to the marketing authorisation for Ivacaftor down to one month of age.

• Cystic Fibrosis
• Infant's Health
• Children's Health
• Pharmacology
• Personalized Medicine
• Pharmaceuticals
• Diseases and Conditions
• Healthy Aging
• Cystic fibrosis
• Drug addiction
• Drug discovery
• Double blind
• Sudden infant death syndrome

Story Source:

Materials provided by RCSI . Note: Content may be edited for style and length.

Journal Reference :

• Paul McNally, Alvin Singh, Susanna A. McColley, Jane C. Davies, Mark Higgins, Meng Liu, Jennifer Lu, Violeta Rodriguez-Romero, Judy L. Shih, Margaret Rosenfeld. Safety and efficacy of ivacaftor in infants aged 1 to less than 4 months with cystic fibrosis . Journal of Cystic Fibrosis , 2024; DOI: 10.1016/j.jcf.2024.03.012

Cite This Page :

Explore More

• Ozone Removes Mating Barriers Between Fly ...
• Parkinson's: New Theory On Origins and Spread
• Clash of Stars Solves Stellar Mystery
• Secure Quantum Computing at Home
• Ocean Currents: Collapse of Antarctic Ice ...
• Pacific Cities Much Older Than Previously ...
• The Milky Way in Ancient Egyptian Mythology
• Physical Activity Best in the Evening
• How the Body Switches out of 'Fight' Mode
• New Drug Prevents Flu-Related Lung Damage

Trending Topics

Strange & offbeat.

• News & Analysis on Clinical Trial Services & Contract Research And Development

Landmark study validates Cystic Fibrosis drug for infants as young as four weeks old

11-Apr-2024 - Last updated on 11-Apr-2024 at 12:24 GMT

• Email to a friend

This discovery marks a significant moment for Cystic Fibrosis treatment, with experts hailing it as a breakthrough.

Lead researchers have emphasized the monumental nature of this finding, especially as it pertains to the treatment of Cystic Fibrosis in infants. The drug, Ivacaftor (Kalydeko), originally formulated for adults, has gradually gained approval for use in younger age groups over the years. However, this latest research suggests its effectiveness in infants as young as four weeks, a milestone previously unexplored.

Cystic Fibrosis specialists underscore the importance of early intervention in slowing or halting the progression of the disease in children. With this study's results, there is newfound optimism that eligible newborns could commence treatment immediately following diagnosis, revolutionizing current practices that typically delay treatment until infants reach four months of age.

“This is a huge moment in Cystic Fibrosis,” said Paul McNally, associate professor of paediatrics at RCSI and Consultant in Respiratory Medicine at CHI. McNally is one of the authors of the new study, which was published in the Journal of Cystic Fibrosis.

“Over the years Ivacaftor, or Kalydeko, has been put through clinical trials in younger and younger children. Now, through this study, it has been shown to be safe and effective all the way down to four weeks of age,” he said.

Cystic Fibrosis, a hereditary condition predominantly affecting the lungs and digestive system, poses significant challenges for affected individuals and their families. With Ireland experiencing the highest incidence of the disease globally, the implications of this study resonate deeply within the local community and beyond.

The study's impact extends beyond academic circles, touching the lives of real families like that of siblings Kara and Isaac Moss. Participating in the study through Children’s Health Ireland, both children have defied expectations, experiencing remarkable health despite their diagnosis. Their mother, Debbie, emphasizes the importance of such research endeavors in ensuring timely access to life-changing treatments for children with Cystic Fibrosis.

Siblings Kara, 5, and Isaac Moss, 2, both participated in the study through Children’s Health Ireland. Kara was part of an earlier phase of the study that paved the approval of the drug in older infants and led to the latest trial that Isaac took part in.

Isaac was the first baby with Cystic Fibrosis in the world to be diagnosed from birth and enrolled directly in a trial of these ground-breaking treatments.

“Both Kara and Isaac are doing well and remarkably are not experiencing any of the typical symptoms of Cystic Fibrosis at the moment,” said their mother, Debbie.

“Research studies like this one are so important to ensuring that children get access to the right treatments as early as possible. With the right medications, they can enjoy a healthy childhood and look forward to a brighter future.”

Manufactured by Vertex Pharmaceuticals, the drug Ivacaftor is currently undergoing regulatory review for expanded authorization, potentially reaching infants as young as one month old. This development represents a significant step forward in the fight against Cystic Fibrosis and offers renewed hope for countless families worldwide.

The study, titled ‘Safety and efficacy of Ivacaftor in infants aged one to less than four months with Cystic Fibrosis,’ published in the Journal of Cystic Fibrosis, underscores the collaborative efforts of researchers from RCSI, Children’s Health Ireland, the USA, and the UK in advancing Cystic Fibrosis treatment for the most vulnerable patients—infants.

Related news

Related products

Saama accelerates data review processes

Content provided by Saama | 25-Mar-2024 | Infographic

In this new infographic, learn how Saama accelerates data review processes. Only Saama has AI/ML models trained for life sciences on over 300 million data...

More Data, More Insights, More Progress

Content provided by Saama | 04-Mar-2024 | Case Study

The sponsor’s clinical development team needed a flexible solution to quickly visualize patient and site data in a single location

Generic method approach for determination of residual solvents in active pharmaceutical ingredients by gas chromatography

Content provided by Almac Group | 29-Nov-2023 | White Paper

Solvents are defined as organic chemicals that are used to dissolve components. They are used during the manufacture of drug substances and can also potentially...

Using Define-XML to build more efficient studies

Content provided by Formedix | 14-Nov-2023 | White Paper

It is commonly thought that Define-XML is simply a dataset descriptor: a way to document what datasets look like, including the names and labels of datasets...

Related suppliers

• Saama accelerates data review processes Saama | Download Infographic
• More Data, More Insights, More Progress Saama | Download Case Study
• Ultra Low Temperature Packaging solutions Almac Group | Download Case Study
• Three Ways to Leverage AI in Clinical Trials Right Now Saama | Download Technical / White Paper
• When Every Day Counts Saama | Download Case Study

Upcoming supplier webinars

• 24 Apr 2024 Wed How to reduce crosslinking and ensure fast dissolution in soft caps

Upcoming editorial webinars

• 18 Apr 2024 Thu Webinar Cell and Gene Therapy Manufacturing

On-demand webinars

• Innovation in Drug Delivery Webinar

Promotional Features

Outsourcing-Pharma

• Advertise with us
• Why Register?
• Apply to reuse our content
• Press Releases – Guidelines
• Contact the Editor
• Report a technical problem
• Whitelist our newsletters
• Editorial Calendar

Case study: cystic fibrosis

• PMID: 7072751

Publication types

• Case Reports
• Cystic Fibrosis / complications
• Cystic Fibrosis / diagnosis*
• Cystic Fibrosis / genetics
• Electrolytes / analysis
• Pseudomonas Infections / complications
• Respiratory Tract Infections / complications
• Sweat / analysis
• Electrolytes

An official website of the United States government

The .gov means it's official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you're on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Relating variation to medicine

• Introduction
• Data authorities
• Classification
• Review status
• HGVS expressions
• Data validation
• Data dictionary
• Access and releases
• Linking to ClinVar
• How to search ClinVar
• Accessions and identifiers
• Using the ClinVar variation display
• Using the ClinVar record display
• Comparing the variation and record displays
• Submission overview
• Spreadsheets
• Instructions for spreadsheets
• Submission Portal
• FAQ for submissions
• Assertion criteria
• Expert panels and practice guidelines
• List of submitters
• Submitting groups
• Go to the FTP site

NM_000492.4(CFTR):c.443T>C (p.Ile148Thr) AND Cystic fibrosis

Allele description [variation report for nm_000492.4(cftr):c.443t>c (p.ile148thr)], nm_000492.4(cftr):c.443t>c (p.ile148thr).

• Chr7: 117531068 (on Assembly GRCh38)
• Chr7: 117171122 (on Assembly GRCh37)
• NC_000007.14:g.117531068T>C
• NG_016465.4:g.70285T>C
• NM_000492.4:c.443T>C MANE SELECT
• NP_000483.3:p.Ile148Thr
• LRG_663t1:c.443T>C
• LRG_663:g.70285T>C
• LRG_663p1:p.Ile148Thr
• NC_000007.13:g.117171122T>C
• NM_000492.3:c.443T>C
• P13569:p.Ile148Thr
• c.443T>C
• NM_000492.4:c.443T>C - missense variant - [Sequence Ontology: SO:0001583 ]

Condition(s)

Assertion and evidence details.

• Clinical assertions

Summary from all submissions

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice.

Castellani C, Cuppens H, Macek M Jr, Cassiman JJ, Kerem E, Durie P, Tullis E, Assael BM, Bombieri C, Brown A, Casals T, Claustres M, Cutting GR, Dequeker E, Dodge J, Doull I, Farrell P, Ferec C, Girodon E, Johannesson M, Kerem B, Knowles M, et al.

J Cyst Fibros. 2008 May;7(3):179-96. doi: 10.1016/j.jcf.2008.03.009. Review.

Details of each submission

From invitae, scv000075151.11, from counsyl, scv000790922.1, from sib swiss institute of bioinformatics, scv000803630.1, description.

This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Cystic fibrosis, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PS3 => Well-established functional studies show a deleterious effect (PMID:16822950,11242048). BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BP2 => Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID:12394343).

From Mendelics, SCV000886144.3

From cftr-france, scv001169190.1.

the variant does not result in CFTR-RD neither

From Ambry Genetics, SCV001184227.3

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

From Johns Hopkins Genomics, Johns Hopkins University, SCV001425332.1

From natera, inc., scv001453949.1, from genome-nilou lab, scv001737321.1, from institute of human genetics, university of leipzig medical center, scv002574072.1.

This variant was identified in 2 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM5, PP4, BS2, BS3, BP2

Last Updated: Apr 6, 2024

Connect with NLM

National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894

Web Policies FOIA HHS Vulnerability Disclosure

Help Accessibility Careers