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Case report: Boy, 3, has combination of CFTR mutations, no CF symptoms

Challenge of predicting outcomes in CF shown in study

by Patricia Inácio, PhD | September 5, 2024

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A 3-year-old boy who carries a new combination of two mutations in the CFTR gene, but with no clinical signs of cystic fibrosis (CF), was described by researchers in a case report.

“The case presented has no clinical symptoms so far and doesn’t meet the criteria for a CF diagnosis , despite carrying a mutation combination that was predicted to cause CF,” the researchers wrote.

The case underscores the challenges of predicting outcomes in CF, especially with rarer mutations. “Caution is needed when interpreting prenatal genetic results,” the researchers wrote in “ Clinical Course of a Child With Cystic Fibrosis and the Genotype F508del/CFTRdup1_11: A Case Report ,” which was published in Cureus .

CF is caused by CFTR gene mutations, which impair or stops production of CFTR, a protein responsible for controlling the flow of chloride ions into and out of cells. This malfunction causes thick mucus to accumulate in a number of organs, including the lungs and the pancreas, along with salty sweat. Mucus building up in the lungs promotes lung infections, while, in the pancreas, it blocks the release of enzymes needed to digest food, particularly fats, resulting in pancreatic insufficiency. This can lead to nutritional deficiencies and impaired growth.

More than 2,000 mutations have been described in the CFTR gene, but not all are disease-causing. The most common mutation is called F508del.

To develop CF, a person must inherit two disease-causing mutations from their parents. CF is often screened in prenatal genetic tests, but the correlation between specific CFTR mutations and clinical presentations is not easy to predict.

A scientist in a laboratory is shown testing samples from a set of vials.

Study IDs rare CFTR mutations that could respond to CFTR modulators

No symptoms despite cftr mutations.

Here, researchers in Greece write about a boy with CF who harbors the F508del mutation in one CFTR gene copy and another mutation known as CFTRdup1_11 in the other. F508del results in abnormal folding and the early destruction of the CFTR protein. CFTRdup1_11 represents a duplication of a small part of the gene.

Prenatal screening test revealed the mother carried the F508del mutation. The father was subsequently found to carry the CFTRdup1_11 defect. Following an amniocentesis, which collects amniotic fluid from the womb, a genetic test confirmed the fetus was positive for the F508del/CFTRdup1_11 combination, which isn’t described in available CF databases. Smaller duplications have been reported in the same region of the CFTR gene in combination with F508del, however, so computer models helped predict the baby would have CF with pancreatic insufficiency.

The parents were informed of the CF-related mutations in genetic counseling and decided to continue the pregnancy. The baby was born at term and a genetic analysis confirmed them.

The period after birth was uneventful. A blood sample collected shortly after the baby was born was tested for levels of immunoreactive trypsinogen , a protein typically elevated in the blood of people with CF. The test was negative. The infant continued to grow and develop normally, and his ability to absorb food was also normal.

At the time the study concluded, the child was being tested nearly every three months for airway infections. He did test positive for Staphylococcus aureus , a bacteria commonly present in the airways of people with CF, but was successfully treated with a combination of antibiotics. No worrisome microbes have been detected in his airways ever since and he hasn’t been hospitalized.

A sweat test , a standard for diagnosing CF, was conducted at age 3. Similar to results at two weeks of age, the results were borderline, meaning just below the threshold for a CF diagnosis.

The researchers described the case as one that “adds to the pool of data indicating limitations to [computer] models, as clinical phenotype [presentation] can greatly differ from predicted.”

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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

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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.

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Maggie’s Illness

Protein Structure and Function in Cystic Fibrosis

By Michaela Gazdik Stofer

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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.

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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

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Undergraduate lower division, Undergraduate upper division

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

CHAPTER 20: Case Study: Cystic Fibrosis

Carole A. Tucker, PT, PhD, PCS, RCEP

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Introduction.

Examination: Age 2 Months
Evaluation, Diagnosis, and Prognosis Including Plan of Care
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Termination of Episode of Care
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Cystic fibrosis (CF) is an autosomal recessive condition affecting approximately 30,000 Americans and 60,000 people worldwide. According to the Centers for Disease Control and Prevention (CDC), 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 cystic fibrosis 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 cystic fibrosis transmembrane conductance regulator (CFTR) protein. This mutation alters the production, structure, and function of cAMP (cyclic adenosine monophosphate), 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.

CF involves the exocrine mucous glands and typically affects the lungs, liver, pancreas, gastrointestinal tract, sweat glands, and genitourinary tracts. The severity of the disease and the organs affected depends largely on the specific type of genetic mutation involved. To date there are more than 1,200 known mutations of the CFTR gene, not all of which cause CF.

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Cystic fibrosis and survival to 40 years: a case–control study

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The clinical course of patients with cystic fibrosis (CF) is variable and probably determined by many interacting factors. We aimed to examine the influence of early social and clinical factors on long-term survival.

A case–control study of adult CF patients was used to compare long-term survivors (aged ≥40 yrs) with patients who died before reaching 30 yrs of age. Each case (n = 78) was matched by birth date with at least one control (n = 152), after exclusion of “late diagnosis” patients. Probability-weighted logistic regression models were used to identify influences on survival.

Factors resulting in increased probabilities of survival included high body mass index (OR 1.76, 95% CI 1.40–2.22), forced expiratory volume in 1 s (OR per 5% increase 1.54, 95% CI 1.32–1.80), and forced vital capacity (OR per 5% increase 1.54, 95% CI 1.33–1.78) at transfer to the adult clinic and the exclusive use of oral antibiotics (OR 8.31, 95% CI 3.02–22.88). Factors resulting in decreased probabilities of survival were Pseudomonas aeruginosa acquisition (OR 0.18, 95% 0.05–0.65) or pneumothorax before transfer to the adult clinic (OR 0.02, 95% CI 0.004–0.08) and referral from a paediatric clinic in a deprived area (OR 0.13, 95% CI 0.04–0.38).

Long-term survival is associated with the clinical features present by the time of referral to an adult clinic. Even “early-diagnosis” disease appears to have different phenotypes, possibly independent of CF gene function, that have different survival patterns.

cystic fibrosis

The life expectancy of patients with cystic fibrosis (CF) has been steadily increasing despite the lack of a cure for the underlying cellular defect. Patients born today are expected to have a median survival into their 6th decade 1 . The improvement has been explained in several ways including through the introduction of pancreatic enzymes, better nutrition, specialist-centre care, improved physiotherapy and more intensive antimicrobial treatment 2 – 4 .

CF covers a wide spectrum of disease, from milder phenotypes with “non-classic” disease (with pancreatic sufficiency, milder lung disease and a later diagnosis), to more severe cases with a “classic” phenotype 5 . However, even within different groups there is variation in the rate of disease progression; some patients with features of classic disease run a mild course and indeed an important proportion of patients with the common “severe” δF508 mutation survive beyond 40 yrs of age with relatively well-maintained lung function and weight 6 , 7 .

Thus, it has been hypothesised that other factors influence survival in CF. These include variations in the function of the responsible gene, the cystic fibrosis transmembrane conductance regulator ( CFTR ), and other independent genetic factors (“modifier” genes). None, however, has yet been shown directly to influence survival 8 . Other potential, nongenetic determinants of survival are so-called environmental influences; these cover a diverse range of factors, broadly divided into biological effectors ( e.g. microorganisms, nutrition, sex and pollutants), social and cultural influences ( e.g. socioeconomic status and adherence to treatment) and healthcare-related factors, such as access to care and interclinic treatment variations 9 . Evidence for or against these factors is variable and when they are most influential, or when an individual is most vulnerable to them, is not well understood. In view of this, we conducted a case–control study of long-term survival among patients registered with a specialist adult CF clinic with the aim of identifying early potential influences of long-term survival in patients diagnosed with CF in childhood.

Since 1965, details of all patients referred to the adult unit at Royal Brompton Hospital (RBH; London, UK) and confirmed to have CF have been entered onto a database. The diagnosis is based on clinical features and a positive sweat sodium (>70 mmol·L −1 ) or chloride (>60 mmol·L −1 ) test or, in cases with a borderline or negative sweat test result, the presence of a known disease-causing mutation on each CFTR gene, or of an abnormal nasal potential difference measurement. Patients were referred as adults from an adult physician or by their general practitioner, or directly through transition from paediatric clinics (at ∼15 yrs of age). Clinical and demographic details are collected at the first consultation and are subsequently updated at annual review.

We studied only patients with a diagnosis of CF before the age of 17 yrs. These were identified from the database and classified as cases or controls as follows. Cases (long-term survivors) were all patients with complete records who had reached 40 yrs of age without transplantation by December 31, 2004. Controls were selected from all patients with complete records who had died before 30 yrs of age or required transplantation at <30 yrs of age by December 31, 2004. We excluded controls (n = 27) who had died from a non-CF related cause ( e.g. road traffic accident).

80 cases and 400 controls were identified from the original population. To ensure that cases and controls were similar in terms of era of birth, as it is likely that this would have influenced the nature of care received, cases were matched by date of birth (±365 days) to all eligible controls. Of the 80 cases identified, 78 were matched to at least one control. Each control was matched with as many cases as eligible and controls could be matched to more than one case. Of the 400 controls identified, 152 were matched to at least one case.

Information on source of referral, guardian's occupation, genotype and clinical state (weight, height, lung function, sputum microbiology, diabetic status, use of pancreatic enzymes, previous pneumothoraces, episodes of major haemoptysis and number of previous hospital admissions or antibiotic courses) prior to and at referral was collected from the initial assessment at the adult clinic; the remaining data were collected from annual reviews (school disruption, number of Advanced (“A”)-level school examinations and number of siblings). Antibiotic treatments before first attendance at the adult clinic were categorised as oral, aerosolised or i.v.

Statistical analysis

Differences between cases and controls were described by frequencies and proportions for categorical variables, and medians and interquartile ranges for continuous variables. Development of CF-related diabetes (CFRD) and the acquisition of Staphylococcus aureus , Pseudomonas aeruginosa and Haemophilus influenzae were assessed in terms of whether the patient developed these conditions before the age of 16 yrs. As such, analyses of these variables were limited to those who arrived at RBH by 16 yrs of age (69 cases and 109 controls). Physical measurements at initial assessment, history of antibiotic use and number of hospital admissions prior to initial assessment were limited to those arriving at RBH by the age of 15 yrs (73 cases and 131 controls).

We used probability-weighted logistic regression models to assess the association between possible predictors and survival to 40 yrs of age (case status). Using this method, controls were weighted according to the cases to which they were matched; thus, making the distribution of the matching variable (date of birth) similar in both groups. Each control was weighted by the sum, across its matched case, of 1/(number of controls to which the case is matched). Cases were allocated a weight of 1. Model results are presented as OR and 95% CI. Since patients were transferred to the adult clinic at varying ages, ORs for physical measures and medical history prior to initial assessment (use of antibiotics, prior hospital admissions, history of pneumothorax and major haemoptysis prior to initial assessment) were adjusted for age at assessment. ORs for physical measures were also adjusted for sex. Analyses were conducted in SAS v9.1 (SAS Institute, Cary, NC, USA) or STATA (StataCorp LP, College Station, TX, USA).

All patients consented for their anonymised data to be included in the database for research purposes. The study was approved by the RBH Research Ethics Committee.

Clinical characteristics

Half of the participants were born between 1960 and 1965 and most (80.4%) were diagnosed with CF before the age of 5 yrs ( table 1 ). 70% were first seen in the adult clinic before 21 yrs of age. 97% had pancreatic insufficiency and there were similar proportions of males in cases (long-term survivors) and controls. Genotyping was only possible for patients surviving beyond 1989 ( i.e. the year CFTR was discovered); therefore, genetic data were available for 74 patients (67 cases). Of the long-term survivors genotyped (86%), 32 (48%) were homozygous for δF508, 13 (19%) were compound heterozygous for δF508 and 19 (28%) were heterozygous for δF508 (with an unidentifiable second CF mutation). The remaining three cases were 621+1G→T, R553X (both with unidentifiable second genes) and R347P/3659delC. The seven controls genotyped were homozygous δF508.

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Features significantly associated with case status ( i.e. long-term survivors) included diagnosis after 5 yrs of age. Patients whose initial presentation had been with respiratory disease were significantly less likely to be cases. Patients who had suffered a pneumothorax prior to referral to the adult clinic were significantly less likely to be cases after adjusting for age at first attendance. There was little heterogeneity in the distributions of pancreatic insufficiency, haemoptysis and CFRD prior to referral; none was associated with case status. After adjusting for age at initial assessment and sex, the probability of survival to 40 yrs increased with increasing height, weight, body mass index (BMI), forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity as recorded at the initial assessment in the adult clinic.

Sociodemographic factors and patients’ educational background

Associations between long-term survival and measures of socio-economic status and educational attainment are shown in table 2 . Patients referred from paediatric clinic B (paediatric clinic in a low social economic status area) were less likely to be cases. Those whose guardians were in managerial or manual (skilled or unskilled) occupations were more likely to be cases than those in professional occupations, but the difference was not statistically significant. Patients classified as having “mildly” or “grossly” disrupted schooling were statistically more likely to be controls, but there was no association between case status and the number of A-levels achieved. We found no association between sibling number (with or without CF) and case status.

Sputum microbiology, antibiotic courses and hospital admissions

Table 3 displays the association between long-term survival and sputum microbiology, antibiotic courses and hospital admissions prior to referral to the adult clinic. Acquiring P. aeruginosa, but not H. influenza e or S. aureus, in the sputum prior to 16 yrs of age, was associated with a reduced probability of being a case.

Patients who had received oral antibiotics (as intermittent courses and/or long-term/prophylaxis), and had not received aerosolised or i.v. antibiotics, were significantly more likely to be cases than those who had not taken oral antibiotics. Conversely, the prior use of aerosolised or i.v. antibiotics was inversely associated with case status. Patients requiring annual or more frequent hospital admissions were significantly less likely to be cases.

This carefully matched case–control study is the first to report on the potential early influences of long-term survival in patients diagnosed with CF in childhood. Patients with a later diagnosis ( i.e. at 5–16 yrs of age), those whose CF did not present with respiratory disease and those with higher weight, height, BMI and lung function (% predicted) at the time of their first assessment at the adult clinic were statistically more likely to reach 40 yrs of age. Acquiring P. aeruginosa , but not H. influenza e or S. aureus , in the sputum prior to 16 yrs of age, was associated with a reduced probability of long-term survival. Factors that did not influence long-term survival included sex, parental occupation and major haemoptysis or the development of diabetes before 16 yrs of age. These findings suggest that the long-term survival of adults diagnosed with CF in childhood is determined predominantly by an intrinsically severe phenotype in early life, with little evidence of major modification by socioeconomic influences, and that maintaining good health in childhood is an important determinant of long-term survival.

We elected to study only patients whose disease had been diagnosed during childhood, and thus remove the bias associated with the good prognosis of disease when diagnosed in adulthood 10 , 11 . Moreover, by studying long-term survivors under the care of a single institution and by matching them with “controls” born within a year of their birth date, we reduced the effects of different adult treatment strategies between centres and changing strategies over time, each of which may have independent effects on survival 9 . We may, in this way, have “over-matched” patients, leaving insufficient heterogeneity of exposure to examine some important determinants of survival. For example, it is widely accepted that socioeconomic factors have a strong influence on prognosis 9 , 12 , 13 but our findings demonstrated only limited evidence of this. In contrast to a previous UK study in 1989, we found no correlation of parental occupation (an index of family socioeconomic status) with long-term survival 14 . The association of poor survival with referral from paediatric clinic B (situated in an area of relatively low socioeconomic status) may reflect differences in resources and provision of care, as well as patients’ sociodemographics.

However, the present study provides an important extra dimension to published studies on predictors of mortality. The earliest, observational, studies recognised the association of poor nutritional status and low FEV 1 with a worse outcome 15 – 17 . Since then, more robust epidemiological studies have confirmed this correlation, including a large population study of the Canadian Patient Data Registry 3 . More recently, an Irish study investigated factors relating to mortality in their adult patients, concluding that lower FEV 1 and BMI, and higher infection rates of P. aeruginosa and Burkholderia cepacia were associated with patients who had died 18 . They assessed differences in predetermined clinical parameters between patients who died during a 10-yr period and those who remained alive, therefore making it difficult to draw conclusions about the timing of the events ( i.e. when they were most influential). Our study adds to this by clearly showing the importance of these factors at an early stage.

The present study demonstrated a worse outcome in patients diagnosed with CF early (before 5 yrs of age) and also in those with an initial disease presentation of respiratory symptoms. This supports the findings of a US registry-based study, demonstrating variable survival among patients with inherently different degrees of baseline risk, reflected by their age at diagnosis and their degree of disease severity at presentation 19 . They also showed that meconium ileus was associated with reduced survival, which provides an explanation for the lack of correlation found in our study, as only a few patients presenting with meconium ileus survived to adulthood. Contrary to their findings, we found that sex did not predict survival, which, in part, might be explained by the historical higher mortality among CF females, particularly around puberty, taking its toll, thus leaving those who have a predetermined survival advantage to progress through to the adult clinic 20 . However, others have argued that the so-called “gender gap” does not exist, highlighting the complex interaction of this much-debated relationship 21 . Patients with an increased baseline risk are predisposed to developing worse lung disease and an accelerated decline in their general health. Consequently, they develop more complications and ultimately require more hospital admissions and i.v. antibiotic courses, as demonstrated by the strong correlation of these factors with control status in our study.

The negative impact on survival of P. aeruginosa infection is consistent with previous studies and, although there is still some controversy regarding causality and ascertainment bias, it should be regarded as a poor prognostic factor 22 , 23 . The insignificant impact of H. influenzae and S. aureus is consistent with other studies. A European cross-sectional study demonstrated that S. aureus was not associated with worse pulmonary status and others have shown a deleterious effect on symptoms only, including the risk of massive haemoptysis 24 – 26 . The finding of a survival benefit for patients receiving oral antibiotics (without aerosolised or i.v. antibiotics) is interesting, as oral flucloxicillin is usually given as long-term prophylactic anti-staphylococcal treatment, suggesting indirectly that S. aureus may be relevant to survival, although this association may also be an indicator of milder disease 27 .

We were unable to explore the impact on survival of specific CFTR mutations, as the majority of controls died before the discovery of the CF gene in 1989, making regression analysis impossible 28 . However, as 48% of the long-term survivors were homozygous for δF508 (compared with 50% in the total UK adult CF population 29 ), their survival advantage cannot be attributed to “milder” genotypes with less severe disease expression. We chose to use 17 yrs of age as our age criterion, as it has been demonstrated previously that this differentiates two distinct phenotypes of long-term survivors 11 . We acknowledge that we cannot be certain that all non-classic phenotypes have been excluded but combined with the genotype data and the fact that 97% of the total study population had pancreatic insufficiency, bias from genuine non-classic disease would have been minimal. Additionally, the use of a younger age of diagnosis would have further selected out “mild” cases; but with the recognition of significant disease heterogeneity even for homozygous δF508, reducing the age would have excluded patients with “classic” disease genotypes that follow a milder disease course ( e.g. due to gene modifiers), i.e. the group of patients of particular interest to this study.

There are several limitations to our findings. The incidence of complications such as CFRD and major haemoptysis increase with age 24 , thus numbers were small in both groups at the time of assessment in the adult clinic, limiting the likelihood of finding an effect on survival. We were unable to assess the impact of B. cepacia complex infection as the importance of this pathogen in CF became apparent only in the mid-1980s 30 . Asymptomatic patients, diagnosed at birth through neonatal screening, are also not included in this study, as such programmes have only recently been introduced. The study was further limited by the data available to us and, therefore, in some instances, proxy markers ( e.g. parental occupation) had to be used and patient numbers were small, making interpretation difficult. The information on socioeconomic status was therefore limited, as the broad category of “parental occupation” and the recognised limitations of “source of referral” do not allow for definitive conclusions to be made.

In summary, this study demonstrates the importance for long-term survival of achieving optimal growth and lung health by the time a patient attends an adult clinic. Effective clinical care is needed to facilitate this but, from our findings, we conclude that longevity is determined early, possibly by factors independent of CFTR function ( e.g. gene modifiers) that determine early phenotype, disease severity and, ultimately, the probability of long-term survival.

Statement of interest

None declared.

Received January 5, 2010.
Accepted March 27, 2010.
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↵ UK Cystic Fibrosis Database . Annual Data Report 2004. University of Dundee 2006 . www.cystic-fibrosis.org.uk/pdfs/annualreport/AuditReport2004.pdf Date last accessed: October 4, 2010. Date last updated: April, 2: 2010 .
Maclusky I ,
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The state-of-the-art of mycobacterium chimaera infections and the causal link with health settings: a systematic review.

1. Introduction

2. materials and methods, 4. discussion, 4.1. mycobacterium chimaera’s characteristics and ecosystem, 4.2. heater-cooler units, medical devices, water, and air-conditioned implants, 4.3. incubation period and symptoms presentation, 4.4. presence in the lung system, 4.5. modality of transmission, 4.6. detection, 4.7. disinfection, 4.8. causal link assessment, 5. limitations, 6. conclusions, supplementary materials, author contributions, institutional review board statement, informed consent statement, data availability statement, conflicts of interest, abbreviations.

MAC	mycobacterium avium complex
NTM	non-tuberculosis mycobacterium
M. chimaera	Mycobacterium chimaera
HCU	heater-cooler units
OPPP	opportunistic premise plumbing pathogens
ECMO	extra-corporal mechanical oxygenation
HAI	healthcare-associated infection

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Click here to enlarge figure

References	Author, Year	N. of Patients	Surgery	Mean Time of Presentation If Previous Surgery	Setting (Country)	Organ and/or Tissue Involved
[ ]	(Bills et al., 2009)	1	None	Na	Not healthcare (USA)	Lung, nodules in chronic obstructive pulmonary disease
[ ]	(Cohen-Bacrie et al., 2011)	1	None	Na	Possible frequent healthcare contact (Réunion Island, FR)	Lung infections in cystic fibrosis
[ ]	(Alhanna et al., 2012)	1	None	Na	Not healthcare (Germany)	Lung infection
[ ]	(Gunaydin et al., 2013)	5 (of 90)	None	Na	Possible healthcare contact (Turkey)	Lung (reassessment of sputum specimens)
[ ]	(Boyle et al., 2015)	125 (of 448)	None	Na	Possible healthcare contact (USA)	Lung (reassessment of sputum specimens)
[ ]	(Mwikuma et al., 2015)	1 (of 54)	None	Na	Not healthcare (Zambia)	Lung (reassessment of sputum specimens)
[ ]	(Moon et al., 2016)	11	None	Na	Not healthcare (South Korea)	Lung infection (reassessment of sputum specimens)
[ ]	(Moutsoglou et al., 2017)	1	None	Na	Not healthcare (USA)	Disseminated with spinal osteomyelitis and discitis
[ ]	(Bursle et al., 2017)	1	Tricuspid valve repair and mitral annuloplasty	13 months	Underwent surgery (Australia)	Disseminated
[ ]	Kim et al., 2017	8 (of 91)	None	Na	Possible healthcare contact (Korea)	Lung (reassessment of sputum specimens)
[ ]	(Chand et al., 2017) *	4	Valvular cardiac surgery	1.15 (0.25–5.1) years	Underwent surgery (UK)	1 osteomyelitis and 3 disseminated
[ ]	(Truden et al., 2018)	49 (of 102)	None	Na	Possible healthcare contact (Slovenia)	Lung (reassessment of sputum specimens)
[ ]	(Larcher et al., 2019)	4	None	Na	Possible frequent healthcare contact (France)	Lung (reassessment of sputum specimens in cystic fibrosis)
[ ]	(Shafizadeh et al., 2019) *	5	Valvular cardiac surgery	20.6 (14–29) months	Underwent surgery (USA)	Disseminated with liver infection
[ ]	(Rosero and Shams, 2019)	1	None but operating room nurse 10 years ago	>10 years	Possible frequent healthcare contact (USA)	Lung infection
[ ]	(Watanabe et al., 2020)	1	None	Na	Not healthcare (Japan)	Tendons, hand tenosynovitis
[ ]	(Chen et al., 2020)	28	None	Na	Not healthcare (Taiwan)	Lung infection (reassessment of sputum specimens)
[ ]	(Maalouly et al., 2020)	1	Kidney transplantation	One week	Underwent surgery (Belgium)	Kidney, urinary tract infection in a kidney transplant recipient with concomitant Mycobacterium malmoense lung infection and fibro anthracosis
[ ]	(de Melo Carvalho et al., 2020)	1	None	Na	Possible healthcare contact (Portugal)	Disseminated in B-cell lymphoma
[ ]	(Sharma et al., 2020)	2	None	Na	Not healthcare (India)	Meninges, meningitis
[ ]	(Zabost et al., 2021)	88 (of 200)	None	Na	Possible healthcare contact (Poland)	Lung infection (reassessment of sputum specimens)
[ ]	(Kim et al., 2021)	4 (of 320)	None	Na	Possible healthcare contact (Korea)	Lung infection (reassessment of sputum specimens)
[ ]	(Kavvalou et al., 2022)	1	None	Na	Possible healthcare contact (Germany)	Central venous catheter infection in cystic fibrosis
[ ]	(Robinson et al., 2022)	1	None	Na	Not healthcare (USA)	Lung infection in drug abuser
[ ]	(Ahmad et al., 2022)	1	None	Na	Not healthcare (USA)	Lung infection in sarcoidosis
[ ]	(George et al., 2022)	1	None	Na	Not healthcare (India)	Skin, periapical abscess with chin ulcer
[ ]	(Lin et al., 2022)	1	None	Na	Possible frequent healthcare contact (Taiwan)	Disseminated in adult-onset immunodeficiency syndrome
[ ]	(Łyżwa et al., 2022)	1	None	Na	Not healthcare (Poland)	Lung infection in silicosis
[ ]	(McLaughlin et al., 2022)	1	Coronary artery bypass grafting	1 year	Underwent surgery (USA)	Tendons, hand tenosynovitis in ipsilateral elbow wound in fisherman
[ ]	(Gross et al., 2023)	23	None	Na	Healthcare (USA)	Lung infections in cystic fibrosis (genomic analysis for cluster correlation to hospital outbreaks)
[ ]	(Azzarà et al., 2023)	1	None	Na	Possible healthcare contact (Italy)	Lung infection in lung adenocarcinoma treated with immune checkpoint inhibitors
[ ]	(Pradhan et al., 2023)	1	Bioprosthetic mitral valve replacement	7 years	Underwent surgery (Australia)	Spinal osteomyelitis and discitis
[ ]	(Garcia-Prieto et al., 2024)	1	None	Na	Not healthcare (Spain)	Lung infection in fibro anthracosis
[ ]	(Paul et al., 2024)	1	None	Na	Possible healthcare contact (UK)	Lung infection in unilateral pulmonary artery agenesis on the right side

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Bolcato, V.; Bassetti, M.; Basile, G.; Bianco Prevot, L.; Speziale, G.; Tremoli, E.; Maffessanti, F.; Tronconi, L.P. The State-of-the-Art of Mycobacterium chimaera Infections and the Causal Link with Health Settings: A Systematic Review. Healthcare 2024 , 12 , 1788. https://doi.org/10.3390/healthcare12171788

Bolcato V, Bassetti M, Basile G, Bianco Prevot L, Speziale G, Tremoli E, Maffessanti F, Tronconi LP. The State-of-the-Art of Mycobacterium chimaera Infections and the Causal Link with Health Settings: A Systematic Review. Healthcare . 2024; 12(17):1788. https://doi.org/10.3390/healthcare12171788

Bolcato, Vittorio, Matteo Bassetti, Giuseppe Basile, Luca Bianco Prevot, Giuseppe Speziale, Elena Tremoli, Francesco Maffessanti, and Livio Pietro Tronconi. 2024. "The State-of-the-Art of Mycobacterium chimaera Infections and the Causal Link with Health Settings: A Systematic Review" Healthcare 12, no. 17: 1788. https://doi.org/10.3390/healthcare12171788

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Maggie's Illness
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 ...
A longitudinal study assessing the impact of elexacaftor/tezacaftor
Gastrointestinal (GI) symptoms in cystic fibrosis (CF) are common [1,2] and negatively impact upon quality of life [2,3]. These symptoms persist even following the use of CFTR modulators [2]. The most common GI symptoms experienced by people with CF (pwCF) include flatulence, bloating, straining, abdominal pain, and fatty stools [1,2,4]. These symptoms may be severe and result in up to two ...
Transforming the lives of people with Cystic Fibrosis
Cystic Fibrosis is a progressive, life-limiting genetic disease that causes severe respiratory and digestive problems as well as other complications such as infections and diabetes. There are over 80,000 people living with Cystic Fibrosis globally, including 10,500 in the UK accounting for 9,500 hospital admissions and over 100,000 bed days per ...
CHAPTER 20: Case Study: Cystic Fibrosis
Cystic fibrosis (CF) is an autosomal recessive condition affecting approximately 30,000 Americans and 60,000 people worldwide. According to the Centers for Disease Control and Prevention (CDC), approximately 1,000 new cases are diagnosed yearly in the United States, with a known incidence of 1 per 3,900 live births.
Gene therapy for cystic fibrosis: new tools for precision medicine
Cystic fibrosis. Cystic fibrosis (CF) is the most common life-limiting fatal genetic disorder, affecting approximately 90,000 individuals worldwide [].It is an autosomal recessive disorder that requires mutations in the CF gene in both genetic alleles [].The CF gene encodes for a protein the cystic fibrosis transmembrance conductance regulator (CFTR) which is a protein chloride channel that ...
Case Study
Case Study - Cystic Fibrosis. Get a hint. What type of genetic disorder is CF and what is the pattern of inheritance? Click the card to flip 👆. autosomal recessive. single-point mutation. the common form is a missense mutation on the 508 position of the amino acid in the CFTR gene [cystic fibrosis transport regulator] Click the card to flip ...
Cystic fibrosis and survival to 40 years: a case-control study
The clinical course of patients with cystic fibrosis (CF) is variable and probably determined by many interacting factors. We aimed to examine the influence of early social and clinical factors on long-term survival. A case-control study of adult CF patients was used to compare long-term survivors (aged ≥40 yrs) with patients who died before reaching 30 yrs of age. Each case (n = 78) was ...
PDF Case 12. Cystic Fibrosis
In addition, many states have introduced newborn screening for CF, resulting in the detection of asymptomatic infants with CF. Case 12. Failure to Thrive: Workup Results in Diagnosis of Cystic Fibrosis. Mr. and Mrs. M, a white couple, have two children, a four-year-old son and a three-month-old daughter. The three-month-old has had considerable ...
PDF Cystic Fibrosis in a Case Report
Case Presentation. A 13 -year-old male teenager presented to our emergency department in May 2018. He complained of fainting once and had a mild cough for 3 days and low-grade fever (38.0C) prior to admission. He had history of frequent respiratory infections and no chronic diarrhea.
Gene Therapy
Gene Therapy Case Study: Cystic Fibrosis. Funding. Supported by a Science Education Partnership Award (SEPA) Grant No. R25RR023288 from the National Center for Research Resources. The contents provided here are solely the responsibility of the authors and do not necessarily represent the official views of NIH.
Case Report: Diagnosis of cystic fibrosis in a patient of Egyptian
Cystic fibrosis (CF) is the most common genetically inherited condition in European-derived populations. However, it is being increasingly recognised in other populations, including people of Asian, Black African and Caribbean descent. We present a case detailing the diagnosis of CF in a 12-year-old patient of Egyptian background who had been ...
The State-of-the-Art of Mycobacterium chimaera Infections and the
(1) Background. A definition of healthcare-associated infections is essential also for the attribution of the restorative burden to healthcare facilities in case of harm and for clinical risk management strategies. Regarding M. chimaera infections, there remains several issues on the ecosystem and pathogenesis. We aim to review the scientific evidence on M. chimaera beyond cardiac surgery, and ...