justin ewing cystic fibrosis case study

Log in using your username and password

• Search More Search for this keyword Advanced search
• Latest content
• Global health
• BMJ Journals More You are viewing from: Google Indexer

You are here

• Volume 14, Issue 11
• Cystic fibrosis: a diagnosis in an adolescent
• Article Text
• Article info
• Citation Tools
• Rapid Responses
• Article metrics

• http://orcid.org/0000-0001-9674-0879 Monica Bennett 1 ,
• Andreia Filipa Nogueira 1 ,
• Maria Manuel Flores 2 and
• Teresa Reis Silva 1
• 1 Pediatric , Centro Hospitalar e Universitario de Coimbra EPE , Coimbra , Portugal
• 2 Pediatric , Centro Hospitalar do Baixo Vouga EPE , Aveiro , Aveiro , Portugal
• Correspondence to Dr Monica Bennett; acinomaicila{at}gmail.com

Most patients with cystic fibrosis (CF) develop multisystemic clinical manifestations, the minority having mild or atypical symptoms. We describe an adolescent with chronic cough and purulent rhinorrhoea since the first year of life, with diagnoses of asthma, allergic rhinitis and chronic rhinosinusitis. Under therapy with long-acting bronchodilators, antihistamines, inhaled corticosteroids, antileukotrienes and several courses of empirical oral antibiotic therapy, there was no clinical improvement. There was no reference to gastrointestinal symptoms. Due to clinical worsening, extended investigations were initiated, which revealed Pseudomonas aeruginosa in sputum culture, sweat test with a positive result and heterozygosity for F508del and R334W mutations in genetic study which allowed to confirm the diagnosis of CF. In this case, heterozygosity with a class IV mutation can explain the atypical clinical presentation. It is very important to consider this diagnosis when chronic symptoms persist, despite optimised therapy for other respiratory pathologies and in case of isolation of atypical bacterial agents.

• cystic fibrosis
• pneumonia (respiratory medicine)

https://doi.org/10.1136/bcr-2021-245971

Statistics from Altmetric.com

Request permissions.

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

A high degree of diagnostic suspicion is of fundamental importance when chronic symptoms persist, despite optimised therapy for previous diagnoses and in case of isolation of atypical bacterial agents in microbiological studies.

This case describes an adolescent with a chronic cough since the first year of life, adequate weight gain and normal pubertal development, without improvement with optimised therapy for other respiratory pathologies. There was no reference to gastrointestinal symptoms. There was clinical worsening at 13 years of age and isolation of Pseudomonas aeruginosa in sputum culture. After extensive investigation, including sweat test and genetic study, it was possible to confirm the diagnosis of cystic fibrosis (CF).

Case presentation

A 13-year-old female teenager presented with chronic cough and purulent rhinorrhoea with periods of intermittent clinical worsening with associated fever since the first year of life. This was accompanied by various medical specialties, with diagnoses of asthma, allergic rhinitis and chronic rhinosinusitis. She was under therapy with long-acting bronchodilators, antihistamines, inhaled corticosteroids, and antileukotrienes and submitted to several courses of empirical oral antibiotic therapy, without sustained and effective clinical improvement. She presented an adequate height–weight evolution, with a body mass index (BMI) at 50th−85th percentile and normal pubertal development, no reference to gastrointestinal symptoms or previous hospitalisations. Her family background was irrelevant. Due to clinical worsening, with emetising cough associated with intermittent fever and night sweats, a pulmonary CT scan was performed, which revealed parenchymal densification, air bronchogram, thickened bronchi, mucoid impaction and mediastinal adenopathies. Observed in the emergency department, the objective examination highlighted bibasal crackles on pulmonary auscultation, without other alterations. She was treated with clarithromycin, later associated with co-amoxiclav. An extended investigation was initiated, which revealed erythrocyte sedimentation rate of 52 mm/hour, C reactive protein test of 4.10 mg/dL, negative BK and interferon gamma release assay test, and isolation of P. aeruginosa in sputum culture. The antibiotic therapy was changed to ciprofloxacin and sweat tests were performed with positive results on two occasions (102 and 110 mmol/L). Later, a genetic study revealed heterozygosity for the F508del and R334W mutations, which confirmed the diagnosis of CF. Faecal elastase was performed, and the result was normal (>500 µg/g).

After antimicrobial therapy with ciprofloxacin, she maintained P. aeruginosa, and methicillin-sensitive Staphylococcus aureus (MSSA) was now discovered in the sputum. For this reason, she was hospitalised for intravenous eradication. After 2 weeks of antibiotic therapy with meropenem, gentamicin and teicoplanin, P. aeruginosa was eradicated but not MSSA. Linezulide was prescribed for 2 weeks, with a good response, and the microbiological study was negative.

Outcome and follow-up

During the follow-up period (2 years), she continued having frequent respiratory infections, with isolation of P. aeruginosa and MSSA in respiratory secretions intermittently, requiring the need for several courses of antibiotic therapy. The antibiogram of P. aeruginosa has remained sensible. Currently, she continues follow-up in a specialised fibrosis cystic centre, under inhaled therapy with colistin/tobramycin, hypertonic saline, salbutamol, dornase alfa, budesonide/formoterol, chest physiotherapy and oral azithromycin prophylaxis. Her pulmonary function is normal with a currently forced expiratory volume in 1 s of 87% and she shows adequate height−weight evolution, with BMI maintained at P50–85. The sweat chloride test was not repeated after confirmed diagnosis.

CF is one of the most commonly diagnosed genetic disorders 1 and the most common life-shortening autosomal recessive disease among Caucasian populations, with a frequency of 1 in 2000–3000 live births. 2 CF is caused by mutations in a single large gene on chromosome 7 that encodes the cystic fibrosis transmembrane conductance regulator ( CFTR ) protein.

There are more than 2000 mutations/variations of the CFTR gene reported and listed in the CFTR mutation database. A small subset are CF disease-causing mutations, of which the majority are associated with pancreatic insufficiency and a smaller subset are associated with pancreatic sufficiency. Most of the known mutations/variations related to CF are described in the CFTR2 database (Clinical and Functional Translation of CFTR). This website provides information about what is currently known about specific genetic variants or variant combination and is a useful resource to correlate clinical measures to the large number of variants identified to date. 3 4

Clinical disease requires disease-causing mutations in both copies of the CFTR gene. Mutations of the CFTR gene have been divided into five different classes. The most common mutation is F508del which is included in category class II mutations—defective protein processing. Approximately 50% of patients with CF are homozygous for this mutation, and 90% will carry at least one copy of this gene. In general, mutations in classes I−III cause more severe disease than those in classes IV and V. Class IV and V mutations are associated with moderate phenotypes and pancreatic sufficiency. 5 The R334W is a rare mutation included in class IV—defective conduction and associated with pancreatic sufficiency. 5 6 Those with less severe mutations present with pancreatic sufficiency and single organ manifestations of CF. Some of these patients would fulfil the diagnostic criteria for CF and some would be classified as having a CFTR-related disorder if the diagnosis of CF cannot be fulfilled. 7

The phenotypic expression of disease varies widely, based on CFTR-related (genotype-related) and non-CFTR-related factors (environmental and other genetic modifiers). Genotype–phenotype correlations are weak for pulmonary disease in CF and somewhat stronger for the pancreatic insufficiency phenotype. 5

Many studies in different individuals heterozygous for CFTR gene mutation have been performed to find out the association of CFTR gene mutation with asthma. The results are inconclusive, as some of the studies have shown positive association, whereas other could find either protective or no association. 8 Also, at this time, there is no evidence for a specific association between CFTR gene mutation and other allergic manifestations.

Clinical manifestations are multisystemic and heterogeneous. 9 The first symptoms of the disease usually appear in the first years of life, and most patients develop a multisystem disease, with predominantly respiratory and digestive symptoms. 2 5 10 The usual presenting symptoms and signs include persistent pulmonary infection, pancreatic insufficiency and elevated sweat chloride levels. However, many patients demonstrate mild or atypical symptoms, and clinicians should remain alert to the possibility of CF even when only a few of the usual features are present. 2 Progressive pulmonary involvement is the main cause of morbidity and mortality. Clinically significant pancreatic insufficiency eventually develops in approximately 85% of individuals with CF. The remaining 10%–15% of patients with CF remain pancreatic sufficient throughout childhood and early adulthood, but these individuals are at risk of pancreatitis. Pancreatic exocrine function may be evaluated indirectly by measurement of faecal elastase, which is clinically practical but has limited accuracy. Low levels of faecal elastase suggest pancreatic insufficiency and support a diagnosis of CF. 2 5 11–13

The diagnosis of CF is based on compatible clinical findings with biochemical or genetic confirmation. The sweat chloride test is the mainstay of laboratory confirmation, although tests for specific mutations, nasal potential difference (NPD), immunoreactive trypsinogen, stool faecal fat or pancreatic enzyme secretion may also be useful in some cases.

Both of the following criteria must be met to diagnose CF: (1) clinical symptoms consistent with CF in at least one organ system, or positive newborn screen or having a sibling with CF; and (2) evidence of cystic CFTR dysfunction (any of the following): elevated sweat chloride ≥60 mmol/L; presence of two disease-causing mutations in the CFTR gene, one from each parental allele; abnormal NPD.

Sweat chloride test ≥60 mmol/L is considered abnormal. If confirmed on a second occasion, this is sufficient to confirm the diagnosis of CF in patients with clinical symptoms of CF. Positive results of sweat testing should be further evaluated by CFTR sequencing. Determining the CFTR genotype is important because the results may affect treatment choices as well as confirm the diagnosis. For patients with inconclusive results of sweat chloride and DNA testing, measurement of NPD can be used to further evaluate for CFTR dysfunction. 5 14

Newborn screening programmes for CF are now performed routinely in several countries, which contributed to a dramatic increase in the number of CF cases identified before presenting with symptoms. The rationale for this screening is that early detection of CF may lead to earlier intervention and improved outcomes because the affected individuals are diagnosed, referred and treated earlier in life compared with individuals who are diagnosed after presenting with symptomatic CF. In Portugal and some other European countries, this programme was implemented less than 10 years ago, contributing to a late diagnosis in older children.

There are different neonatal screening programmes that include biochemical screening and/or DNA assays with panels to test for the most common CFTR mutations in the local population. Most programmes test for between 23 and 40 mutations, and some programmes even perform adjunctive full gene sequencing. Screening for a greater number of mutations increases the likelihood of identifying infants with CF and also increases the identification of rare or unique sequence mutations, making interpretation of the result more complicated. As only a limited number of mutations are evaluated on the genetic screens, it is possible to miss the diagnosis. Thus, it is important to follow such children closely, with particular attention to weight gain and recurrent respiratory infections. Clinicians should consider CF in individuals with suggestive symptoms, even when results of the newborn screen are negative or equivocal. 5 14

In the case described here, heterozygosity with a class IV mutation, usually associated with an intermediate phenotype and pancreatic sufficiency, may explain the atypical clinical presentation and consequent diagnosis only in adolescents. We also hypothesise that this child’s allergic manifestations may have delayed the diagnosis.

As the spectrum of clinical presentation is very variable, it is very important for clinicians from multiple specialties to be vigilant and suspect this diagnosis in conditions such as recurrent pulmonary infection, male infertility, pancreatitis, nasal polyposis and malabsorption even in patients with negative newborn screening. 2 10 13

Learning points

There is a wide spectrum of manifestations of cystic fibrosis (CF). These variations and wide spectrum are based on cystic fibrosis transmembrane conductance regulator (CFTR)-related (genotype-related) and non-CFTR-related factors (environmental and other genetic modifiers).

Most patients with CF develop multisystemic and heterogeneous clinical manifestations, with predominantly respiratory and digestive symptoms.

A minority have mild or atypical symptoms.

Heterozygosity with a class IV mutation usually is associated with an intermediate phenotype and pancreatic sufficiency and can explain the atypical clinical presentation.

It is very important to consider this diagnosis when chronic symptoms persist, despite optimised therapy for other respiratory pathologies and in case of isolation of atypical bacterial agents in microbiological studies.

Ethics statements

Patient consent for publication.

Consent obtained from parent(s)/guardian(s)

• Dickinson KM ,
• ↵ Cystic fibrosis mutation database . Available: http://www.genet.sickkids.on.ca/Home.html
• ↵ Clinical and functional translation of CFTR . Available: https://cftr2.org/
• Ellis L , et al
• Awasthi S ,
• Gartner S ,
• Salcedo Posadas A ,
• García Hernández G
• Castellani C ,
• Linnane B ,
• Pranke I , et al
• Farrell PM ,
• Ren CL , et al
• Kharrazi M ,
• Bishop T , et al

Contributors MB cared for study patient, planned and wrote the article. AFN collected data. MMF provided and cared for study patient, served as scientific advisors and critically reviewed the study proposal. TRS cared for study patient, served as scientific advisors and critically reviewed the study proposal.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

Read the full text or download the PDF:

We have a new app!

Take the Access library with you wherever you go—easy access to books, videos, images, podcasts, personalized features, and more.

Download the Access App here: iOS and Android . Learn more here!

• Remote Access
• Save figures into PowerPoint
• Download tables as PDFs

Chapter 19:  Case Study: Cystic Fibrosis

Julie M. Skrzat; Carole A. Tucker

• Download Chapter PDF

Disclaimer: These citations have been automatically generated based on the information we have and it may not be 100% accurate. Please consult the latest official manual style if you have any questions regarding the format accuracy.

Download citation file:

• Search Book

Jump to a Section

Introduction.

• Examination: Age 2 Months
• Evaluation, Diagnosis, and Prognosis
• Intervention
• Conclusion of Care
• Examination: Age 8 Years
• Examination: Age 16 Years
• Recommended Readings
• Full Chapter
• Supplementary Content

C ystic fibrosis (CF) is an autosomal recessive condition affecting approximately 30,000 Americans and 70,000 people worldwide. According to the Cystic Fibrosis Foundation ( Cystic Fibrosis Foundation, 2019a ), approximately 1,000 new cases are diagnosed yearly in the United States, with a known incidence of 1 per 3,900 live births. The disease prevalence varies greatly by ethnicity, with the highest prevalence occurring in Western European descendants and within the Ashkenazi Jewish population.

The CF gene, located on chromosome 7, was first identified in 1989. The disease process is caused by a mutation to the gene that encodes for the CF transmembrane conductance regulator (CFTR) protein. This mutation alters the production, structure, and function of cyclic adenosine monophosphate (cAMP), a dependent transmembrane chloride channel carrier protein found in the exocrine mucus glands throughout the body. The mutated carrier protein is unable to transport chloride across the cell membrane, resulting in an electrolyte and charge imbalance. Diffusion of water across the cell membrane is thus impaired, resulting in the development of a viscous layer of mucus. The thick mucus obstructs the cell membranes, traps nearby bacteria, and incites a local inflammatory response. Subsequent bacterial colonization occurs at an early age and ultimately this repetitive infectious process leads to progressive inflammatory damage to the organs involved in individuals with CF.

Pop-up div Successfully Displayed

This div only appears when the trigger link is hovered over. Otherwise it is hidden from view.

Please Wait

Disclaimer » Advertising

• HealthyChildren.org

• Previous Article
• Next Article

Materials and Methods

Selection criteria, data sources and searches, comprehensiveness of reporting, data analysis, literature search, gaining resilience, lifestyle restriction, resentment of chronic treatment, temporal limitations, emotional vulnerability, transplant expectations and uncertainty, children’s experiences of cystic fibrosis: a systematic review of qualitative studies.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships 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

Nathan Jamieson , Dominic Fitzgerald , Davinder Singh-Grewal , Camilla S. Hanson , Jonathan C. Craig , Allison Tong; Children’s Experiences of Cystic Fibrosis: A Systematic Review of Qualitative Studies. Pediatrics June 2014; 133 (6): e1683–e1697. 10.1542/peds.2014-0009

Download citation file:

• Ris (Zotero)
• Reference Manager

Cystic fibrosis (CF) is a common life-shortening genetic disease and is associated with poor psychosocial and quality of life outcomes. The objective of this study was to describe the experiences and perspectives of children and adolescents with CF to direct care toward areas that patients regard as important.

MEDLINE, Embase, PsycINFO, and Cumulative Index to Nursing and Allied Health Literature were searched from inception to April 2013. We used thematic synthesis to analyze the findings.

Forty-three articles involving 729 participants aged from 4 to 21 years across 10 countries were included. We identified 6 themes: gaining resilience (accelerated maturity and taking responsibility, acceptance of prognosis, regaining control, redefining normality, social support), lifestyle restriction (limited independence, social isolation, falling behind, physical incapacity), resentment of chronic treatment (disempowerment in health management, unrelenting and exhausting therapy, inescapable illness), temporal limitations (taking risks, setting achievable goals, valuing time), emotional vulnerability (being a burden, heightened self-consciousness, financial strain, losing ground, overwhelmed by transition), and transplant expectations and uncertainty (confirmation of disease severity, consequential timeliness, hope and optimism).

Adolescents and children with CF report a sense of vulnerability, loss of independence and opportunities, isolation, and disempowerment. This reinforces the importance of the current model of multidisciplinary patient-centered care that promotes shared decision-making, control and self-efficacy in treatment management, educational and vocational opportunities, and physical and social functioning, which can lead to optimal treatment, health, and quality of life outcomes.

Cystic fibrosis (CF) is a common life-shortening inherited disease with an estimated incidence of 1 in 2500 newborns. 1 , – 4 Most patients with CF develop chronic pulmonary disease and bronchiectasis, as well as pancreatic insufficiency and subsequent malnutrition. 5 , – 7  

Because of advances in screening, treatment, and infection control, patients diagnosed with CF within the past decade are now expected to survive into their 50s. 8 , 9 However, treatment of CF involves daily adherence to intensive antibiotic regimens, vitamin and enzyme supplements, consumption of a calorie-rich diet, inhaler use, and physically demanding chest physiotherapy. Limited daily functioning, poor adherence to treatment, low self-esteem, short stature, and impaired psychosocial outcomes have been reported. 10 , – 15  

What remains less well known is how young patients cope with the symptoms, prognostic uncertainty, and treatment burden of CF. In-depth insights into people’s beliefs and attitudes can be gained by qualitative research, and synthesis of multiple qualitative studies can provide a broader scope of data across different health care contexts and generate new and more comprehensive understandings of social phenomena. 16 We aimed to describe the breadth of experiences and perspectives of children and adolescents with CF, to inform ways to deliver patient-centered care for optimal treatment, health, and quality of life outcomes, and to direct care toward areas that patients regard as important.

We followed the Enhancing Transparency of Reporting the Synthesis of Qualitative research framework. 16  

Qualitative studies that explored the experiences and perspectives of children and adolescents (≤21 years of age) diagnosed with CF were included. We excluded observational studies, randomized controlled trials, genetic and microbiological studies, non–primary research articles (letters, commentaries, and reviews), studies that did not elicit data from children and adolescents with CF, quantitative surveys, and non-English articles due to lack of resources for translation.

The search strategy is provided in Supplemental Table 3 . We conducted searches in Medline, Embase, PsycINFO, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) from inception to April 2013. We also searched Google Scholar and the reference lists of relevant studies and reviews. We screened the abstracts and excluded those that that did not meet the inclusion criteria, then assessed the full-text versions of potentially relevant studies.

We evaluated the transparency of reporting of each qualitative study using the Consolidated Criteria for Reporting Qualitative Health Research. 17 This framework included criteria specific to the research team, study methods, context of the study, analysis, and interpretations. Two reviewers (N.J. and C.H.) assessed each study independently, and disagreements were resolved by discussion with A.T.

We used thematic synthesis as described by Thomas and Harden. 18 For each study, all participant quotations and text under the “Results/Findings” or “Conclusion/Discussion” sections were extracted and entered verbatim into HyperRESEARCH (version 3.5.2; ResearchWare, Inc, Randolph, MA), software for storing, coding, and searching qualitative data. N.J. conducted line-by-line coding of the text into concepts inductively derived from the data and transferred concepts between studies by adding coded text into existing concepts or creating additional codes for new concepts. Similar codes were grouped into themes. The preliminary themes were discussed in a research team meeting to ensure that the themes reflected the full range of experiences reported across all studies. Patterns and relationships within and across themes were examined and mind mapped to develop an analytical thematic schema.

Our search yielded 1862 articles. Of these, 43 articles involving at least 729 children with CF were included ( Fig 1 ). The number of participants was not reported in 7 studies ( Table 1 ).

Search process and results. *Minimum 729 participants; 7 articles did not specify the number of pediatric patients with CF in the sample.

Characteristics of Included Studies

NS = not stated or not applicable.

Grounded theory means theories that are grounded in the empirical data and built up inductively through a process of careful analysis and comparisons. Phenomenology entails studying people’s understandings and interpretations of their experiences in their own terms and emphasizing them as explanations for their actions. Mixed methods include both quantitative and qualitative methods. Narrative methodology is based on the belief that what people think and mean is transparent and readily accessible. Ethnography is the attempt to discover and describe individual social and cultural groups. Roy adaptation model considers the process of individual adjustment in response to groups. Hermeneutics is the examination of the way people develop interpretations of their lives in relation to life experiences.

Studies reported between 7 and 20 of the 24 Consolidated Criteria for Reporting Qualitative Health Research ( Supplemental Table 4 ). Fifteen studies (35%) described the participant selection strategy. Twenty-eight studies (65%) reported researcher triangulation, and 15 (35%) reported on theoretical saturation, defined as a lack of new concepts found after subsequent data collection. Member checking (seeking feedback on the research findings from participants) was reported in 2 (5%) studies.

We identified 6 main themes: gaining resilience, lifestyle restriction, resentment of chronic treatment, temporal limitations, emotional vulnerability, and transplant expectations and uncertainty. Selected participant quotations that conveyed the meaning of the theme were chosen from the included the studies and integrated as examples in the results. Additional illustrative quotations are presented in Table 2 .

Illustrative Quotations

Possible conceptual links between themes are presented in Fig 2 . Participants with CF experienced emotional vulnerability and at the same time expressed capacities to gain resilience in coping with their illness. Heightened self-consciousness due to manifestations of CF contributed to participants’ sense of vulnerability. The chronic treatment burden imposed restrictions on lifestyle and independence, which intensified participants’ resentment of their illness. Regaining control contributed to the development of resilience but also reinforced risk-taking attitudes and decisions, particularly in adolescents who sought to demonstrate independence and ability to make their own choices. The need to value time and reprioritize was driven by an acute awareness and realization of their disease severity.

Thematic schema.

Accelerated Maturity and Taking Responsibility

Participants felt that they were more mature and compassionate compared with their well peers. Having faced the challenges of living with CF, some believed they gained coping skills, resilience, and appreciation of life and were less concerned about trivial matters. One adolescent stated, “I feel that having CF has pushed me into adulthood...in a good way.” 19 They emphasized the importance of a positive attitude in staying motivated to take their medications. Signs and symptoms such as hemoptysis encouraged some participants to be more health conscious.

Acceptance of Prognosis

Some participants described having to accept the reality of their incurable condition and shortened life expectancy to live an “enjoyable life.” 20 Although they could not be optimistic about their survival, some believed in the need to maintain a positive attitude and to “be happy and make the most of it.” 21  

Regaining Control

Invasive medical procedures caused some participants to feel a loss of control of their own body. One participant explained, “If you have a [IV] line, the control is with the other people.” 22 However, strategies such as needle plans and play therapy helped alleviate their anxieties as participants felt that they had reclaimed control. Also, participants believed that the ability to manage their own health and to participate in physical and recreational activities meant that CF had not defeated or limited them. They derived a sense of normality, “mastery,” and “competence” from taking control over their health, with 1 girl describing physical activity as her “sanctuary.” 23  

Redefining Normality

Over time, some believed that they became less concerned about the differences in their physical appearance and capabilities compared with their healthy peers. One participant described that he had “nothing to hide and nothing to advertise.” 24 By meeting other young people with CF, some learned to respect and accept their own physical capacities rather than compare themselves with their well peers. Younger children reported a loss of having a normal identity at the time of diagnosis: “I just thought she must be insane...because I always thought I was just like everybody else.” 25  

Social Support

Emotional and practical support from carers, friends, and family was described as a resource that enabled participants to cope with their day-to-day disease management. Having a shared experience and interacting with other patients with CF promoted social connectedness and sharing of coping strategies and information. Children and adolescents, particularly girls, reported that they depended on their parents to encourage adherence to medications and therapy. One participant believed that the loss of accountability to their parents after moving out of home contributed to the onset of depression.

Falling Behind

The participants felt socially “out of the loop” 26 and out of place because of frequent absences from school and extracurricular activities, mainly due to pulmonary exacerbations and lung deterioration. Some felt they lacked capacity and support to perform academically. For example, 1 adolescent described having to leave school being unable to achieve second grade literacy.

Limited Independence

Most participants felt their lives were marked by a loss of freedom and opportunities because of their poor health and time-consuming treatments. Some described their parents as interfering, domineering, and overprotective. They felt exasperated and patronized by constant reminders from parents about taking medications; however, some felt that these reminders were essential “or else [they] won’t do it.” 27 Others felt that they should be given more responsibility as they got older, 28 and 1 participant suggested they should be given a trial period to prove they could independently manage their illness. 29 To avoid having additional restrictions imposed, some refrained from asking for advice from their doctors about high-risk activities such as drinking alcohol, which led to high-risk behaviors including defiance 29 and hiding problems with adherence: “I’ll not do [physical therapy] just to spite them.” 27 Being highly dependent on care, some older participants stated that their career and education options were limited to those that were located in close proximity to their home or CF clinic.

Physical Incapacity

Short stature, weakness, fatigue, and susceptibility to infections contributed to participants’ frustration, social isolation, and feelings of being different. They had “to try twice as hard...to do as good as the other kids” 30 and found that physical exertion took a toll on their health and energy. Children felt upset about being too tired to play. Adolescents, particularly boys, were concerned about being unable to achieve their ideal masculine physique.

Social Isolation

Participants felt ostracized when others avoided them because of their coughing or differences in their physical appearance, such as finger clubbing. Frequent absences from school also made it harder to establish friendships, because participants “never got to know people as well.” 26 Children described being bullied or abandoned by others who thought CF was contagious: “All the kids saying ‘eww’...then they would say ‘Oh shut up AIDS girl.’” 30 Some felt that others accused them of using CF as an excuse to avoid school. CF was also believed to “jeopardize” romantic relationships, with 1 participant reporting that her past boyfriend “split” 31 when he found out she had CF. Having to avoid “high-risk” environments and being isolated from other patients in wards, participants felt socially excluded and expressed “boredom.” 32  

Inescapable Illness

Participants wanted “escape” or a “break” from their illness. However, the relentless need to take medications and undergo physical therapy served as constant reminders of their incurable illness. One participant stated that “it drives the nail home that you do have lung disease,” 23 and another was “unbearably depressed” 33 about how the treatment reminded her of her illness. Some saw treatment as another indication of being different or weaker than their well peers.

Disempowerment in Health Management

Some participants felt that doctors used only “high level talk” 31 and complex medical terminology. When they perceived their doctors were communicating solely to their parents, participants felt ignored and devalued. They wanted clinicians to listen to their needs rather than “just clinically going through [the illness and treatment],” 34 and they believed doctors should communicate directly with them. Some participants appreciated nurses who “treat you like you are part of their family.” 35  

Unrelenting and Exhausting Therapy

Treatment of CF, particularly medications, physical therapy, and lung clearance, was described as intensive, invasive, and physically strenuous. Children were frightened of the pain of injections, and they experienced fatigue due to prescribed physical exercise. Despite the physical demands of treatment, some adolescents believed that persevering with therapy was necessary to prevent health deterioration and lung infections. One participant said, “I’m just fighting to get rid of something for a certain amount of time.... It’s a never-ending battle.” 26  

Valuing Time

Being acutely aware of their “shadowy future” 21 and shortened life expectancy, some participants chose to “make the most out of life now” 21 rather than waste time worrying about the future. Some were concerned that they had wasted their time so far (“I just sometimes feel I haven’t done much with my life” 36 ) and despaired at how their physical therapy “robbed” 23 them of their precious time. Participants chose to spend as much time as possible with family and friends.

Setting Achievable Goals

Some participants accounted for the health and lifestyle limitations caused by CF when they set career and relationships goals, and they needed to consider air quality and associated workplace risks, employment benefits and health insurance, and the availability of flexible hours or part-time work. They also developed alternative strategies if they could not pursue their initial vocational goals. In particular, boys expressed optimism and refused to allow their condition to define their career goals. Conversely, some adolescent girls felt insecure about their future career pathway and doubted their opportunities for full-time employment.

Taking Risks

Some adolescents wanted to take risks because they felt they had nothing to lose in their limited time. They described taking drugs, drinking alcohol, smoking, and “blow[ing] off treatment,” 20 choices that allowed them to show CF had not restricted their lifestyle. Some acknowledged that certain environments would expose them to infection risk but believed that complete avoidance “could take it too far” and lead to “missing out.” 32 For some, the consequences of poor health after smoking or refusing treatment and therapy “caught up” with them, and in turn they became motivated to continue with their treatments.

Being a Burden

Some participants deemed themselves highly dependent on family members for day-to-day medical treatment. For this reason, they felt guilty for taking parental attention away from their siblings and for depriving their families of vacation time because of their ill health. One participant believed that her parents’ arguments about her CF care caused their marital problems.

Financial Strain

In a study conducted in the United States, adolescents were anxious about the financial burden of their disease, including insurance, medications, and costs of nutrient-dense foods. A major concern was negotiating with insurance companies to cover the costs of equipment and medications.

Heightened Self-Consciousness

Many participants expressed embarrassment about their small physical stature, coughing, and taking medications in public. Feelings of being different were exacerbated by symptoms that prohibited them from engaging in social and physical activities. Some participants developed a “private cough and a social cough” 30 or avoided taking medications in an effort to appear normal. Being defined as “patients or handicapped” 24 and being treated differently by their peers, teachers, and coaches caused frustration, and participants felt demeaned. In an effort to appear normal, many participants chose not to tell their friends and teachers about their CF.

Losing Ground

Some participants felt powerless as the illness progressed: “I feel helpless, how I used to be able to do [activities], and now, I can’t.” 21 Participants were anxious about potentially developing other illnesses that they perceived were associated with CF, including diabetes and depression.

Overwhelmed by Transition

Many participants felt overwhelmed and unprepared for the transition from pediatric to adult care. Some felt that there had been “no real discussion” 34 about transition until it had occurred. They had difficulty coping with the unfamiliar setting and lack of rapport with new health care workers. One participant was concerned about perceived greater exposure to infection in the adult setting. Conversely, some found the transition process beneficial and enjoyed experiencing what they felt was age-appropriate care.

Confirmation of Disease Severity

Being listed for lung transplantation was alarming for some participants because it signaled that their health had deteriorated to a critical stage. Some believed they were listed too soon because they did not perceive themselves to be seriously ill, and they felt unprepared and shocked.

Consequential Timeliness

The importance of timing of being waitlisted or receiving a lung transplant at the right time was described by some as being a “very strange balance” having to “find the exact point at which to get you on the list, because if you go too early, you are sacrificing maybe a year of good health.” 37 The time from being placed on the transplant list to being transplanted was marked by uncertainty, anxiety, disappointing false alarms, and the feeling that life was like a “video recorder...on pause. I’m not really living, I’m just getting by.” 38 Some felt that more regular contact with the transplant center would reassure them that they had not been forgotten.

Hope and Optimism

Some participants held hope that a transplant would provide them with better health, greater life expectancy, and the chance to be “normal like everyone else.” Transplant was perceived to offer a chance of good health, without “[lungs with] scars and years of infection and damage.” 37 Others were optimistic about the potential for future medical advances to find a cure and improve their health.

Children and adolescents with CF have a shortened life expectancy, significant comorbidities, and treatment burdens that impair their identity, daily functioning, and life goals. Our study highlights the personally significant experiences of children with CF, including their emotional vulnerabilities and their strategies and capacities to develop resilience. Challenges of living with CF include accepting their prognosis, adhering to a demanding treatment regimen, losing independence, transitioning to adult care, limiting social participation, and missing education and career opportunities, which reinforced their sense of abnormality, resentment, and disempowerment. Social support from family, friends, and other patients with CF is valued, and internal coping strategies encompass redefining normality, taking responsibility, setting achievable or realistic goals, and holding hope for lung transplantation and medical advances.

The feeling of being different from others appeared to be more acute in younger children. Some adolescents believed that CF caused them to mature beyond their chronological age, which motivated them to accept their illness and adhere to their prescribed treatment, but others chose to engage in high-risk behaviors to demonstrate that they were not limited by CF. Those with milder diseases were still able to retain a sense of control through participation in physical, school, and social activities. However, patients with more severe CF contended with feelings of powerlessness.

The themes identified in our review may help explain why some children and adolescents with CF report lower quality of life than their well peers. 40 , 41 Of note, girls with CF have reported more emotional symptoms and greater pain, spend more time in the hospital than boys with a similar level of illness, 41 , – 43 and have a worse prognosis than boys. 44 , – 48 Our findings suggest that boys may emphasize taking responsibility for their treatments and maintaining a positive attitude, whereas some girls expressed the value of sharing responsibility for their health management with, for example, their parent or doctor. Some boys reported body image concerns and were motivated to exercise to achieve a more muscular physique. Studies have also found that a decrease in lung function predicts a poor health-related quality of life over time. 49 This is supported by our findings that many of the psychosocial issues in CF relate to issues of fatigue and physical incapacity.

Children and adolescents living with other chronic and life-limiting illnesses including cancer, juvenile idiopathic arthritis, and chronic kidney disease also experience a loss of normality and of control over their bodies because of regular invasive procedures, social isolation, lifestyle restraints, and heightened self-consciousness about the differences in their physical appearance compared with their well peers. 50 , – 55 Being able to participate in physical activity is viewed as important in both the CF and asthma populations. 56  

What may be unique in children and adolescents with CF is how their susceptibility to infections (including cross-infection necessitating segregation 32 , 57 , 58 ) limits their lifestyle, reduces their capacity to participate in physical activity, and perpetuates anxiety, isolation, and uncertainty. Also, some felt embarrassed and worried that they would be abandoned by peers who thought their illness was spread by coughing.

In our review, we undertook a comprehensive search and a rigorous independent assessment of the transparency of study reporting. Researcher triangulation was achieved by involving several researchers in the process of analyzing the data, which ensured that the coding framework captured the breadth of data reported in the primary studies. Software was used to code the data, allowing an auditable development of the findings. However, our study has some limitations. We were unable to describe age differences because the majority of the data (quotations) from the included studies were not tagged to a specific age or age group. Most studies were conducted in developed countries, and non–English language articles were excluded, making the transferability of our findings uncertain.

CF care sets a benchmark in terms of providing comprehensive multidisciplinary care in pediatrics. 59 , – 61 Nonadherence to treatment remains a significant problem, particularly in the pediatric population. 62 , – 64 Our study suggests that this may result from self-consciousness and striving to appear normal, engaging in risk-taking behaviors to gain a sense of control and independence, needing to “escape” the illness and exhaustion from the demands of treatment, and a sense of disempowerment. Motivating factors for treatment adherence included determination to maintain health in their hope for transplantation and the desire to take responsibility and demonstrate maturity.

To promote independence, empowerment, and confidence in self-management, which may lead to improved adherence, we suggest shared decision-making processes where patients are actively involved in decisions about their own treatment and feel in control of their treatment. 65 , 66  

There is now a need to better meet the longer-term needs of patients with CF who will live longer, especially their psychosocial needs, as described in our review. The Home, Education, Activities, Drug and Alcohol Use, Sexuality and Suicide Youth is a validated tool that can be used to assess psychosocial status and health-risk behaviors in adolescents. 67 Such tools may be used to identify patients who will benefit from psychosocial services, 68 , 69 which could be adapted for the CF population and thereby support clinicians in promoting psychosocial coping among children with CF.

Transitioning from pediatric to adult health care services remain a challenge, 70 , – 73 with some adolescents reporting difficulties in coping with pressures of their new health care responsibilities. 71 Our findings suggest the need to individualize the transition approach, focusing on the individual’s readiness and expectations for transition, which can be facilitated by creating a care plan with the patient and their family. 74 A collaborative process through introduction of the adult-style clinic in the pediatric setting has been implemented in CF clinics in the United Kingdom and Australia. Successful collaboration can be promoted through the appointment of a transition coordinator within the CF team to liaise between the pediatric and adult teams and provide education to families.

Also, our findings highlight the benefits of peer support from other patients with CF, but face-to-face interaction is not possible if patients are physically isolated to prevent cross-infection in clinical settings. 75 , 76 Therefore, social media and facilitated online support networks for pediatric patients with CF may be particularly useful, but they must be closely monitored to ensure exchange of accurate information. There is some reported success in the literature in the field of peer-to-peer health care, where patients and their families use the Internet to find and share practical health care tips.

We suggest that more qualitative research is needed to assess the attitudes and experiences of children and adolescents regarding lung transplantation. Also, there is a paucity of qualitative data on perceptions and concerns about sexuality and infertility that could be explored further. Comprehensive and validated CF-specific quality of life instruments, such as the Cystic Fibrosis Questionnaire–Revised, are available but may be adapted to capture domains relating to decision-making in health care, empowerment, financial and employment concerns, and future outlook.

Children and adolescents living with CF experience vulnerability, resentment, and disempowerment. Health care decision-making can be challenging given the high treatment burden and uncertainties about their prognosis, and it is arguably more difficult in the context of lung transplantation because the marked the severity of their disease and timing of waitlisting have consequences for expected survival and life goals. We suggest that multidisciplinary patient-centered care should encompass strategies that promote shared decision-making, control and self-efficacy in treatment management, educational and vocational opportunities, and physical and social functioning, which may lead to optimal treatment, health, and quality of life outcomes.

cystic fibrosis

Cumulative Index to Nursing and Allied Health Literature

Mr Nathan Jamieson carried out the data collection and analyses, coded the data, and drafted the initial manuscript; Dr Fitzgerald, Dr Singh-Grewal, Ms Hanson, and Dr Craig contributed to the initial analyses and reviewed and revised the manuscript; Dr Tong conceptualized and designed the study and drafted the initial manuscript; and all authors approved the final manuscript as submitted.

FUNDING: No external funding. Dr Tong is supported by the National Health and Medical Research Council Fellowship (1037162).

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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

Lingering Identity as Chronically Ill and the Unanticipated Effects of Life-Changing Precision Medicine in Cystic Fibrosis: A Case Report

Affiliation.

• 1 School of Nursing, University of Alabama at Birmingham, Birmingham, AL, USA.
• PMID: 34179383
• PMCID: PMC8205364
• DOI: 10.1177/2374373521996971

Cystic fibrosis (CF) is the leading genetic disease among Caucasians; however, advances in diagnosis and treatment have improved both quality and quantity of life for those affected. A remarkable recent discovery is the triple-drug combination, elexacaftor/tezacaftor/ivacaftor, which has been touted as a "miracle drug" for CF because of its demonstrated efficacy and safety. This case study reports on an adult woman with CF who experienced positive life-changing results from elexacaftor/tezacaftor/ivacaftor, and yet discovered that she lived in fear that its effectiveness would diminish, and her debilitating symptoms would return. Her lingering identity as chronically ill tainted her view of her new life with skepticism and pervasive anxiety. This case highlights a critical need to engage in early, regular and sensitive discussions with patients before initiating treatments that may affect their emotional and mental health and provide referrals or services to meet those emergent needs.

Keywords: TrikaftaTM; cystic fibrosis; elexacaftor/tezacaftor/ivacaftor; lingering identity; precision medicine.

© The Author(s) 2021.

Publication types

• Case Reports

Grants and funding

• P30 DK072482/DK/NIDDK NIH HHS/United States

Advertisement

Impact of gene editing on the study of cystic fibrosis

• Published: 21 June 2016
• Volume 135 , pages 983–992, ( 2016 )

Cite this article

• Patrick T. Harrison 1 ,
• David J. Sanz 1 &
• Jennifer A. Hollywood 1 , 2  

1975 Accesses

14 Citations

1 Altmetric

Explore all metrics

Cystic fibrosis (CF) is a chronic and progressive autosomal recessive disorder of secretory epithelial cells, which causes obstructions in the lung airways and pancreatic ducts of 70,000 people worldwide (for recent review see Cutting Nat Rev Genet 16(1):45–56, 2015 ). The finding that mutations in the CFTR gene cause CF ( Kerem et al. Science 245(4922):1073–1080, 1989 ; Riordan et al. Science 245(4922):1066–1073, 1989 ; Rommens et al. Science 245(4922):1059–1065, 1989 ), was hailed as the very happy middle of a story whose end is a cure for a fatal disease ( Koshland Science 245(4922):1029, 1989 ). However, despite two licensed drugs (Ramsey et al. N Engl J Med 365(18):1663–1672, 2011 ; Wainwright et al. N Engl J Med 373(3):220–231, 2015 ), and a formal demonstration that repeated administration of CFTR cDNA to patients is safe and effects a modest but significant stabilisation of disease (Alton et al. Lancet Respir Med 3(9):684–691, 2015 ), we are still a long way from a cure, with many patients taking over 100 tablets per day, and a mean age at death of 28 years. The aim of this review is to discuss the impact on the study of CF of gene-editing techniques as they have developed over the last 30 years, up to and including the possibility of editing as a therapeutic approach.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price includes VAT (Russian Federation)

Instant access to the full article PDF.

Rent this article via DeepDyve

Institutional subscriptions

Similar content being viewed by others

Epigenomic insights into common human disease pathology

Christopher G. Bell

Cystic fibrosis: a clinical view

Carlo Castellani & Baroukh M. Assael

Ethics and Genomic Editing Using the Crispr-Cas9 Technique: Challenges and Conflicts

David Lorenzo, Montse Esquerda, … Grup Investigació en Bioética

Alton EW, Armstrong DK, Ashby D, Bayfield KJ, Bilton D, Bloomfield EV, Boyd AC, Brand J, Buchan R, Calcedo R, Carvelli P, Chan M, Cheng SH, Collie DD, Cunningham S, Davidson HE, Davies G, Davies JC, Davies LA, Dewar MH, Doherty A, Donovan J, Dwyer NS, Elgmati HI, Featherstone RF, Gavino J, Gea-Sorli S, Geddes DM, Gibson JS, Gill DR, Greening AP, Griesenbach U, Hansell DM, Harman K, Higgins TE, Hodges SL, Hyde SC, Hyndman L, Innes JA, Jacob J, Jones N, Keogh BF, Limberis MP, Lloyd-Evans P, Maclean AW, Manvell MC, McCormick D, McGovern M, McLachlan G, Meng C, Montero MA, Milligan H, Moyce LJ, Murray GD, Nicholson AG, Osadolor T, Parra-Leiton J, Porteous DJ, Pringle IA, Punch EK, Pytel KM, Quittner AL, Rivellini G, Saunders CJ, Scheule RK, Sheard S, Simmonds NJ, Smith K, Smith SN, Soussi N, Soussi S, Spearing EJ, Stevenson BJ, Sumner-Jones SG, Turkkila M, Ureta RP, Waller MD, Wasowicz MY, Wilson JM, Wolstenholme-Hogg P; UK Cystic Fibrosis Gene Therapy Consortium (2015) Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med 3(9):684–691

Article   CAS   PubMed   PubMed Central   Google Scholar  

Butler CR, Hynds RE, Gowers KH, Lee DD, Brown JM, Crowley C, Teixeira VH, Smith CM, Urbani L, Hamilton NJ, Thakrar RM, Booth HL, Birchall MA, De Coppi P, Giangreco A, O’Callaghan C, Janes SM (2016) Rapid expansion of human epithelial stem cells suitable for airway tissue engineering. Am J Respir Crit Care Med. doi: 10.1164/rccm.201507-1414OC

PubMed   Google Scholar  

Cai Y, Bak RO, Mikkelsen JG (2014) Targeted genome editing by lentiviral protein transduction of zinc-finger and TAL-effector nucleases. Elife 3:e01911

Article   PubMed   PubMed Central   Google Scholar  

Campbell KH, McWhir J, Ritchie WA, Wilmut I (1996) Sheep cloned by nuclear transfer from a cultured cell line. Nature 380(6569):64–66

Article   CAS   PubMed   Google Scholar  

Cao H, Machuca TN, Yeung JC, Wu J, Du K, Duan C, Hashimoto K, Linacre V, Coates AL, Leung K, Wang J, Yeger H, Cutz E, Liu M, Keshavjee S, Hu J (2013) Efficient gene delivery to pig airway epithelia and submucosal glands using helper-dependent adenoviral vectors. Mol Ther Nucleic Acids 2:e127. doi: 10.1038/mtna.2013.55

Cao H, Wu J, Duan C, Du K, Lee CM, Yeger H, Hu J (2016) Long-term expression of the human cftr gene in mouse airway via helper-dependent adenoviral vector delivery and transient immunosuppression. Hum Gene Ther 27(1):83–91. doi: 10.1089/hum.2015.108

Castellani C, CFTR2 team (2013) CFTR2: how will it help care? Paediatr Respir Rev 14(Suppl 1):2–5

Article   PubMed   Google Scholar  

Cathomen T (2004) AAV vectors for gene correction. Curr Opin Mol Ther 6(4):360–366

CAS   PubMed   Google Scholar  

Cermak T, Doyle EL, Christian M, Wang L, Zhang Y, Schmidt C, Baller JA, Somia NV, Bogdanove AJ, Voytas DF (2011) Efficient design and assembly of custom TALEN and other TAL effector-based constructs for DNA targeting. Nucleic Acids Res 39(12):e82. doi: 10.1093/nar/gkr218 (Epub 2011 Apr 14. Erratum in: Nucleic Acids Res. 39(17):7879)

Choi JG, Dang Y, Abraham S, Ma H, Zhang J, Guo H, Cai Y, Mikkelsen JG, Wu H, Shankar P, Manjunath N (2016) Lentivirus pre-packed with Cas9 protein for safer gene editing. Gene Ther. doi: 10.1038/gt.2016.27

Google Scholar  

Chu CS, Trapnell BC, Curristin SM, Cutting GR, Crystal RG (1992) Extensive posttranscriptional deletion of the coding sequences for part of nucleotide-binding fold 1 in respiratory epithelial mRNA transcripts of the cystic fibrosis transmembrane conductance regulator gene is not associated with the clinical manifestations of cystic fibrosis. J Clin Invest 90(3):785–790

Colledge WH, Abella BS, Southern KW, Ratcliff R, Jiang C, Cheng SH, MacVinish LJ, Anderson JR, Cuthbert AW, Evans MJ (1995) Generation and characterization of a delta F508 cystic fibrosis mouse model. Nat Genet 10(4):445–452

Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F (2013) Multiplex genome engineering using CRISPR/Cas systems. Science 339(6121):819–823

Corvol H, Blackman SM, Boëlle PY, Gallins PJ, Pace RG, Stonebraker JR, Accurso FJ, Clement A, Collaco JM, Dang H, Dang AT, Franca A, Gong J, Guillot L, Keenan K, Li W, Lin F, Patrone MV, Raraigh KS, Sun L, Zhou YH, O’Neal WK, Sontag MK, Levy H, Durie PR, Rommens JM, Drumm ML, Wright FA, Strug LJ, Cutting GR, Knowles MR (2015) Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis. Nat Commun 6:8382

Corvol H, Thompson KE, Tabary O, le Rouzic P, Guillot L (2016) Translating the genetics of cystic fibrosis to personalized medicine. Transl Res 168:40–49

Crane AM, Kramer P, Bui JH, Chung WJ, Li XS, Gonzalez-Garay ML, Hawkins F, Liao W, Mora D, Choi S, Wang J, Sun HC, Paschon DE, Guschin DY, Gregory PD, Kotton DN, Holmes MC, Sorscher EJ, Davis BR (2014) Targeted correction and restored function of the CFTR gene in cystic fibrosis induced pluripotent stem cells. Stem Cell Rep 4(4):569–577

Article   Google Scholar  

Cutting GR (2015) Cystic fibrosis genetics: from molecular understanding to clinical application. Nat Rev Genet 16(1):45–56

De Boer DA, Ritsema T (2014) Oligonucleotides for making a change in the sequence of a target RNA molecule present in a living cell. Patent WO 2014011053 A1

Dominguez AA, Lim WA, Qi LS (2016) Beyond editing: repurposing CRISPR-Cas9 for precision genome regulation and interrogation. Nat Rev Mol Cell Biol 17(1):5–15

Dorin JR, Dickinson P, Alton EW, Smith SN, Geddes DM, Stevenson BJ, Kimber WL, Fleming S, Clarke AR, Hooper ML, Anderson L, Beddington RSP, Porteous DJ (1992) Cystic fibrosis in the mouse by targeted insertional mutagenesis. Nature 359(6392):211–215

Dreier B, Beerli RR, Segal DJ, Flippin JD, Barbas CF 3rd (2001) Development of zinc finger domains for recognition of the 5′-ANN-3′ family of DNA sequences and their use in the construction of artificial transcription factors. J Biol Chem 276(31):29466–29478

Drumm ML, Pope HA, Cliff WH, Rommens JM, Marvin SA, Tsui LC, Collins FS, Frizzell RA, Wilson JM (1990) Correction of the cystic fibrosis defect in vitro by retrovirus-mediated gene transfer. Cell 62(6):1227–1233

Farinha CM, Matos P (2016) Repairing the basic defect in cystic fibrosis—one approach is not enough. FEBS J 283(2):246–264

Firth AL, Menon T, Parker GS, Qualls SJ, Lewis BM, Ke E, Dargitz CT, Wright R, Khanna A, Gage FH, Verma IM (2015) Functional gene correction for cystic fibrosis in lung epithelial cells generated from patient iPSCs. Cell Rep 12(9):1385–1390

Geurts AM, Cost GJ, Freyvert Y, Zeitler B, Miller JC, Choi VM, Jenkins SS, Wood A, Cui X, Meng X, Vincent A, Lam S, Michalkiewicz M, Schilling R, Foeckler J, Kalloway S, Weiler H, Ménoret S, Anegon I, Davis GD, Zhang L, Rebar EJ, Gregory PD, Urnov FD, Jacob HJ, Buelow R (2009) Knockout rats via embryo microinjection of zinc-finger nucleases. Science 325(5939):433

Goncz KK, Kunzelmann K, Xu Z, Gruenert DC (1998) Targeted replacement of normal and mutant CFTR sequences in human airway epithelial cells using DNA fragments. Hum Mol Genet 7(12):1913–1919

Goncz KK, Colosimo A, Dallapiccola B, Gagné L, Hong K, Novelli G, Papahadjopoulos D, Sawa T, Schreier H, Wiener-Kronish J, Xu Z, Gruenert DC (2001) Expression of DeltaF508 CFTR in normal mouse lung after site-specific modification of CFTR sequences by SFHR. Gene Ther 8(12):961–965

Gosalia N, Harris A (2015) Chromatin dynamics in the regulation of CFTR expression. Genes (Basel) 6(3):543–558

CAS   Google Scholar  

Gray MA, Plant S, Argent BE (1993) cAMP-regulated whole cell chloride currents in pancreatic duct cells. Am J Physiol 264(3 Pt 1):C591–C602

Gregory RJ, Cheng SH, Rich DP, Marshall J, Paul S, Hehir K, Ostedgaard L, Klinger KW, Welsh MJ, Smith AE (1990) Expression and characterization of the cystic fibrosis transmembrane conductance regulator. Nature 347(6291):382–386

Harrison MJ, Murphy DM, Plant BJ (2013) Ivacaftor in a G551D homozygote with cystic fibrosis. N Engl J Med 369(13):1280–1282

Holkers M, Maggio I, Henriques SF, Janssen JM, Cathomen T, Gonçalves MA (2014) Adenoviral vector DNA for accurate genome editing with engineered nucleases. Nat Methods 11(10):1051–1057

Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E (2012) A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337(6096):816–821

Johnson LG, Olsen JC, Sarkadi B, Moore KL, Swanstrom R, Boucher RC (1992) Efficiency of gene transfer for restoration of normal airway epithelial function in cystic fibrosis. Nat Genet 2(1):21–25

Keiser NW, Engelhardt JF (2011) New animal models of cystic fibrosis: what are they teaching us? Curr Opin Pulm Med 17(6):478–483

PubMed   PubMed Central   Google Scholar  

Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A, Buchwald M, Tsui LC (1989) Identification of the cystic fibrosis gene: genetic analysis. Science 245(4922):1073–1080

Kim YG, Cha J, Chandrasegaran S (1996) Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain. Proc Natl Acad Sci USA 93(3):1156–1160

Kleinstiver BP, Pattanayak V, Prew MS, Tsai SQ, Nguyen NT, Zheng Z, Joung JK (2016) High-fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects. Nature 529(7587):490–495

Koller BH, Hagemann LJ, Doetschman T, Hagaman JR, Huang S, Williams PJ, First NL, Maeda N, Smithies O (1989) Germ-line transmission of a planned alteration made in a hypoxanthine phosphoribosyltransferase gene by homologous recombination in embryonic stem cells. Proc Natl Acad Sci USA 86(22):8927–8931

Koshland DE Jr (1989) The cystic fibrosis gene story. Science 245(4922):1029

Kucherlapati RS, Eves EM, Song KY, Morse BS, Smithies O (1984) Homologous recombination between plasmids in mammalian cells can be enhanced by treatment of input DNA. Proc Natl Acad Sci USA 81(10):3153–3157

Kunzelmann K, Schwiebert EM, Zeitlin PL, Kuo WL, Stanton BA, Gruenert DC (1993) An immortalized cystic fibrosis tracheal epithelial cell line homozygous for the delta F508 CFTR mutation. Am J Respir Cell Mol Biol 8(5):522–529

Kunzelmann K, Legendre JY, Knoell DL, Escobar LC, Xu Z, Gruenert DC (1996) Gene targeting of CFTR DNA in CF epithelial cells. Gene Ther 3(10):859–867

Lee CM, Flynn R, Hollywood JA, Scallan MF, Harrison PT (2012) Correction of the ΔF508 mutation in the cystic fibrosis transmembrane conductance regulator gene by zinc-finger nuclease homology-directed repair. Biores Open Access 1(3):99–108

Li H, Haurigot V, Doyon Y, Li T, Wong SY, Bhagwat AS, Malani N, Anguela XM, Sharma R, Ivanciu L, Murphy SL, Finn JD, Khazi FR, Zhou S, Paschon DE, Rebar EJ, Bushman FD, Gregory PD, Holmes MC, High KA (2011) In vivo genome editing restores haemostasis in a mouse model of haemophilia. Nature 475(7355):217–221

Liu Q, Xia Z, Zhong X, Case CC (2002) Validated zinc finger protein designs for all 16 GNN DNA triplet targets. J Biol Chem 277(6):3850–3856

Liu J, Walker NM, Ootani A, Strubberg AM, Clarke LL (2015) Defective goblet cell exocytosis contributes to murine cystic fibrosis-associated intestinal disease. J Clin Invest 125(3):1056–1068

Long C, McAnally JR, Shelton JM, Mireault AA, Bassel-Duby R, Olson EN (2014) Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA. Science 345(6201):1184–1188

Maeder ML, Thibodeau-Beganny S, Osiak A, Wright DA, Anthony RM, Eichtinger M, Jiang T, Foley JE, Winfrey RJ, Townsend JA, Unger-Wallace E, Sander JD, Müller-Lerch F, Fu F, Pearlberg J, Göbel C, Dassie JP, Pruett-Miller SM, Porteus MH, Sgroi DC, Iafrate AJ, Dobbs D, McCray PB Jr, Cathomen T, Voytas DF, Joung JK (2008) Rapid “open-source” engineering of customized zinc-finger nucleases for highly efficient gene modification. Mol Cell 31(2):294–301

Mahiny AJ, Dewerth A, Mays LE, Alkhaled M, Mothes B, Malaeksefat E, Loretz B, Rottenberger J, Brosch DM, Reautschnig P, Surapolchai P, Zeyer F, Schams A, Carevic M, Bakele M, Griese M, Schwab M, Nürnberg B, Beer-Hammer S, Handgretinger R, Hartl D, Lehr CM, Kormann MS (2015) In vivo genome editing using nuclease-encoding mRNA corrects SP-B deficiency. Nat Biotechnol 33(6):584–586

Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, Norville JE, Church GM (2013) RNA-guided human genome engineering via Cas9. Science 339(6121):823–826

Mandegar MA, Huebsch N, Frolov EB, Shin E, Truong A, Olvera MP, Chan AH, Miyaoka Y, Holmes K, Spencer CI, Judge LM, Gordon DE, Eskildsen TV, Villalta JE, Horlbeck MA, Gilbert LA, Krogan NJ, Sheikh SP, Weissman JS, Qi LS, So PL, Conklin BR (2016) CRISPR interference efficiently induces specific and reversible gene silencing in human iPSCs. Cell Stem Cell 18(4):541–553

Maresca M, Lin VG, Guo N, Yang Y (2013) Obligate ligation-gated recombination (ObLiGaRe): custom-designed nuclease-mediated targeted integration through nonhomologous end joining. Genome Res 23(3):539–546

McNeer NA, Anandalingam K, Fields RJ, Caputo C, Kopic S, Gupta A, Quijano E, Polikoff L, Kong Y, Bahal R, Geibel JP, Glazer PM, Saltzman WM, Egan ME (2015) Nanoparticles that deliver triplex-forming peptide nucleic acid molecules correct F508del CFTR in airway epithelium. Nat Commun 6:6952

Miller JC, Holmes MC, Wang J, Guschin DY, Lee YL, Rupniewski I, Beausejour CM, Waite AJ, Wang NS, Kim KA, Gregory PD, Pabo CO, Rebar EJ (2007) An improved zinc-finger nuclease architecture for highly specific genome editing. Nat Biotechnol 25(7):778–785

Mini guts for Cystic Fibrosis. http://www.ncfs.nl/organoids . Accessed 17 May 2016

Miyaoka Y, Berman JR, Cooper SB, Mayerl SJ, Chan AH, Zhang B, Karlin-Neumann GA, Conklin BR (2016) Systematic quantification of HDR and NHEJ reveals effects of locus, nuclease, and cell type on genome-editing. Sci Rep 6:23549

Munye MM, Tagalakis AD, Barnes JL, Brown RE, McAnulty RJ, Howe SJ, Hart SL (2016) Minicircle DNA provides enhanced and prolonged transgene expression following airway gene transfer. Sci Rep 6:23125

Mussolino C, Morbitzer R, Lütge F, Dannemann N, Lahaye T, Cathomen T (2011) A novel TALE nuclease scaffold enables high genome editing activity in combination with low toxicity. Nucleic Acids Res 39(21):9283–9293

Pearson H (2009) Human genetics: one gene, twenty years. Nature 460(7252):164–169

Article   CAS   Google Scholar  

Poirot L, Philip B, Schiffer-Mannioui C, Le Clerre D, Chion-Sotinel I, Derniame S, Potrel P, Bas C, Lemaire L, Galetto R, Lebuhotel C, Eyquem J, Cheung GW, Duclert A, Gouble A, Arnould S, Peggs K, Pule M, Scharenberg AM, Smith J (2015) Multiplex genome-edited T-cell manufacturing platform for “off-the-shelf” adoptive T-cell immunotherapies. Cancer Res 75(18):3853–3864

Poulsen JH, Fischer H, Illek B, Machen TE (1994) Bicarbonate conductance and pH regulatory capability of cystic fibrosis transmembrane conductance regulator. Proc Natl Acad Sci USA 91(12):5340–5344

ProQR clinical trials. https://clinicaltrials.gov/ct2/show/NCT02532764 and https://clinicaltrials.gov/ct2/show/NCT02564354 . Accessed 17 May 2016

Quinton PM (2001) The neglected ion: HCO 3 − . Nat Med 7(3):292–293

Ramalingam S, London V, Kandavelou K, Cebotaru L, Guggino W, Civin C, Chandrasegaran S (2013) Generation and genetic engineering of human induced pluripotent stem cells using designed zinc finger nucleases. mStem Cells Dev 22(4):595–610

Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen F, Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordoñez C, Elborn JS, VX08-770-102 Study Group (2011) A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 365(18):1663–1672

Ran FA, Cong L, Yan WX, Scott DA, Gootenberg JS, Kriz AJ, Zetsche B, Shalem O, Wu X, Makarova KS, Koonin EV, Sharp PA, Zhang F (2015) In vivo genome editing using Staphylococcus aureus Cas9. Nature 520(7546):186–191

Ratcliff R, Evans MJ, Cuthbert AW, MacVinish LJ, Foster D, Anderson JR, Colledge WH (1993) Production of a severe cystic fibrosis mutation in mice by gene targeting. Nat Genet 4(1):35–41

Rich DP, Anderson MP, Gregory RJ, Cheng SH, Paul S, Jefferson DM, McCann JD, Klinger KW, Smith AE, Welsh MJ (1990) Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells. Nature 347(6291):358–363

Richardson CD, Ray Graham J, DeWitt Mark A, Curie Gemma L, Corn Jacob E (2016) Enhancing homology-directed genome editing by catalytically active and inactive CRISPR-Cas9 using asymmetric donor DNA. Nat Biotechnol 34:339–344

Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL et al (1989) Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 245(4922):1066–1073

Rogers CS, Hao Y, Rokhlina T, Samuel M, Stoltz DA, Li Y, Petroff E, Vermeer DW, Kabel AC, Yan Z, Spate L, Wax D, Murphy CN, Rieke A, Whitworth K, Linville ML, Korte SW, Engelhardt JF, Welsh MJ, Prather RS (2008) Production of CFTR-null and CFTR-DeltaF508 heterozygous pigs by adeno-associated virus-mediated gene targeting and somatic cell nuclear transfer. J Clin Invest 118(4):1571–1577

Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N et al (1989) Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 245(4922):1059–1065

Rosen C, Shezen E, Aronovich A, Klionsky YZ, Yaakov Y, Assayag M, Biton IE, Tal O, Shakhar G, Ben-Hur H, Shneider D, Vaknin Z, Sadan O, Evron S, Freud E, Shoseyov D, Wilschanski M, Berkman N, Fibbe WE, Hagin D, Hillel-Karniel C, Krentsis IM, Bachar-Lustig E, Reisner Y (2016) Preconditioning allows engraftment of mouse and human embryonic lung cells, enabling lung repair in mice. Nat Med 21(8):869–879. doi: 10.1038/nm.3889 (Epub 2015 Jul 13)

Rouet P, Smih F, Jasin M (1994) Expression of a site-specific endonuclease stimulates homologous recombination in mammalian cells. Proc Natl Acad Sci USA 91(13):6064–6068

Sakuma T, Nakade S, Sakane Y, Suzuki KT, Yamamoto T (2016) MMEJ-assisted gene knock-in using TALENs and CRISPR-Cas9 with the PITCh systems. Nat Protoc 11(1):118–133. doi: 10.1038/nprot.2015.140

Sangiuolo F, Scaldaferri ML, Filareto A, Spitalieri P, Guerra L, Favia M, Caroppo R, Mango R, Bruscia E, Gruenert DC, Casavola V, De Felici M, Novelli G (2008) Cftr gene targeting in mouse embryonic stem cells mediated by Small Fragment Homologous Replacement (SFHR). Front Biosci 13:2989–2999

Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, Clevers H (2009) Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459(7244):262–265

Schwank G, Koo BK, Sasselli V, Dekkers JF, Heo I, Demircan T, Sasaki N, Boymans S, Cuppen E, van der Ent CK, Nieuwenhuis EE, Beekman JM, Clevers H (2013) Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell 13(6):653–658

Shah VS, Meyerholz DK, Tang XX, Reznikov L, Abou Alaiwa M, Ernst SE, Karp PH, Wohlford-Lenane CL, Heilmann KP, Leidinger MR, Allen PD, Zabner J, McCray PB Jr, Ostedgaard LS, Stoltz DA, Randak CO, Welsh MJ (2016) Airway acidification initiates host defense abnormalities in cystic fibrosis mice. Science 351(6272):503–507

Slaymaker IM, Gao L, Zetsche B, Scott DA, Yan WX, Zhang F (2016) Rationally engineered Cas9 nucleases with improved specificity. Science 351(6268):84–88

Smithies O, Gregg RG, Boggs SS, Doralewski MA, Kucherlapati RS (1985) Insertion of DNA sequences into the human chromosomal beta-globin locus by homologous recombination. Nature 317:230–234

Snouwaert JN, Brigman KK, Latour AM, Malouf NN, Boucher RC, Smithies O, Koller BH (1992) An animal model for cystic fibrosis made by gene targeting. Science 257(5073):1083–1088

Sun X, Yan Z, Yi Y, Li Z, Lei D, Rogers CS, Chen J, Zhang Y, Welsh MJ, Leno GH, Engelhardt JF (2008) Adeno-associated virus-targeted disruption of the CFTR gene in cloned ferrets. J Clin Invest 118(4):1578–1583. doi: 10.1172/JCI34599

Suzuki S, Sargent RG, Illek B, Fischer H, Esmaeili-Shandiz A, Yezzi MJ, Lee A, Yang Y, Kim S, Renz P, Qi Z, Yu J, Muench MO, Beyer AI, Guimarães AO, Ye L, Chang J, Fine EJ, Cradick TJ, Bao G, Rahdar M, Porteus MH, Shuto T, Kai H, Kan YW, Gruenert DC (2016) TALENs facilitate single-step seamless SDF correction of F508del CFTR in airway epithelial submucosal gland cell-derived CF-iPSCs. Mol Ther Nucleic Acids 5:e273. doi: 10.1038/mtna.2015.43

Szczepek M, Brondani V, Büchel J, Serrano L, Segal DJ, Cathomen T (2007) Structure-based redesign of the dimerization interface reduces the toxicity of zinc-finger nucleases. Nat Biotechnol 25(7):786–793

Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, Spratt SK, Surosky RT, Giedlin MA, Nichol G, Holmes MC, Gregory PD, Ando DG, Kalos M, Collman RG, Binder-Scholl G, Plesa G, Hwang WT, Levine BL, June CH (2014) Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med 370(10):901–910

Thomas KR, Folger KR, Capecchi MR (1986) High frequency targeting of genes to specific sites in the mammalian genome. Cell 44(3):419–428

Thompson S, Clarke AR, Pow AM, Hooper ML, Melton DW (1989) Germ line transmission and expression of a corrected HPRT gene produced by gene targeting in embryonic stem cells. Cell 56(2):313–321

Tuggle KL, Birket SE, Cui X, Hong J, Warren J, Reid L, Chambers A, Ji D, Gamber K, Chu KK, Tearney G, Tang LP, Fortenberry JA, Du M, Cadillac JM, Bedwell DM, Rowe SM, Sorscher EJ, Fanucchi MV (2014) Characterization of defects in ion transport and tissue development in cystic fibrosis transmembrane conductance regulator (CFTR)-knockout rats. PLoS One 9(3):e91253

Urnov FD, Miller JC, Lee YL, Beausejour CM, Rock JM, Augustus S, Jamieson AC, Porteus MH, Gregory PD, Holmes MC (2005) Highly efficient endogenous human gene correction using designed zinc-finger nucleases. Nature 435(7042):646–651

van Doorninck JH, French PJ, Verbeek E, Peters RH, Morreau H, Bijman J, Scholte BJ (1995) A mouse model for the cystic fibrosis delta F508 mutation. EMBO J 14(18):4403–4411

Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T, Turnbull A, Singh A, Joubran J, Hazlewood A, Zhou J, McCartney J, Arumugam V, Decker C, Yang J, Young C, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu P (2009) Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci USA 106(44):18825–18830

Verkman AS, Edelman A, Amaral M, Mall MA, Beekman JM, Meiners T, Galietta LJ, Bear CE (2015) Finding new drugs to enhance anion secretion in cystic fibrosis: toward suitable systems for better drug screening. Report on the pre-conference meeting to the 12th ECFS Basic Science Conference, Albufeira, 25–28 March 2015. J Cyst Fibros 14(6):700–705

Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, Colombo C, Davies JC, De Boeck K, Flume PA, Konstan MW, McColley SA, McCoy K, McKone EF, Munck A, Ratjen F, Rowe SM, Waltz D, Boyle MP, TRAFFIC Study Group, TRANSPORT Study Group (2015) Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 373(3):220–231

Wang H, Yang H, Shivalila CS, Dawlaty MM, Cheng AW, Zhang F, Jaenisch R (2013) One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell 153(4):910–918

Wilke M, Buijs-Offerman RM, Aarbiou J, Colledge WH, Sheppard DN, Touqui L, Bot A, Jorna H, de Jonge HR, Scholte BJ (2011) Mouse models of cystic fibrosis: phenotypic analysis and research applications. J Cyst Fibros 10(Suppl 2):S152–S171

Yan Z, Stewart ZA, Sinn PL, Olsen JC, Hu J, McCray PB Jr, Engelhardt JF (2015) Ferret and pig models of cystic fibrosis: prospects and promise for gene therapy. Hum Gene Ther Clin Dev 26(1):38–49

Yang D, Xu J, Zhu T, Fan J, Lai L, Zhang J, Chen YE (2014) Effective gene targeting in rabbits using RNA-guided Cas9 nucleases. J Mol Cell Biol 6(1):97–99

Yang R, Kerschner JL, Gosalia N, Neems D, Gorsic LK, Safi A, Crawford GE, Kosak ST, Leir SH, Harris A (2016) Differential contribution of cis-regulatory elements to higher order chromatin structure and expression of the CFTR locus. Nucleic Acids Res 44(7):3082–3094. doi: 10.1093/nar/gkv1358

Zamecnik PC, Raychowdhury MK, Tabatadze DR, Cantiello HF (2004) Reversal of cystic fibrosis phenotype in a cultured Delta508 cystic fibrosis transmembrane conductance regulator cell line by oligonucleotide insertion. Proc Natl Acad Sci USA 101(21):8150–8155

Zeiher BG, Eichwald E, Zabner J, Smith JJ, Puga AP, McCray PB Jr, Capecchi MR, Welsh MJ, Thomas KR (1995). A mouse model for the delta F508 allele of cystic fibrosis. J Clin Invest. 1995 Oct;96(4):2051-64

Zetsche B, Gootenberg JS, Abudayyeh OO, Slaymaker IM, Makarova KS, Essletzbichler P, Volz SE, Joung J, van der Oost J, Regev A, Koonin EV, Zhang F (2015) Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR-Cas system. Cell 163(3):759–771

Zijlstra M, Li E, Sajjadi F, Subramani S, Jaenisch R (1989) Germ-line transmission of a disrupted beta 2-microglobulin gene produced by homologous recombination in embryonic stem cells. Nature 342(6248):435–438

Download references

Author information

Authors and affiliations.

University College Cork, Cork, Ireland

Patrick T. Harrison, David J. Sanz & Jennifer A. Hollywood

The University of Auckland, Auckland, New Zealand

Jennifer A. Hollywood

You can also search for this author in PubMed   Google Scholar

Corresponding author

Correspondence to Patrick T. Harrison .

Rights and permissions

Reprints and permissions

About this article

Harrison, P.T., Sanz, D.J. & Hollywood, J.A. Impact of gene editing on the study of cystic fibrosis. Hum Genet 135 , 983–992 (2016). https://doi.org/10.1007/s00439-016-1693-3

Download citation

Received : 10 April 2016

Accepted : 31 May 2016

Published : 21 June 2016

Issue Date : September 2016

DOI : https://doi.org/10.1007/s00439-016-1693-3

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
• Duchenne Muscular Dystrophy
• Cystic Fibrosis Patient
• Gene Editing
• Airway Surface Liquid
• Find a journal
• Publish with us
• Track your research

• Publications
• Conferences & Events
• Professional Learning
• Science Standards
• Awards & Competitions
• Daily Do Lesson Plans
• Free Resources
• American Rescue Plan
• For Preservice Teachers
• NCCSTS Case Collection
• Partner Jobs in Education
• Interactive eBooks+
• Digital Catalog
• Regional Product Representatives
• e-Newsletters
• Bestselling Books
• Latest Books
• Popular Book Series
• Prospective Authors
• Web Seminars
• Exhibits & Sponsorship
• Conference Reviewers
• National Conference • Denver 24
• Leaders Institute 2024
• National Conference • New Orleans 24
• Submit a Proposal
• Latest Resources
• Professional Learning Units & Courses
• For Districts
• Online Course Providers
• Schools & Districts
• College Professors & Students
• The Standards
• Teachers and Admin
• eCYBERMISSION
• Toshiba/NSTA ExploraVision
• Junior Science & Humanities Symposium
• Teaching Awards
• Climate Change
• Earth & Space Science
• New Science Teachers
• Early Childhood
• Middle School
• High School
• Postsecondary
• Informal Education
• Journal Articles
• Lesson Plans
• e-newsletters
• Science & Children
• Science Scope
• The Science Teacher
• Journal of College Sci. Teaching
• Connected Science Learning
• NSTA Reports
• Next-Gen Navigator
• Science Update
• Teacher Tip Tuesday
• Trans. Sci. Learning

MyNSTA Community

• My Collections

Maggie’s Illness

Protein Structure and Function in Cystic Fibrosis

By Michaela Gazdik Stofer

Share Start a Discussion

This directed case study examines the molecular basis of cystic fibrosis to emphasize the relationship between the genetic code stored in a DNA sequence and the encoded protein’s structure and function. Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein that functions to help maintain salt and water balance along the surface of the lung and gastrointestinal tract. This case introduces students to “Maggie,” who has just been diagnosed with cystic fibrosis. The students must identify the mutation causing Maggie’s disease by transcribing and translating a portion of the wildtype and mutated CFTR gene. Students then compare the three-dimensional structures of the resulting proteins to better understand the effect a single amino acid mutation can have on the overall shape of a protein. Students also review the concepts of tonicity and osmosis to examine how the defective CFTR protein leads to an increase in the viscosity of mucus in cystic fibrosis patients. This case was developed for use in an introductory college-level biology course but could also be adapted for use in an upper-level cell or molecular biology course.

Download Case

Date Posted

• Generate a protein sequence through transcription and translation of a given DNA gene sequence.
• Explain the chemistry of amino acid side chains and their importance in protein folding.
• Describe how a mutation in a protein sequence leads to changes in the overall tertiary structure of the protein.
• Examine various levels of protein structure using Cn3D to view three-dimensional protein structures from NCBI’s Entrez Structure database.
• Relate the loss of function of the CFTR protein to the physiological causes of cystic fibrosis.

Protein structure; transcription; translation; DNA mutation; cystic fibrosis; genetic disease; protein function; protein folding; protein; CFTR; Cn3D

Subject Headings

EDUCATIONAL LEVEL

Undergraduate lower division, Undergraduate upper division

TOPICAL AREAS

TYPE/METHODS

Teaching Notes & Answer Key

Teaching notes.

Case teaching notes are protected and access to them is limited to paid subscribed instructors. To become a paid subscriber, purchase a subscription here .

Teaching notes are intended to help teachers select and adopt a case. They typically include a summary of the case, teaching objectives, information about the intended audience, details about how the case may be taught, and a list of references and resources.

Download Notes

Answer Keys are protected and access to them is limited to paid subscribed instructors. To become a paid subscriber, purchase a subscription here .

Download Answer Key

Materials & Media

Supplemental materials.

The following two files should be viewed with the Cn3D software to view a single domain of the CFTR and ∆F508 CFTR proteins.

You may also like

Web Seminar

Join us on Thursday, June 13, 2024, from 7:00 PM to 8:00 PM ET, to learn about the science and technology of firefighting. Wildfires have become an e...

Join us on Thursday, October 10, 2024, from 7:00 to 8:00 PM ET, for a Science Update web seminar presented by NOAA about climate science and marine sa...

• Reference Manager
• Simple TEXT file

People also looked at

Case report article, difficulties in the management of an askin tumor in a pediatric patient with cystic fibrosis: case report and literature review.

• 1 Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
• 2 Bihor County Clinical Emergency Hospital, Oradea, Romania

Treating Ewing's Sarcoma of the thorax (Askin's tumor) with antineoplastic therapy in a malnourished cystic fibrosis patient colonized with Pseudomonas aeruginosa and Staphylococcus aureus may carry a significant potential for complications. We present the case of a known cystic fibrosis patient, diagnosed with Askin's tumor 5 years ago. Despite facing severe neutropenia, exacerbations of cystic fibrosis with Pseudomonas aeruginosa infections, and challenges in maintaining adequate caloric intake during the oncological treatment, the patient's outcome has been favorable. Chemotherapy doses had to be adjusted, and continuous antibiotic treatment was introduced throughout the course of therapy to reduce the frequency and intensity of exacerbations. Approximately 5 years after the cancer diagnosis, with no signs of relapse, the patient was started on CFTR (Cystic fibrosis transmembrane conductance regulator) modulator treatment. This intervention has successfully corrected the weight deficit. The coincidence of Ewing's sarcoma of the chest wall and cystic fibrosis in a single patient is 2.857 × 10 −5 % and to the best of our knowledge, this scenario has not been documented before.

Introduction

The survival rates for patients with cystic fibrosis (CF) have consistently increased since the initial description of the disease in 1938, when the majority of patients did not live beyond their first year. By 2008, the median survival of CF patients in the UK reached 38.8 years. The enhanced survival in CF can be attributed to various interventions, including enhanced diagnostics and screening, improved nutritional care and access to pancreatic enzyme replacement therapies, the development of specific and specialized physiotherapy approaches, the concentration and specialization of CF treatment at regional centers, the availability and effective utilization of antibacterial therapies targeting Pseudomonas infections, and the use of CFTR (Cystic fibrosis transmembrane conductance regulator) modulators in disease management ( 1 ). Currently the predicted survival rate is at 65.6 years ( 2 ). As the survival age increases, associated conditions of various types, including cancer, arise, posing challenges in their management due to both the underlying pathology and the limited clinical experience and literature data regarding the association of these conditions.

Long-term cohort studies conducted across multiple centers have indicated a slight elevation in the risk of malignancy among individuals with CF. It is important to note that the overall incidence of cancer in CF patients remains relatively low, however, they do face an increased susceptibility to cancers affecting the digestive tract, especially after undergoing transplantation. Additionally, CF patients have a higher risk of developing lymphoid leukemia and testicular cancer, while their risk of melanoma appears to be reduced ( 3 ).

Ewing sarcoma, peripheral primitive neuroectodermal tumors, and Ewing's sarcoma of the thorax (also called Askin's tumor) are classified as part of the Ewing family of tumors, which exhibit varying degrees of neuroectodermal differentiation. Askin tumors specifically manifest as respiratory issues, including pain, dyspnea, and noticeable weight loss accompanied by the presence of a mass. These tumors are highly malignant, typically associated with a poor prognosis, and have a shorter overall survival rate ( 4 ).

We highlight the diagnostic and treatment challenges, and favorable outcome despite significant obstacles, of a case that presented to us: a cystic fibrosis patient, with chronic Pseudomonas aeruginosa and Staphylococcus aureus pulmonary infections and malnutrition who develops an Askin tumor.

Case report

We describe the case of B.R., a 9-year-old girl, who is in our care since infancy.

The girl is the first child of the family, born to healthy parents, from a normal pregnancy, delivered spontaneously at full term, weighing 2,700 grams, with good adaptation to extrauterine life, and an Apgar score of 9/10. Newborn screening for cystic fibrosis was not performed.

At the age of 3 months, after a persistent bronchopneumonia, chronic diarrhea, and failure to thrive, a suspicion of cystic fibrosis arose. This was later confirmed by two positive sweat tests and through complete sequencing of the CFTR gene, revealing the mutations c.54_273del (exons 2 + 3) and c.1521_1523del (exon 11), leading to the diagnosis of compound heterozygous cystic fibrosis, with the ΔF508 variant in its complete clinical form. While the ΔF508 genotype is associated with pancreatic insufficiency, neither fecal elastase nor the 72-hour stool fat were measured. However, fat globules were visualized by microscopy, prompting the initiation of pancreatic enzyme replacement therapy, which improved the steatorrhea. No evidence of CF hepatobiliary disease was found during clinical assessment, in blood work, or on liver ultrasound. The child was started on a comprehensive treatment regimen including medications to facilitate mucus clearance (daily Dornase alpha and hypertonic saline nebulization), pancreatic enzyme replacement therapy (Kreon – 10,000 UI with each meal) and vitamin (A, D, E, K) supplements, probiotics. Additionally, airway clearance techniques were incorporated into the daily management plan. Also at this age, the child was diagnosed with Pseudomonas aeruginosa infection (confirmed by pharyngeal aspirate culture) and Staphylococcus aureus infection (confirmed by catheter tip culture).

From the age of 3 months until 4 years, the child experienced multiple hospitalizations due to metabolic alkalosis, hyponatremia, and hypokalemia, leading to the diagnosis of Pseudo-Bartter syndrome. Additionally, during this period, the child had repeated respiratory infections with Pseudomonas aeruginosa and Staphylococcus aureus, and was diagnosed with protein-calorie malnutrition.

In October 2018, at age 4, during an episode of acute respiratory infection, bilateral basal pulmonary consolidation processes were observed, more significant on the right side. The condition improved with antibiotic treatment for the left-sided lesion, but the right-sided lesion persisted. A follow-up chest CT scan performed after 14 days of treatment, revealing a parenchymal lesion measuring 61/56/39 mm with aggressive features (osteolysis and pericardial reaction) located at the base of the left hemithorax ( Figure 1 ).

Figure 1 . CT scan showing a voluminous parenchymal mass (M) of the anterior left thoracic wall, relatively well delimited, with bone destruction, which invades the lung parenchyma up to the level of the heart, with mass effect on left ventricle.

A biopsy of the lesion (rib and soft tissue) was performed, showing histopathological features consistent with a malignant proliferation of small round-oval cells with dispersed chromatin. Immunohistochemistry (IHC) tests were positive for CD99 and negative for CD56, S100, chromogranin A, muscle actin, CD45, and CD34. Ki-67 proliferation index was 60%. FISH testing revealed rearrangements of the EWSR1 gene (22q12) in 65% of tumor cells, leading to the conclusion of Ewing/PNET sarcoma, with architectural and localization characteristics of an Askin tumor ( Figure 2 ).

Figure 2 . Microscopic examination of the biopsied lesion displaying small round to oval cells with dispersed chromatin [( A ) 10× and ( B ) 40× magnification].

Prior to the treatment course, the case was reevaluated through imaging. An 85 × 60 × 35 mm formation in the lower half of the left hemithorax, with a tumor volume of 140.1 cm 3 , and a hypodense formation of approximately 15 mm in segment VII of the liver were identified ( Figure 3 ).

Figure 3 . ( A ) - CT scan revealing voluminous parenchymal mass (M) of the anterior left thoracic wall, relatively well delimited, with bone destruction, which invades the lung parenchyma up to the level of the heart, with mass effect on left ventricle; and ( B ) - hypodense formation in the segment VII of the liver.

Chemotherapy treatment was initiated consisting of 6 cycles of VIDE (Vincristine 1.5 mg/m 2 /d, day 1; Ifosfamide 3.0 g/m 2 /d, day 1, 2, 3; Doxorubicin 20 mg/m 2 /d, day 1, 2, 3; and Etoposide 150 mg/m 2 /d, day 1, 2, 3), at 21 days intervals, followed by surgical removal of the residual tumor and 8 cycles of VAI (Vincristine 1.5 mg/m 2 /d, day 1; Actinomycin D 0.75 mg/m 2 /d, day 1, 2; Ifosfamide 3.0 g/m 2 /d, day 1, 2) at 21 days intervals, according to EURO-EWING 99 protocol. The child showed favorable evolution of the oncological disease, with the tumor shrinking by 88% to 16.5 cm 3 after 2 cycles of VIDE, and further reducing to 9 cm 3 after 4 cycles. The hepatic lesion also decreased in size from 15 mm to 8 mm in diameter. Hematological recovery was obtained on average after 5 days of substitutive and supportive treatment, but with each aplasia episode, pulmonary decompensation occurred due to bacterial overgrowth, leading to life-threatening conditions (marked respiratory distress, tachypnea, oxygen dependency) and causing delays in the chemotherapy protocol (3th VIDE cycle delayed by 7 days, 4th VIDE cycle delayed by 11 days, 5th VIDE cycle delayed by 16 days).

Initially, antibiotic treatment was administered only during infectious exacerbation periods with systemic antipseudomonal antibiotics in usual, therapeutic doses (carbapenems – Meropenem 20 mg/kg/dose i.v. every 8 h; aminoglycosides – Amikacin 6 mg/kg/dose i.v. every 8 h; fluoroquinolones - Ciprofloxacin 10 mg/kg/dose i.v. every 8 h; or oxazolidinones – Linezolid 10 mg/kg/dose i.v. every 8 h). During one of these pulmonary decompensations a right-sided basal consolidation adjacent to an expanding bronchial path was identified. Culture of sputum, lavage, and tracheal aspirate revealed once again Pseudomonas aeruginosa. After this, concomitant with the 5th VIDE cycle, continuous intravenous (antipseudomonal agents in usual doses) and nebulized antibiotic therapy (Tobramycin 300 mg and/or Colistin 1,000,000 UI aerosols at 12 h intervals) antibiotic therapy was introduced in an attempt to reduce Pseudomonas aeruginosa and Staphylococcus aureus colonies Additionally, the dosage of Etoposide was reduced by 20%. These measures led to a decrease in the severity of exacerbations.

After 6 cycles of VIDE chemotherapy, surgical intervention was performed, carrying out a left thoracotomy in the 6th intercostal space. The remaining tumor formation is resected, along with the resection of the sixth and seventh rib, and an atypical left lower lobe lobectomy. The hepatic metastasis was not detected. The histopathological result reveals the presence of tumor cells with post-therapeutic reactive changes, which constitute less than 5% of the tumor volume (Salzer-Kuntschik: grade 2 histopathological response). Pseudomonas aeruginosa is isolated once again from the culture obtained from the tip of the orotracheal intubation tube. However, the patient's condition continues to improve under antibiotic treatment (Ceftazidime 50 mg/kg/dose i.v. every 8 h and Colistin nebulization), and she is retransferred to the oncology department for further oncological treatment. Complete response was declared at this point (June 2019), along with the complete disappearance of all visible disease. The treatment is continued with 8 cycles of consolidation chemotherapy with VAI, which, along with continuous treatment with Colistin aerosols and supportive care, is well tolerated.

Throughout the therapy, we have also faced feeding issues as the child, who already had weight deficit and pseudo-Bartter syndrome, refuses oral feeding, necessitating nasogastric tube feeding and parenteral nutrition.

Regular follow-up examinations have been conducted, and up to the present - 5 years from the initial diagnosis, no disease recurrence has been detected.

In March 2023, CFTR modulator therapy with Elexacaftor/Tezacaftor/Ivacaftor (ETI) was initiated and has been well-tolerated, resulting in a remarkable improvement in the weight curve ( Figure 4 ). However, despite achieving adequate weight gain, there is persistent pulmonary colonization with Pseudomonas aeruginosa, necessitating ongoing treatment with inhaled and systemic antibiotics, as well as mucolytic medication.

Figure 4 . A graph depicting the child's weight curve over the past 6 years reveals a notable weight loss during the oncological treatment period, and significant increase upon the initiation of EIT (elexacaftor/tezacaftor/ivacaftor) treatment.

Discussions

Chest wall tumors in children and adolescents are uncommon, occurring with an incidence of 1 in 1,000,000 ( 5 ). Basharkhah et al. ( 6 ) report a five-year survival rate of 86% in a group of patients with Askin tumors from a single center, with an overall survival rate of 71%; the authors report significantly improved prognoses compared to Contosso et al. ( 7 )., a study conducted a decade earlier, when the prognosis is generally unfavorable, with survival rates at 2 and 6 years being 38% and 14% respectively. The Basharkhah et al. reports similar values to those cited in acute lymphoblastic leukemia in children ( 8 ). While the majority of Askin tumors are situated in the ribs, instances of localization in the paravertebral, sternal, and scapular regions have been documented ( 9 ). Some tumors have also been found in the lung ( 10 ).These tumors often become apparent relatively late, typically following considerable local enlargement of the tumor or when presenting as a painful mass; as a result of their delayed appearance, some patients present with metastases or malignant pleural effusion. Imaging studies commonly reveal bone destruction in the affected rib, and a substantial extension of the tumor mass into neighboring regions ( 6 ). Askin tumors exhibit a high degree of aggressiveness. They primarily manifest in children and adolescents, although they can develop at any age, with a notable predominance among females (75% of cases) ( 11 , 12 ).

Cystic fibrosis stands as the most prevalent autosomal recessive disorder within the Caucasian population, with an incidence of roughly 1 in 3,500 births ( 13 ). The majority of patients display symptoms either at birth or shortly thereafter, with respiratory infections and inadequate weight gain being the most common initial presentations ( 14 ). Numerous countries have implemented newborn screening for CF due to the fact that early diagnosis enhances treatment outcomes ( 15 ). For our patient, screening wasn't conducted at birth; during that period in Romania, newborn screening through national program only included phenylketonuria and congenital hypothyroidism ( 16 ).

As individuals with CF experience increased longevity new risks such as cancer emerge. Although the overall occurrence of cancer in individuals with CF is relatively low, they do exhibit a heightened vulnerability to cancers affecting the digestive tract, particularly following transplantation ( 17 ). Adult patients with cystic fibrosis are markedly vulnerable to the premature and aggressive development of colorectal tumors; by the age of forty, 50% of individuals with CF will develop adenomas, of which 25% will progress to advanced aggressive adenomas, and a portion of these may have already transitioned to adenocarcinomas ( 18 ). The incidence of colorectal cancer in adults with CF is 5–10 times higher than that in the general population. Additionally, after undergoing an organ transplantation, CF patients face a significantly elevated risk due to immunosuppressive therapy, which is 25–30 times greater ( 19 ).

While literature extensively covers digestive system cancers in patients with cystic fibrosis, reports describing other types of cancers are scarce. And very few of these are in pediatric cases.

A case series describes 11 patients with cystic fibrosis that were diagnosed with a malignant disease ( 20 ). Among these are four cases of gynecological malignancies (including cervical intraepithelial neoplasia and cervical cancer), two instances of hematological malignancies (acute lymphocytic leukemia), one case of gastrointestinal malignancy (peritoneal mesothelioma), and four occurrences of malignancies originating from various sources (such as malignant melanoma, neuroblastoma, adrenocortical carcinoma, and thyroid cancer). Three patients were pediatric patients: a 9-month-old girl with neuroblastoma, 14-year-old girl with acute lymphocytic leukemia and another 17-year-old girl with acute lymphocytic leukemia. The first patient died three years after the initial diagnosis, after a systemic relapse and a pulmonary exacerbation which forced the discontinuation of chemotherapy; the two leukemia patients died within months from the initial diagnosis of malignancy due to infections complications.

Okuda et al. ( 21 ) and Ruffles et al. ( 22 ) describe two cases of osteogenic sarcomas in patients with a similar background to our pediatric cystic fibrosis patient. In the first case the patient was colonized intermittently with typical bacteria, such as Staphylococcus aureus, Haemophilus influenza, Serratia marcescens, and Escherichia coli, and in the second case the patient had a chronic Pseudomonas aeruginosa infection. In the case presented by Okuda et al., during neutropenic phases, prophylactic intravenous cefuroxime was given. Two febrile neutropenic episodes were managed with antibiotics following standard protocols. The authors concluded that the antineoplastic treatment was well-managed without worsening of CF lung disease. Similarly, in the second case, severe complications of immunosuppression were prevented, despite the chronic infection with Pseudomonas aeruginosa.

To the best of our knowledge, no other association between cystic fibrosis and tumors from the Ewing sarcoma family in a pediatric patient has been described in the existing literature. Taking into consideration the incidence of Ewing's sarcoma of the chest wall and the incidence of cystic fibrosis, it is possible to calculate, by multiplying these individual events, the chance of the occurrence of this disease association in a patient. This is 2.857 × 10 −5 %.

Our case provides valuable insights as the patient encountered and overcame distinct challenges associated with the persistent presence of Pseudomonas aeruginosa and Staphylococcus aureus in her sputum and feeding issues during her treatment. Fatal outcomes have been documented for CF patients due to hemorrhagic bronchopneumonia resulting from Pseudomonas aeruginosa infection during immunosuppression ( 23 ). The medical care of such a patient necessitated the attention of a multidisciplinary team whose collaboration enabled the overcoming of challenges that arose during the course of oncological treatment.

In our case, during the neutropenic phases after chemotherapy, exacerbations of cystic fibrosis with Pseudomonas infections led to life-threatening situations. Antipseudomonal agents were used according to standard protocols; however, these exacerbations delayed the administration of VIDE cycles according to the protocol. In an attempt to reduce treatment toxicity, the dose of Etoposide was decreased by 20%, which was allowed by the oncologic protocol. After multiple exacerbations, the need for preventing them became evident. A continuous treatment with anti-pseudomonal antibiotics was initiated, both intravenously and through aerosol administration. These measures, combined with the standard treatment for cystic fibrosis, respiratory physiotherapy, and mucolytics, led to significantly reduced intensity of exacerbations. This improvement allowed adherence to the required timelines dictated by the oncologic protocol.

While treatment for Askin's tumor lacks standardization ( 24 ), the majority of authors recommend a combination of neoadjuvant chemotherapy, radiotherapy, and surgical resection as the most suitable and adaptive treatment measures ( 12 ). The absence of clinical guidelines that establish standardized management contributes to an unfavorable prognosis and a limited survival rate ( 24 ) In our patient's case, initial tissue biopsy was followed by neoadjuvant chemotherapy before surgical resection. This approach is supported by Sirivella et al. ( 25 ), whose report suggests that the implementation of neoadjuvant chemotherapy led to an improvement in the 10-year survival free of disease indicator, observed in up to 84% of patients without metastases. Surgical resection is essential, and neoadjuvant chemotherapy leads to negative margins in 71% of cases, compared to 37% when surgical resection is the initial approach ( 26 ). Although most authors recommend it ( 24 , 27 ), radiotherapy was not employed in our patient's case. Considering the complete resection with clear margins of the tumor, as well as the known pulmonary toxicity associated with both radiotherapy and certain chemotherapeutic agents like vincristine ( 28 , 29 ), and taking into account the pre-existing lung disease, radiotherapy was not deemed suitable for our patient.

The weight deficit reached during the oncological treatment persisted for an extended period, with a noticeable improvement becoming evident only recently, after the initiation of CFTR modulator treatment. This period partially overlaps with the COVID pandemic period, which led to reduced patient-doctor interactions due to the limited contact opportunities. This issue becomes evident at all levels, particularly affecting patients with chronic conditions ( 30 ). The initiating of ETI therapy, alongside more effective monitoring of the patient's disease progression, has led to an improvement in the overall condition, with fewer pulmonary exacerbations and a favorable trend in the weight curve, with no signs of modulator-induced liver injury. Unfortunately, the lack of an initial fecal elastase level prevented us from tracking any enhancements in pancreatic function after 12 months of ETI therapy.

Adverse effects on breast tissue have been noted with the use of CFTR modulators, primarily among adult patients. Breast-related issues such as breast masses, breast inflammation, gynecomastia, and nipple disorders have been reported in both genders. A case report illustrated an unusual dose-dependent side effect of breast development in a 7-year-old girl with CF who was undergoing treatment with ivacaftor ( 31 ).

Up until the time of publication of this article there is a reassuring absence of any signs of cancer relapse. However, despite achieving adequate weight gain, there is persistent pulmonary colonization with Pseudomonas aeruginosa, necessitating ongoing treatment with inhaled and systemic antibiotics, as well as mucolytic medication and nutritional support.

The incidence of cancer is anticipated to rise in the coming years, in tandem with the aging of the cystic fibrosis population and the growing number of adults with cystic fibrosis who have undergone lung transplantation. The impact of CFTR modulators on cancer risk remains uncertain and will necessitate further evaluation ( 32 ).

The strengths of this study lie in its capacity to illuminate a rare and complex clinical scenario, serving as a foundational platform for more rigorous research. This case report underscores the significance of tailored, patient-centric oncologic care, particularly for this susceptible patient demographic. However, the study is constrained by the inherent limitations of any single-patient case reports. The insights and experiences of the individual patient may not be broadly generalizable to a larger population, and establishing causality between the observed outcomes and the treatment or other factors is challenging. Furthermore, with respect to the CFTR modulator treatment, while the initial results are encouraging, the observation period for its effects has been relatively short, a more extended period of observation is essential to draw conclusive insights.

Data availability statement

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article.

Ethics statement

The studies involving humans were approved by Ethics Committee of the Oradea County Emergency Clinical Hospital (27090/09.08.2023). The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants' legal guardians/next of kin. Written informed consent was obtained from the participant legal guardians for the publication of this case report.

Author contributions

CM: Writing – review & editing. AC: Writing – review & editing. CS: Writing – review & editing. AI: Writing – original draft, Writing – review & editing. LN: Writing – review & editing. AS: Writing – review & editing. LR: Writing – review & editing. AB: Writing – review & editing. CJ: Writing – review & editing.

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

The article publishing fees were provided by the University of Oradea.

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.

1. Parkins MD, Parkins VM, Rendall JC, Elborn S. Changing epidemiology and clinical issues arising in an ageing cystic fibrosis population. Ther Adv Respir Dis . (2011) 5(2):105–19. doi: 10.1177/1753465810386051

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Cystic Fibrosis Foundation Patient Registry. 2021 Annual Data Report, Bethesda, Maryland, 2022. Available at: https://www.cff.org/sites/default/files/2021-11/Patient-Registry-Annual-Data-Report.pdf (Accessed July, 2023).

3. Maisonneuve P, Marshall BC, Knapp EA, Lowenfels AB. Cancer risk in cystic fibrosis: a 20-year nationwide study from the United States. J Natl Cancer Inst . (2013) 105:122–9. doi: 10.1093/jnci/djs481

4. Singh A, Abhinay A, Kumar A, Prasad R, Ghosh A, Mishra OP. Askin tumor: a rare neoplasm of thoracopulmonary region. Lung India . (2016) 33(2):196–8. doi: 10.4103/0970-2113.177458

5. van den Berg H, van Rijn RR, Merks JH. Management of tumors of the chest wall in childhood: a review. J Pediatr Hematol Oncol . (2008) 30(3):214–21. doi: 10.1097/MPH.0b013e318162bd54

6. Basharkhah A, Pansy J, Urban C, Höllwarth ME. Outcomes after interdisciplinary management of 7 patients with askin tumor. Pediatr Surg Int . (2013) 29(5):431–6. doi: 10.1007/s00383-013-3272-1

7. Contesso G, Llombart-Bosch A, Terrier P, Peydro-Olaya A, Henry-Amar M, Oberlin O, et al. Does malignant small round cell tumor of the thoracopulmonary region (askin tumor) constitute a clinicopathologic entity? An analysis of 30 cases with immunohistochemical and electron-microscopic support treated at the institute gustave roussy. Cancer . (1992) 69(4):1012–20. doi: 10.1002/1097-0142(19920215)69:4%3C1012::aid-cncr2820690431%3E3.0.co;2-v

8. Sava CN, Ritli L, Balmos AB, Iuhas AR, Marian P, Motorca MA, et al. Unusual extramedullary relapses in a case of common B-cell acute lymphoblastic leukemia. Case report and review of literature. Rom J Morphol Embryol . (2019) 60(1):249–54. 31263852.31263852

PubMed Abstract | Google Scholar

9. Jürgens H, Bier V, Harms D, Beck J, Brandeis W, Etspüler G, et al. Malignant peripheral neuroectodermal tumors. A retrospective analysis of 42 patients. Cancer . (1988) 61(2):349–57. doi: 10.1002/1097-0142(19880115)61:2%3C349::aid-cncr2820610226%3E3.0.co;2-0

CrossRef Full Text | Google Scholar

10. Verfaillie G, Hoorens A, Lamote J. Primary primitive neuro-ectodermal tumour of the lung. Acta Chir Belg . (2009) 109(3):381–4. doi: 10.1080/00015458.2009.11680443

11. Hari S, Jain TP, Thulkar S, Bakhshi S. Imaging features of peripheral primitive neuroectodermal tumours. Br J Radiol . (2008) 81(972):975–83. doi: 10.1259/bjr/30073320

12. Bhaisare DK, Tellis DJ, Toshniwal DP. Askin’s tumor: a case report and literature review. Basic Clin Cancer Res . (2023) 14(1):37–43.

Google Scholar

13. Mehta G, Macek M, Mehta A. European registry working group. Cystic fibrosis across Europe: EuroCareCF analysis of demographic data from 35 countries. J Cyst Fibros . (2010) 9:S5–21. doi: 10.1016/j.jcf.2010.08.002

14. De Boeck K, Vermeulen F, Dupont L. The diagnosis of cystic fibrosis. Presse Med . (2017) 46:e97–108. doi: 10.1016/j.lpm.2017.04.010

15. De Boeck K. Cystic fibrosis in the year 2020: a disease with a new face. Acta Paediatr . (2020) 109(5):893–9. doi: 10.1111/apa.15155

16. Iuhas A, Jurca C, Kozma K, Riza AL, Streață I, Petcheși C, et al. PAH pathogenic variants and clinical correlations in a group of hyperphenylalaninemia patients from north-western Romania. Diagnostics . (2023) 13(8):1483. doi: 10.3390/diagnostics13081483

17. Neglia J, FitzSimmmons S, Maisnneuve P, Schöni MH, Schöni-Affolter F, Corey M, et al. The risk of cancer among patients with cystic fibrosis. N Engl J Med . (1995) 332:494–9. doi: 10.1056/NEJM199502233320803

18. Scott P, Anderson K, Singhania M, Cormier R. Cystic fibrosis, CFTR, and colorectal cancer. Int J Mol Sci . (2020) 21(8):2891. doi: 10.3390/ijms21082891

19. Hadjiliadis D, Khoruts A, Zauber AG, Hempstead SE, Maisonneuve P, Lowenfels AB, et al. Cystic fibrosis colorectal cancer screening consensus recommendations. Gastroenterology . (2018) 154(3):736–45.e14. doi: 10.1053/j.gastro.2017.12.012

20. Appelt D, Fuchs T, Steinkamp G, Ellemunter H. Malignancies in patients with cystic fibrosis: a case series. J Med Case Reports . (2022) 16:27. doi: 10.1186/s13256-021-03234-1

21. Okuda KV, Hammermann J, Lange BS, Fischer JC, Thielemann F, Knöfler R, et al. Treatment of high-grade osteoblastic osteosarcoma of the humerus in a 5-year-old boy with cystic fibrosis: a case report. Mol Clin Oncol . (2017) 7(1):148–50. doi: 10.3892/mco.2017.1274

22. Ruffles TJC, Black R, Nicholls W, Laing B, Isles A. Osteogenic sarcoma in an adolescent with cystic fibrosis: successful treatment despite significant obstacles. Front Pediatr . (2018) 6:245. doi: 10.3389/fped.2018.00245

23. Biggs BG, Vaughan W, Colombo JL, Sanger W, Purtilo DT. Cystic fibrosis complicated by acute leukaemia. Cancer . (1986) 57:2441–3. doi: 10.1002/1097-0142(19860615)57:12%3C2441::AID-CNCR2820571232%3E3.0.CO;2-W

24. Cueto-Ramos RG, Ponce-Escobero AN, Montero-Cantu CA. Askin tumor: case report and literature review. Medicina Universitaria . (2015) 17(69):213–7. doi: 10.1016/j.rmu.2015.09.003

25. Sirivella S, Gielchinsky I. Treatment outcomes in 23 thoracic primitive neuroectodermal tumours: a retrospective study. Interact Cardiovasc Thorac Surg . (2013) 17:273–9. doi: 10.1093/icvts/ivt161

26. Gamberi G, Cocchi S, Benini S, Magagnoli G, Morandi L, Kreshak J, et al. Molecular diagnosis in Ewing family tumors: the Rizzoli experience - 222 consecutive cases in four years. J Mol Diagn . (2011) 13:313–24. doi: 10.1016/j.jmoldx.2011.01.004

27. Zhang KE, Lu R, Zhang P, Shen S, Li X. Askin’s tumor: 11 cases and a review of the literature. Oncol Lett . (2016) 11(1):253–6. doi: 10.3892/ol.2015.3902

28. Xu H, Yang J, Tu M, Weng J, Xie M, Zhou Z, et al. Vincristine promotes transdifferentiation of fibroblasts into myofibroblasts via P38 and ERK signal pathways. Front Pharmacol . (2022) 13:901000. doi: 10.3389/fphar.2022.901000

29. Ki KD, Lee JM, Lee SK, Tong SY, Huh CY, Ryu JK, et al. Pulmonary toxicity after a quick course of combinatorial vincristine, bleomycin, and cisplatin neoadjuvant chemotherapy in cervical cancer. J Korean Med Sci . (2010) 25(2):240–4. doi: 10.3346/jkms.2010.25.2.240

30. Sava CN, Bodog TM, Niulas LR, Iuhas AR, Marinau CP, Negrut N, et al. Biomarker changes in pediatric patients with COVID-19: a retrospective study from a single center database. In Vivo . (2022) 36(6):2813–22. doi: 10.21873/invivo.13019

31. Jeyaratnam J, van der Meer R, Berkers G, Heijerman HGM, Beekman JM, van der Ent CK. Breast development in a 7 year old girl with CF treated with ivacaftor: an indication for personalized dosing? J Cyst Fibros . (2021) 20(5):e63–6. doi: 10.1016/j.jcf.2021.06.001

32. Bell SC, Mall MA, Gutierrez H, Macek M, Madge S, Davies JC, et al. The future of cystic fibrosis care: a global perspective [published correction appears in Lancet Respir Med. 2019 Dec;7(12):e40]. Lancet Respir Med . (2020) 8(1):65–124. doi: 10.1016/S2213-2600(19)30337-6

Keywords: Askin’s tumor, Ewing’s sarcoma, pediatric cancer, cystic fibrosis, pseudomonas aeruginosa infection

Citation: Marinău C, Csep A, Sava C, Iuhas A, Niulaș L, Szilagyi A, Ritli L, Balmoș A and Jurca C (2023) Difficulties in the management of an Askin tumor in a pediatric patient with cystic fibrosis: case report and literature review. Front. Pediatr. 11:1289256. doi: 10.3389/fped.2023.1289256

Received: 5 September 2023; Accepted: 17 November 2023; Published: 1 December 2023.

Reviewed by:

© 2023 Marinău, Csep, Sava, Iuhas, Niulaș, Szilagyi, Ritli, Balmoș and Jurca. 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: Alin Iuhas [email protected]

† These authors have contributed equally to this work and share first authorship

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

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• BMC Pulm Med

An adult cystic fibrosis patient presenting with persistent dyspnea: case report

Gary m onady.

1 Medicine-Pediatrics Program, Boonshoft School of Medicine, Wright State University, Suite 500 Elizabeth Place, Dayton, OH, 45408, USA

Catherine L Farinet

2 Piketon Medical Center, 10 Indian Ridge Drive, Suite 1, Piketon, OH 45661, USA

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Persistent dyspnea is a common finding in the cystic fibrosis patient that typically leads to further work up of an alternative pulmonary etiology. Adult cystic fibrosis patients; however, are growing in numbers and they are living into the ages in which coronary artery disease becomes prevalent. Coronary disease should be included in the consideration of diagnostic possibilities.

Case presentation

A 52-year-old white male with cystic fibrosis was evaluated for exertional dyspnea associated with vague chest discomfort. Diagnostic testing revealed normal white blood cell, hemoglobin and platelet count, basic metabolic panel, fasting lipid profile, HbA1c, with chest radiograph confirming chronic cystic findings unchanged from prior radiographs and an electrocardiogram that revealed sinus rhythm with left anterior fascicular block. Stress thallium testing demonstrated a reversible anteroseptal perfusion defect with a 55% left ventricular ejection fraction. Heart catheterization found a 99% occlusion of the left anterior descending artery extending into the two diagonal branches, with 100% obstruction of the left anterior descending artery at the trifurcation and 70% lesion affecting the first posterior lateral branch of the circumflex artery.

This case report represents the first description in the medical literature of a cystic fibrosis patient diagnosed with symptomatic coronary artery disease. Applying a standard clinical practice guide proved useful toward evaluating a differential diagnosis for a cystic fibrosis patient presenting with dyspnea and chest discomfort.

Cystic Fibrosis (CF) is the most common lethal inherited disease in the Caucasian population. It was once considered a childhood disease; however, with advances in health care there is a growing population of adults with CF [ 1 ]. A life expectancy that was only 8 years of age in 1974 had advanced to the age of 21 years in 1994, and today is estimated as high as 40 years of age [ 2 ]. There are patients on the Cystic Fibrosis Foundation Patient Registry in 2003 that are in their eighth decade of life [ 1 ].

With new found longevity comes a new spectrum of disease prevalence associated with aging. Cystic Fibrosis Related Diabetes (43% prevalence) is now the number two chronic illness in the adult CF patient following chronic lung disease and surpassing liver disease (24% prevalence) in patients greater than 30 years of age [ 3 ]. Cardiovascular disease has been essentially isolated to cor pulmonale as a consequence of end stage obstructive pulmonary disease. Hypertension has not been considered a serious problem in this patient population [ 4 ]; however, a 20% prevalence has been observed at our CF adult center. Symptomatic coronary artery disease, one of the most prevalent of diseases in the adult patient population, has never been reported in the CF population from a PubMed literature search to date. Guides for care of health concerns in adult patients with CF were published in a January 2004 Consensus Report to help transition CF health care from pediatrician to internists or other adult care providers [ 3 ]. Many aspects of cardiovascular discussions such as hypertension and forms of heart disease separate from cor pulmonale are missing from this consensus report. The following discussion illustrates the need to continually update and add new information that will lead to optimizing the care of adult CF patients.

A 52-year-old white male with CF presented with persistent exertional dyspnea and cough with scant sputum production. Physical examination demonstrated oxygen saturation of 91%, with normal temperature and vital signs. His weight had fallen from 79.2 to 77.1 kg over 3 months. Cardiovascular exam was entirely normal. Lungs demonstrated coarse breath sounds bilaterally with scattered rales throughout the lung fields. The abdomen was normal, extremities demonstrated significant clubbing and there was no peripheral edema. Forced expiratory volume at 1 second (FEV 1 ) had decreased from 50% to 36%. The chest radiograph resembled baseline findings with no obvious infiltrate or pneumothroax. He received a month-long course of azithromycin, aztreonam and inhaled tobramycin for suspected pulmonary exacerbation of acute super-infection in the setting of underlying chronic CF lung disease.

One month later, follow-up revealed no improvement in dyspnea and no change in the scant sputum production, despite full adherence to the antibiotic regimen and airway clearance techniques. Exertional discomfort located along the sternum and left anterior chest associated with dyspnea without radiation or pressure sensation was further described but was not associated with palpitations, diaphoresis or nausea. This discomfort improved with rest and was not associated with meals. He did report the need to sleep upright in a recliner, but denied paroxysmal nocturnal dyspnea.

CF was diagnosed in this patient by sweat chloride at age 35 after an episode of hemoptysis, with subsequent genetic analysis identifying a ΔF508, 2789+5G>A mutation. He also has gastroesophageal reflux, Barrett's esophagus, azoospermia, and pancreatic insufficiency. He had sinus surgery at age 47. Medications include albuterol, ipratropium, fluticasone, dornase alpha, salmeterol, omeprazole, pancreatin and multivitamin. The patient's father had a myocardial infarction at age 37, his mother had coronary artery bypass surgery at 52 years of age, and a brother underwent coronary bypass at age 61. The patient has never smoked and alcohol intake was minimal.

Diagnostic testing demonstrated normal white blood cell, hemoglobin and platelet count. Electrolytes, albumin, protein and glucose were normal with a 5.1% HbA1c. Total cholesterol was 139 mg/dl, LDL 80 mg/dl, HDL 30 mg/dl and triglycerides at 76 mg/dl. Chronic findings with cystic changes were evident on chest radiograph, but with no obvious consolidation. Electrocardiogram revealed sinus rhythm with a left anterior fascicular block and normal ST findings.

Stress thallium testing was subsequently arranged within a week of the follow up visit, with results positive for moderate anteroseptal area of reversible perfusion with a left ventricular ejection fraction of 55%. Subsequent heart catheterization revealed 99% occlusion of the left anterior descending artery with extension into the two diagonal branches, 100% obstruction of the left anterior descending artery at the trifurcation and 70% lesion affecting the first posterior lateral branch of the circumflex artery. The patient was evaluated for possible coronary artery bypass graft; however, because of his current pulmonary status, angioplasty was elected with successful stenting of the left anterior descending artery. On follow up one year out from stent placement, the patient remained asymptomatic with exercise tolerance and pulmonary function returning to baseline.

This is the first report of a cystic fibrosis patient diagnosed with symptomatic coronary artery disease (CAD) and acknowledges that adult cystic fibrosis patients have indeed survived into the years were coronary artery disease becomes prevalent. Therefore, the likelihood of coronary disease should be included in the diagnostic consideration of persistent dyspnea associated with chest discomfort by applying the same standards used in grading a differential with an anginal presentation in non-CF patients [ 5 ].

The patient presented in this case had a Framingham score estimate that predicted a 10-year cardiovascular risk at 4% [ 6 ]. However, because of the presence of subtle chest discomfort associated with dyspnea, medical decision making includes an active alternative diagnosis of atypical angina based on two of three positive criteria of exertional symptoms with symptom relief upon resting [ 5 ]. Persistent dyspnea may be an occasional finding for a cystic fibrosis patient, and one that typically leads to further work up of a pulmonary etiology; however, cardiovascular disease was additionally considered in this patient.

The typical differential diagnosis of persistent dyspnea in an adult cystic fibrosis patient would include pneumothorax (5% prevalence) [ 7 ], atypical mycobacterial pneumonia (15% prevalence) [ 8 ], allergic bronchopulmonary aspergillosis (30% prevalence) [ 9 ], and cor pulmonale (3% prevalence in association with severe CF pulmonary disease) [ 10 ]. Without a history for hemoptysis, atypical mycobacterium and allergic bronchopulmonary aspergillosis would be less likely. Physical exam and chest radiograph did not support either pneumothorax or congestive heart failure. Symptoms could also be explained by this patient's progression of gastroesophageal reflux and/or Barrett's esophagus.

Atypical angina would be the most prevalent differential diagnosis, at 60%, for our patient's clinical presentation of chest pain in the non-CF male patient at this age [ 5 ]. The risk of CAD is not typically considered as an active alternative diagnosis for the CF patient; yet with aging, even CF patients will be at risk for CAD. This risk may even be greater given higher prevalence of known risk factors such as diabetes mellitus in the CF versus non-CF patient [ 11 ].

Two cases of asymptomatic coronary artery disease have been reported in association with CF with some advanced detail. One case came to diagnosis at autopsy, characterized as generalized atherosclerosis in a 41-year-old female CF patient [homozygous G542X] with diabetes mellitus that died from respiratory failure [ 12 ]. Further review of this case revealed a 200 mg/dl averaged cholesterol level, progressive hypertension with biopsy proven nephrosclerosis by 31-years of age, and a diabetic course complicated by gastrointestinal pseudoparesis, retinopathy and neuropathy. In this case, coronary artery disease was an incidental finding on autopsy as she was asymptomatic for myocardial ischemia during her lifetime.

A second case was described in which segmental hypokinesis with grade 2 systolic function was found as an incidental finding on Doppler echocardiography from a prevalence study looking at pulmonary hypertension that included an adult cystic fibrosis patient population [ 10 ]. This study identified a 40-year-old diabetic male, diagnosed with asymptomatic coronary artery disease after performing a thallium perfusion scan. Further testing by cardiac catheterization was not reported in this study.

What about other coronary risk factors? Cholesterol and hypertension were not identified risk factors present in our patient. The autopsy case report had several risk factors present, most notably, diabetes and hypertension, but with only a borderline elevated cholesterol level. What is the expected lipid level in a CF patient? The largest lipid study conducted on a CF population reported 134 ± 84 mg/dl triacylglycerol and 138 ± 84 mg/dl total cholesterol values [ 14 ]. Only 4% of patients had cholesterol levels >200 mg/dl in this study, with a maximum total cholesterol identified at 240 mg/dl. Serum cholesterol levels can be highly variable in CF patients. Patients with pancreatic insufficiency have low to normal cholesterol levels even with a high fat diet and enzyme supplementation as seen in this case [ 15 ]; however, CF patients with pancreatic sufficiency are likely at the same risk as the general population for complications for hyperlipidemia [ 16 ]. Another study of aortic atherosclerosis in CF patients found that they have less fatty streaking of the aorta than their weight matched counterparts [ 17 ]. Clearly there are other factors that may lead to atherosclerosis than lipid levels; however, applying a clinical practice guide published by the American College of Physicians [ 5 ] proved helpful toward diagnosing CAD in this CF patient presenting with dyspnea associated with a chest discomfort.

Abbreviations

CF – cystic fibrosis; FEV 1 – forced expiratory volume at 1 second; LDL – low density lipoprotein; HDL – high density lipoprotein; CAD – coronary artery disease;

Competing interests

The author(s) declare that they have no competing interests.

Authors' contributions

GMO contributed to the literature review cited in the discussion and editing of the original manuscript. CLF providing medical care for the patient described in this case presentation, and wrote the original manuscript detailing the clinical findings encountered from the clinical assessment. All authors read and approved the final manuscript.

Pre-publication history

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1471-2466/6/9/prepub

Acknowledgements

The authors used no additional resources in preparing this manuscript. Written consent was obtained from the patient for publication of this study.

• Cystic Fibrosis Foundation . Patient registry annual data report 2003. Bethesda MD: Cystic Fibrosis Foundation; 2003. [ Google Scholar ]
• Fogarty A, Hubard R, Britton J. International comparison of median age at death from cystic fibrosis. Chest. 2000; 117 :1656–1660. doi: 10.1378/chest.117.6.1656. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Yankaskas JR, Marshall BC, Sufian B, Simon RH, Rodmann D. Cystic fibrosis adult care consensus conference report. Chest. 2004; 125 [ PubMed ] [ Google Scholar ]
• Super M, Irtiza-Ali A, Roberts SA, Scharz M, Young M, Smith A, Roberts T, Hinks J, Heagerty A. Blood pressure and the cystic fibrosis gene: evidence for lower pressure rises with age in female carriers. Hypertension. 2004; 44 :878–883. doi: 10.1161/01.HYP.0000145901.81989.46. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Panzer RJ. Diagnostic strategies for common medical problems, Coronary Artery Disease. American College of Physicians Press, Philadelphia, PA; 1991. pp. 44–45. [ Google Scholar ]
• Framingham point scores US Department of Health and Human Service. National Institutes of Health, National Heart, Lung and Blood Institute. NIH Publication No 01-3305.
• Kuster P, Bender SW, Posselt HG, Stover B, Wiesemann HG. Spontaneous pneumothorax in cystic fibrosis. Monatsschr Kinderheilkd. 1988; 136 :251–255. [ PubMed ] [ Google Scholar ]
• Pierre-Audigier CP, Feroni A, Sermet-Gaudelus I, Le Bourgeois M, Offredo C, Vu-Thien H, Fauroux B, Mariani P, Munck A, Bingen E, Guillemot D, Quesne G, Vincent V, Berche P, Gaillard JL. Age-related prevalence and distribution of nontuberculous mycobacterial species among patients with cystic fibrosis. J Clin Micro. 2005; 43 :3467–3470. doi: 10.1128/JCM.43.7.3467-3470.2005. [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Fink JN, Kelly J. Immunologic aspects of granulomatous and interstitial lung diseases and of cystic fibrosis. JAMA. 1992; 268 :2874–2881. doi: 10.1001/jama.268.20.2874. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Fraser KL, Tullis E, Sason Z, Hyland RH, Thornley KS, Hanly PJ. Pulmonary hypertension and cardiac function in adult cystic fobrosis. Chest. 1999; 115 :1321–1328. doi: 10.1378/chest.115.5.1321. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Hayes FJ, O'Brien C, FitzGerald MX, McKenna MS. Diabetes mellitus in an adult cystic fibrosis population. Ir Med J. 1994; 87 :59–60. [ PubMed ] [ Google Scholar ]
• Schlesinger DM, Holsclaw DS, Fyfe B. Generalized atherosclerosis in an adult with CF and diabetes mellitus [abstract] Eleventh Annual North American Cystic Fibrosis Conference, Nashville, Tennessee, October 23–26, 1997.
• Vizza CD, Lynch JP, Ochoa LL, Richardson G, Trulock IP. Right and left ventricular dysfunction in patients with severe pulmonary disease. Chest. 1998; 113 :576–583. [ PubMed ] [ Google Scholar ]
• Milla C, Parks EF, Schwarzenberg SJ, Moran A. Abnormal lipid concentrations in cystic fibrosis. Am J Clin Nutr. 2002; 75 :1005–1011. [ PubMed ] [ Google Scholar ]
• Stewart C, Wilson DC, Hanna AK, Corey M. Lipid metabolism in adults with cystic fibrosis [abstract] Eleventh Annual North American Cystic Fibrosis Conference, Nashville, Tennessee, October 23–26, 1997.
• Slesinski MJ, Gloninger MF, Costantino JP, Orenstein DM. Lipid levels in adults with cystic fibrosis. J Am Dietetic Assoc. 1994; 94 :402–408. doi: 10.1016/0002-8223(94)90095-7. [ PubMed ] [ CrossRef ] [ Google Scholar ]
• Holman RL, Blanc W, Anderson D. Decreased aortic atherosclerosis in cystic fibrosis of the pancreas. Pediatrics. 1959; 24 :34–39. [ PubMed ] [ Google Scholar ]

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
• My Account Login
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Open access
• Published: 20 April 2024

The changing epidemiology of pulmonary infection in children and adolescents with cystic fibrosis: an 18-year experience

• Jagdev Singh 1 , 2 ,
• Sharon Hunt 1 ,
• Sharon Simonds 1 ,
• Christie Boyton 1 ,
• Anna Middleton 1 ,
• Matthew Elias 2 ,
• Susan Towns 1 , 3 ,
• Chetan Pandit 1 , 3 ,
• Paul Robinson 1 , 3 ,
• Dominic A. Fitzgerald 1 , 3 &
• Hiran Selvadurai 1 , 3  

Scientific Reports volume  14 , Article number:  9056 ( 2024 ) Cite this article

194 Accesses

Metrics details

• Bacterial infection
• Cystic fibrosis

The impact of evolving treatment regimens, airway clearance strategies, and antibiotic combinations on the incidence and prevalence of respiratory infection in cystic fibrosis (CF) in children and adolescents remains unclear. The incidence, prevalence, and prescription trends from 2002 to 2019 with 18,339 airway samples were analysed. Staphylococcus aureus [− 3.86% (95% CI − 5.28–2.43)] showed the largest annual decline in incidence, followed by Haemophilus influenzae [− 3.46% (95% CI − 4.95–1.96)] and Pseudomonas aeruginosa [− 2.80%95% CI (− 4.26–1.34)]. Non-tuberculous mycobacteria and Burkholderia cepacia showed a non-significant increase in incidence. A similar pattern of change in prevalence was observed. No change in trend was observed in infants < 2 years of age. The mean age of the first isolation of S. aureus ( p  < 0.001), P. aeruginosa ( p  < 0.001), H. influenza ( p  < 0.001), Serratia marcescens ( p  = 0.006) and Aspergillus fumigatus ( p  = 0.02) have increased. Nebulised amikacin (+ 3.09 ± 2.24 prescription/year, p  = 0.003) and colistin (+ 1.95 ± 0.3 prescriptions/year, p  = 0.032) were increasingly prescribed, while tobramycin (− 8.46 ± 4.7 prescriptions/year, p  < 0.001) showed a decrease in prescription. Dornase alfa and hypertonic saline nebulisation prescription increased by 16.74 ± 4.1 prescriptions/year and 24 ± 4.6 prescriptions/year ( p  < 0.001). There is a shift in CF among respiratory pathogens and prescriptions which reflects the evolution of cystic fibrosis treatment strategies over time.

Similar content being viewed by others

Therapeutic beta-lactam dosages and broad-spectrum antibiotics are associated with reductions in microbial richness and diversity in persons with cystic fibrosis

Andrea Hahn, Aszia Burrell, … Edith T. Zemanick

The antibiotic resistance reservoir of the lung microbiome expands with age in a population of critically ill patients

Victoria T. Chu, Alexandra Tsitsiklis, … Charles R. Langelier

Long-term macrolide treatment for non-cystic fibrosis bronchiectasis in children: a meta-analysis

Eun Lee, In Suk Sol, … You Hoon Jeon

Introduction

The management of pulmonary infections is critical in the care of individuals with cystic fibrosis (CF). Despite an increase in the median survival age over recent years, chronic pulmonary infection and concomitant airway inflammation leading to respiratory failure still account for 80–95% of deaths in individuals with CF 1 , 2 . This vicious cycle of infection and inflammation begins early in life, resulting in a decline in lung function, poorer nutrition, and structural lung abnormalities 3 .

Assessing long-term epidemiological trends in CF among children poses significant challenges, with studies often limited to registry reports, of a limited timeframe 4 , involve a small number of children and adolescents 5 , focus on specific organisms of interest 6 , 7 , or are derived from results obtained from bronchioalveolar sampling alone 8 , 9 . Furthermore, larger studies conducted before the year 2000 may not reflect recent advancements in CF treatment 10 , 11 , 12 , 13 , 14 , highlighting the need to evaluate any changes in the incidence and prevalence of CF bacterial pathogens to establish a reference point for future therapeutic interventions.

To this end, we conducted a study to investigate the trends in the incidence and prevalence of respiratory pathogens among children and adolescents with CF since the turn of the new millennium. By evaluating long-term longitudinal data within a clinical setting in the modern era of eradication therapy 15 , we would like to determine the changes that may have occurred in different age groups over time.

Methodology

Study population.

Children and adolescents with CF between birth to 18 years of age who were managed within a large CF centre in Australia between January 2002 and December 2019 were included in this study. Universal newborn screening of cystic fibrosis had been well-established before the study period 16 . Data collected from their existing electronic medical record included; the microbiological culture result (method of collection, date during which sample was collected with the corresponding age of the child or adolescent), and hospital pharmacy-based medication prescription data. This study was approved by the Ethics Committee of the Sydney Children’s Hospital Network (2020/ETH00815) and was conducted based on local guidelines and regulations. Exemption from consent was obtained from, and approved by the same committee.

Clinical routine during the study period

In our centre which encompasses a large region in New South Wales, outpatient (CF clinic) reviews occur four times a year, with infants or those who are clinically unwell reviewed on a more frequent basis. During these visits, airway samples are routinely collected regardless of the presence or absence of symptoms either through spontaneous expectoration (typically in older children), oropharyngeal suctioning performed by a trained CF nurse (typically in younger children), or via bronchoalveolar lavage (BAL). Airway samples microbiological cultures are ordered based on either BAL culture order label (samples obtained via BAL) or sputum CF culture order label (samples obtained through either spontaneously expectorated sputum or airway sample obtained from oropharyngeal suctioning).

All infants less than one year of age have been prescribed oral flucloxacillin or occasionally amoxicillin and clavulanic acid from diagnosis as part of our CF clinics’ routine Staphylococcus aureus prophylaxis approach for over 20 years.

In terms of the microbiological practices which has remained consistent during this study period, sputum specimens have been set up on (1) MacConkey agar for gram-negative bacteria e.g., coliforms, Pseudomonas aeruginosa, and Inquilinus limosus , (2) Anaerobically incubated chocolate agar with Bacitracin for Haemophilus influenzae . (3) Mannitol salt agar for S. aureus (4) Horse blood agar for e.g., Streptococcus pneumoniae and Moraxella catarrhalis . (5) Cepacia agar for Burkholderia cepacia and incubated for 7 days. (6) Non-tuberculous mycobacteria (NTM) testing is performed in an external Mycobacterium Reference Laboratory (MRL) using the automated blood culture system (BD BACTEC™) and testing occurs annually. Matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry (MS) has been used since 2015 for the rapid identification of organisms.

The microbiologist's report on the results of the collected airway samples is routinely reviewed by the CF team within 5–7 days after the samples are obtained. Treatment, where applicable following discussion with the primary CF physician is then prescribed. The treatment strategy includes; admission for parenteral antibiotics, a course of oral antibiotics, and/or nebulised antibiotic treatment.

Case definitions and stratification

Incidence was defined as the first time a respiratory pathogen of interest is isolated from the sputum of the child or adolescent with CF. Once the child or adolescent is an incident case for that particular pathogen, they were excluded from the denominator for the subsequent years.

Prevalence was defined as a child or adolescent with a respiratory pathogen isolated from their sputum in a specific year. Once the child or adolescent is a prevalent case for that particular pathogen, any further positive culture of the same pathogen isolated from the same child or adolescent was excluded for the remainder of that year.

Nine organisms of clinical interest in CF were selected for analysis. This includes; S. aureus, P. aeruginosa, H. influenza, Aspergillus fumigatus, Serratia marcescens, NTM, B. cepacia, Achromobacter xylosoxidans , and Stenotrophomonas maltophilia 17 .

The cohort was divided into four age groups: < 2 years, 2–5 years, 6–11 years, and > 12 years. The rationale behind this age group includes (1) biological variability in terms of differences in microbiome composition, immune system development and environmental exposure e.g. home or pre-school (2) management approaches such as methods of physiotherapy, lung function testing or the availability of medications such as dornase alfa (3) to align with existing clinical trials in CF transmembrane conductance regulator (CFTR) and CF registry reports.

In terms of medications prescribed and obtained from the hospital pharmacy, prescription of oral antimicrobials (including amoxicillin and clavulanic acid, ciprofloxacin, trimethoprim/sulfamethoxazole, flucloxacillin, and itraconazole), nebulised antimicrobials (including amikacin, colistin, and tobramycin), and other medications (including dornase-alfa, hypertonic saline nebules, and CFTR modulators and correctors) were reviewed.

Statistical analysis

We used descriptive statistics to summarise the data, reporting organism incidence and prevalence as n (%). To assess changes over time, we calculated the annual incidence and prevalence of each organism based on individual airway samples, and used regression analysis to evaluate these measures. Based on the coefficients obtained from the regression model, the average change in incidence and prevalence was presented. Prescription trends were also analysed on an individual basis. Results are reported as % change (with 95% confidence intervals) for incidence and prevalence, and as number of prescriptions/year ± standard deviation for medications prescribed. Changes in the mean age of first organism isolation were assessed using analysis of variance. All statistical calculations were performed using the SPSS Statistic Data Editor (IBM Version 28, New York, USA, 2021). Statistical significance was defined as p  < 0.05.

Study population and bacterial samples

During the study period, 419 children and adolescents with CF were followed up with 206 (49.2%) born on, or after 1st January 2002. A total of 18,339 airway samples were collected during the study period with 401 (2.2%) collected via bronchioalveolar lavage, with the remaining samples obtained from expectorated sputum or oropharyngeal suction.

Out of the total airway samples that were collected, 724 (3.9%) samples met the criteria for incidence and 15,332 (83.6%) samples met the criteria for prevalence as defined in the methodology of this study were included in the analysis.

Incidence and prevalence of respiratory pathogens

Throughout the entire study period, S. aureus (25.1%), P. aeruginosa (26.2%), and H. influenzae (17.9%) exhibited the highest incidence among respiratory pathogens. Together, these pathogens accounted for 70% of the overall incidence over 18 years. In contrast, B. cepacia (0.69%), A. xylosoxidans (2.1%), and NTM (3.7%) had the lowest incidence across the study period, collectively representing 6.5% of the overall incidence over 18 years (Table 1 ).

Throughout the entire study period, S. aureus (47.8%), P. aeruginosa (34.5%), and A. fumigatus (8.4%) exhibited the highest prevalence among respiratory pathogens. Together, these organisms constituted almost 95% of the overall prevalence over 18 years. In contrast, the least prevalent respiratory pathogens were NTM (0.72%), B. cepacia (0.69%), and A. xylosoxidans (0.48%) throughout the study period. Collectively, these organisms represented less than two percent of the overall prevalence over 18 years (Table 2 ).

Changes in age of first isolation of respiratory pathogens

The ages at which these pathogens were first isolated are as follows: S. aureus (3.35 ± 2.1 years), H. influenza (4.28 ± 2.7 years), S. marcescens (5.24 ± 4.09 years), P. aeruginosa (5.27 ± 2.9 years), A. fumigatus (7.31 ± 2.85 years). This is followed by S. maltophilia (8.95 ± 2.95 years), B. cepacia (9.055 ± 2.3 years), NTM (11.38 ± 2.06 years), A. xylosoxidans (11.71 ± 2.86 years).

Over time, respiratory pathogens have shown an increase in the mean age of the first isolation: S. aureus ( p  < 0.001), P. aeruginosa ( p  < 0.001), H. influenza ( p  < 0.001), S. marcescens ( p  = 0.006), A. Fumigatus ( p  = 0.02), B. cepacia ( p  = 0.58), NTM ( p  = 0.052), S. marcescens ( p  = 0.308), S. maltophilia ( p  = 0.47), A. xylosoxidans ( p  = 0.80). The changes over years of these respiratory pathogens are illustrated in Fig.  1 .

Mean age group of the first culture of CF organisms.

Changes of overall and age-specific incidence and prevalence of CF organisms from 2002 to 2019

Amongst the organisms with the highest incidence, S. aureus showed the largest decline in incidence over time, followed by H. influenza and P. aeruginosa . Meanwhile, NTM and B. cepacia showed a non-significant increase in incidence. A similar pattern of change in prevalence was observed (Tables 1 , 2 ).

With respect to age groups, incidence of S. aureus, P. aeruginosa, H. influenza and A. fumigatus in children < 2 years of age have remained unchanged. A similar pattern of change in prevalence was observed. Meanwhile, NTM showed a significant increase in both incidence and prevalence in children 6–11 years of age.

Throughout this study, a total of 29,203 medications (oral antimicrobials n = 18,367, 62.9%) were prescribed. The antibiotics that were increasingly prescribed include amikacin (3.09 ± 2.24 prescription/year, p  = 0.003), amoxicillin/clavulanic acid (8.98 ± 2.17 prescriptions/year, p  < 0.001), colistin (1.95 ± 0.3 prescriptions/year, p  = 0.032), trimethoprim/sulfamethoxazole (18.1 ± 8.7, p  < 0.001). Flucloxacillin (− 4.48 ± 1.073, p  < 0.001), tobramycin (− 8.46 ± 4.7, p  < 0.001) showed a decrease in prescription. Ciprofloxacin (− 6.049 ± 5.1 prescriptions/year, p  = 0.068) and itraconazole (− 4.53 ± 1 prescriptions/year, p  = 0.07) did not show any significant change over time.

Dornase alfa prescription increased by 16.74 ± 4.1 prescriptions/year ( p  < 0.001). The prescription of hypertonic saline nebulisation increased by 24 ± 4.6 prescriptions/year ( p  < 0.001). There were 7 children or adolescents on CFTR corrector or modulator therapy.

This paediatric-focused study evaluates annual changes in the incidence and prevalence rates of respiratory pathogens across different age groups, while also comparing medication prescription trends over an 18-year period. This study provides valuable data from a real-world clinical setting where infants under the age of one receive universal antimicrobial prophylaxis and, standardised respiratory pathogen surveillance is conducted by qualified personals using consistent sampling and microbiological testing protocols. In particular, obtaining samples through sputum and oropharyngeal suctioning is considered to have the highest concordance with BAL samples, rendering them more representative of lower airway infections compared to other sampling methods like throat or cough swabs 18 . The findings contribute to our understanding of the long-term trends in respiratory pathogens and associated clinical management in the paediatric population, particularly in the modern era of eradication therapy 15 .

Our study showed that together, S. aureus and P. aeruginosa make up the majority of respiratory pathogens both in terms of incidence (51.3%) and prevalence (82.3%). Data preceding 2000, report prevalence of these two respiratory pathogens to be higher at 95% 14 .

Registry data taken from 2018 to 2020 showed a prevalence of P. aeruginosa of 20.9% 17 and S. aureus of 55.26% in children and adolescents under the age of 18. In comparison, our data shows a recent prevalence of P. aeruginosa of 17.6% and S. aureus of 45.3%. Of the less frequent respiratory pathogens, NTM prevalence was 4.3% from registry data vs 3.7% from our cohort and B .cepacia  was 3.2% vs. 1.3% respectively.

In a recent publication by VanDevanter et al., a trend of decline in P. aeruginosa prevalence was observed, as evidenced by the examination and presentation of registry data within a comparable time frame 19 . Following this, Fischer et al. raised a crucial question regarding whether the observed changes in P. aeruginosa over time were also apparent in other respiratory pathogens of interest in CF 20 . We have demonstrated that over the past 18 years, the incidence and prevalence of the most common respiratory pathogens in CF such as S. aureus , P. aeruginosa , H. influenzae and A. fumigatus have decreased steadily. This significant decline of between 2 and 4% of individual respiratory pathogens are observed both in the incidence and prevalence. Meanwhile, less common organisms such as NTM , B. cepacia and A. xylosoxidans, S. maltophilia showed no significant change in terms of incidence and prevalence.

We also found that the incidence and prevalence of respiratory pathogens remain unchanged for infants up to 2 years of age across all respiratory pathogens. Additionally, we have found that our cohort of children and adolescents with CF are found to have a positive airway sample culture for these respiratory pathogens significantly later that the earlier years of this study.

Our centre has adopted the universal use of S. aureus prophylactic antibiotics in infants diagnosed with CF preceding this study period. In a systematic analysis performed which reviewed four studies, there was a weak indication that P.aeruginosa was isolated less frequently in children under three years and more frequently in children between three to six years in the prophylactic group 21 . In contrast, despite our universal use of prophylactic antibiotics in infants, our study shows (1) a decline in the incidence and prevalence of P. aeruginosa , (2) no  significant increase in the incidence and prevalence of organisms such as NTM and B. cepacia (3) an increase in the mean age of first isolation of respiratory pathogens of interest, (4) no change of incidence and prevalence of respiratory pathogen < 2 years of age. A contributing factor in terms of improvements in infection control practices may have helped keep our incidence and prevalence lower than the national average. While being potentially circumstantial, these findings suggest that the use of prophylactic anti-staphylococcal antibiotics is not associated with an increase in P. aeruginosa or increase in prevalence of other less common respiratory pathogen. Prospective studies such as the CF-START study in evaluating outcomes of prophylactic treatments will hopefully provide conclusive proof of its benefits and safety 21 .

By examining prescription trends, we have found that there is a rise in the use of anti-pseudomonal nebulised antibiotics such as amikacin and colistin. This suggests that P.aeruginosa is being more aggressively treated over time as both this antibiotics are considered as second line after tobramycin 22 . However, the increase in use of amikacin could also be attributed to an increase in NTM incidence and prevalence. Encouragingly, we have found that the emphasis on respiratory clearance has increased over time with the significant increase in the prescription of dornase alpha and hypertonic saline in our cohort.

Our study comes with certain limitations that warrant consideration. Firstly, the sputum and prescription data lack representation from external laboratories or pharmacies, potentially limiting the comprehensiveness of our findings. Additionally, we did not culture anaerobic bacteria and did not routinely test for co-infection with respiratory viruses, leading to an omission in addressing potential co-infections among these organisms in our study. Moreover, the annual frequency of NTM testing, as opposed to routine CF airway sample cultures, may result in an underrepresentation of NTM within our study cohort.

Thirdly, our data originated from a single CF centre in Australia, raising concerns about the generalisability of our findings to a broader population. Fourthly, our incidence calculation may involve a small number of children or adolescents intermittently found to have these respiratory pathogens in their airway samples. Finally, the relatively limited sample size of children and adolescents on CFTR modulators or correctors is noteworthy, as our study predates the widespread adoption that followed the approval and government funding of these medications in Australia. Current evidence suggests that while it may more difficult to obtain sputum samples in children on CFTR therapy, its’ impact on the growth of specific bacterial pathogens needs to be closely examined 23 . The low number of children or adolescents on CFTR modulators or correctors is an important aspect of this study as it will enable future comparison in a post-modulator era in the management of CF.

Our study has several strengths. First, we analysed a large number of sputum samples, both overall and in different age groups, providing a longitudinal comparison of changes in CF treatment over the past 18 years. This is the first study of such magnitude in children and adolescents with CF, providing age-specific incidence and prevalence, as well as prescription trends. In particular, our review of incidences of these organisms and the age of first positive culture provides additional information towards our understanding of CF respiratory pathogens over the past two decades.

Second, our study includes a large cohort of children born on or after January 1st, 2002, when newborn screening has already been well-established, allowing us to assess the acquisition of respiratory pathogens from shortly after birth over the past 18 years. Third, the practice of using prophylactic anti-staphylococcus antibiotics universally has given us the opportunity to assess the outcomes of its’ use over a significantly long period of time. While strong conclusions cannot be made without a non-prophylactic control arm, it does provide insight into the long-term impact of its’ implementation on respiratory pathogens in our cohort.

In summary, our study shows a change in the epidemiology of CF pathogens in a single large paediatric clinic that practices universal prophylaxis in children. First, we observed a decline in the incidence and prevalence of the most commonly found CF pathogens such as S. aureus, P. aeruginosa, H. influenzae, and A. fumigatus , as well as a delay in the first acquisition of these pathogens. However, less common pathogens such as S. marcescens , NTM, B. cepacia, A. xylosoxidans , and S. maltophilia did not show significant changes. Second, we found no change in the incidence or prevalence of respiratory pathogens in infants under 2 years of age over time.

Data availability

Data is available from the corresponding author, upon reasonable request.

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).

Article   CAS   PubMed   Google Scholar  

Lyczak, J. B., Cannon, C. L. & Pier, G. B. Lung infections associated with cystic fibrosis. Clin. Microbiol. Rev. 15 , 194–222. https://doi.org/10.1128/CMR.15.2.194-222.2002 (2002).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Pillarisetti, N. et al. Infection, inflammation, and lung function decline in infants with cystic fibrosis. Am. J. Resp. Crit. Care Med. 184 , 75–81. https://doi.org/10.1164/rccm.201011-1892OC (2011).

Article   PubMed   Google Scholar  

Spicuzza, L. et al. Emerging pathogens in cystic fibrosis: Ten years of follow-up in a cohort of patients. Eur. J. Clin. Microbiol. Infect. Dis. 28 , 191–195 (2009).

Coburn, B. et al. Lung microbiota across age and disease stage in cystic fibrosis. Sci. Rep. 5 , 10241. https://doi.org/10.1038/srep10241 (2015).

Article   ADS   CAS   PubMed   PubMed Central   Google Scholar  

Abidin, N. Z. et al. Trends in nontuberculous mycobacteria infection in children and young people with cystic fibrosis. J. Cystic Fibrosis 20 , 737–741 (2021).

Article   Google Scholar  

Miall, L. S., McGinley, N. T., Brownlee, K. G. & Conway, S. P. Methicillin resistant Staphylococcus aureus (MRSA) infection in cystic fibrosis. Arch. Dis. Childhood 84 , 160–162. https://doi.org/10.1136/adc.84.2.160 (2001).

Article   CAS   Google Scholar  

Breuer, O. et al. Changing prevalence of lower airway infections in young children with cystic fibrosis. Am. J. Resp. Crit. Care Med. 200 , 590–599. https://doi.org/10.1164/rccm.201810-1919OC (2019).

Hilliard, T. N. et al. Bronchoscopy following diagnosis with cystic fibrosis. Arch. Dis. Childhood 92 , 898–899. https://doi.org/10.1136/adc.2006.105825 (2007).

Gilligan, P. H. Microbiology of airway disease in patients with cystic fibrosis. Clin. Microbiol. Rev. 4 , 35–51 (1991).

Burns, J. L. et al. Microbiology of sputum from patients at cystic fibrosis centers in the United States. Clin. Infect. Dis. 27 , 158–163 (1998).

Govan, J. & Nelson, J. Microbiology of lung infection in cystic fibrosis. Br. Med. Bull. 48 , 912–930 (1992).

Millar, F., Simmonds, N. & Hodson, M. Trends in pathogens colonising the respiratory tract of adult patients with cystic fibrosis, 1985–2005. J. Cystic Fibrosis 8 , 386–391 (2009).

Razvi, S. et al. Respiratory microbiology of patients with cystic fibrosis in the United States, 1995 to 2005. Chest 136 , 1554–1560. https://doi.org/10.1378/chest.09-0132 (2009).

Ramsay, K. A. et al. The changing prevalence of pulmonary infection in adults with cystic fibrosis: A longitudinal analysis. J. Cystic Fibrosis Off. J. Eur. Cystic Fibrosis Soc. 16 , 70–77. https://doi.org/10.1016/j.jcf.2016.07.010 (2017).

McKay, K. O., Waters, D. L. & Gaskin, K. J. The influence of newborn screening for cystic fibrosis on pulmonary outcomes in New South Wales. J. Pediatrics 147 , S47–S50. https://doi.org/10.1016/j.jpeds.2005.08.013 (2005).

Ahern, S. et al. The Australian cystic fibrosis data registry: Annual report 2019 (2021).

Schultz, A. & Caudri, D. Cough swabs less useful but induced sputum very useful in symptomatic older children with cystic fibrosis. Lancet Resp. Med. 6 , 410–411 (2018).

VanDevanter, D. R., LiPuma, J. J. & Konstan, M. W. Longitudinal bacterial prevalence in cystic fibrosis airways: Fact and artifact. J. Cystic Fibrosis Off. J. Eur. Cystic Fibrosis Soc. https://doi.org/10.1016/j.jcf.2023.09.011 (2023).

Fischer, A. J. & Planet, P. J. A birth cohort approach to understanding cystic fibrosis lung infections. J. Cystic Fibrosis Off. J. Eur. Cystic Fibrosis Soc. https://doi.org/10.1016/j.jcf.2023.10.014 (2023).

Rosenfeld, M., Rayner, O. & Smyth, A. R. Prophylactic anti-staphylococcal antibiotics for cystic fibrosis. Cochrane Database System. Rev. https://doi.org/10.1002/14651858.CD001912.pub5 (2020).

Elborn, J., Hodson, M. & Bertram, C. Implementation of European standards of care for cystic fibrosis—control and treatment of infection. J. Cystic fibrosis 8 , 211–217 (2009).

Nichols, D. P. et al. PROMISE: Working with the CF community to understand emerging clinical and research needs for those treated with highly effective CFTR modulator therapy. J. Cystic Fibrosis 20 , 205–212. https://doi.org/10.1016/j.jcf.2021.02.003 (2021).

Download references

Acknowledgements

We extend our gratitude to The Cure4CF Foundation and The Team Simon Foundation for Cystic Fibrosis for their generous financial support towards this study.

Author information

Authors and affiliations.

Department of Respiratory Medicine, The Children’s Hospital at Westmead, Sydney, NSW, Australia

Jagdev Singh, Sharon Hunt, Sharon Simonds, Christie Boyton, Anna Middleton, Susan Towns, Chetan Pandit, Paul Robinson, Dominic A. Fitzgerald & Hiran Selvadurai

Department of Pharmacy, The Children’s Hospital at Westmead, Sydney, NSW, Australia

Jagdev Singh & Matthew Elias

Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia

Susan Towns, Chetan Pandit, Paul Robinson, Dominic A. Fitzgerald & Hiran Selvadurai

You can also search for this author in PubMed   Google Scholar

Contributions

H.S. and J.S. conceived the research question. J.S., H.S. and D.F. designed the study and analysis plan. J.S., S.H., S.S., C.B., A.M. and M.E. collected the data. J.S. performed the statistical analysis. H.S., D.F., P.R., S.T. and C.P. reviewed the data. J.S. drafted the initial and final versions of the manuscript. All authors critically reviewed early and final versions of the manuscript.

Corresponding author

Correspondence to Jagdev Singh .

Ethics declarations

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.

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/ .

Reprints and permissions

About this article

Cite this article.

Singh, J., Hunt, S., Simonds, S. et al. The changing epidemiology of pulmonary infection in children and adolescents with cystic fibrosis: an 18-year experience. Sci Rep 14 , 9056 (2024). https://doi.org/10.1038/s41598-024-59658-4

Download citation

Received : 31 August 2023

Accepted : 12 April 2024

Published : 20 April 2024

DOI : https://doi.org/10.1038/s41598-024-59658-4

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

By submitting a comment you agree to abide by our Terms and Community Guidelines . If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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.