Keywords cystic fibrosis - diagnosis - late presentation - CFTR-related disorder - nasal potential
difference - sweat test
The diagnostic pathway for cystic fibrosis (CF) has evolved over decades as our understanding
of the underlying pathology of the disease has increased. Although there is some debate
regarding the first description of the condition, the largest case series to describe
it focused on autopsy specimens of children with pancreatic fibrosis giving rise to
the term “cystic fibrosis.”[1 ] In 1948, a key observation of increased salt losses in sweat during a New York heat
wave led to a further understanding of the condition and ultimately resulted in the
development of the first test for a CF diagnosis in 1959.[2 ]
[3 ] The sweat test measures chloride concentration in induced sweat and remains a cornerstone
of diagnosis to this day. Subsequent research led to the recognition of CF as a monogenic
disease, identifying variants in the cystic fibrosis transmembrane conductance regulator
(CFTR ) gene on the long arm of chromosome 7, as being responsible for the condition.[4 ] These breakthroughs resulted in the modern approach to diagnosis, facilitating a
complementary pathway of testing for CFTR protein dysfunction by way of the sweat
test and the identification of gene variants that may be responsible via genetic analysis.
The purpose of this review is to provide an up-to-date overview of the current diagnostic
pathway with a focus on later presentations of CF. Diagnosis in adulthood remains
an important topic to be considered across many areas of internal medicine.[5 ]
[6 ]
[7 ] With the advent of CF newborn screening (NBS) in many territories in the world,
there may be a belief that the diagnosis is easily delivered in a timely fashion.[8 ] However, several factors are important to note: (1) NBS is not available worldwide
and even in places where it is available false-negative tests are possible,[9 ] (2) many adults presenting later in life will have been born prior to the advent
of NBS programs in their respective countries, and (3) many of those presenting later
in life may have a modified clinical phenotype and degree of residual CFTR protein
function which may not be identified at NBS. Moreover, an accurate diagnosis is of
increasing importance as newer therapies directly targeting CFTR dysfunction are available,
which will be indicated for the majority of individuals with CF according to their
specific gene variants. These have had a transformative effect on clinical phenotype
for many.[10 ]
[11 ] This progress has been built on many successes of multidisciplinary CF care which
have led to progressive increases in survival over decades, emphasizing the importance
of an accurate and timely diagnosis.
Epidemiology of Late Diagnosis in Cystic Fibrosis
Epidemiology of Late Diagnosis in Cystic Fibrosis
The UK CF Registry provides an annual report on relevant clinical information on people
with CF (pwCF) including the number of new diagnoses per year. In their report on
2021 data, the median age at diagnosis was under 2 months (22 days for those diagnosed
at < 16 years) which has remained static since 2016, a reflection of the introduction
of a NBS program throughout the United Kingdom in 2007.[12 ] It is notable that consistently there are 30 to 50 new diagnoses per year which
were not diagnosed by NBS. A more striking figure is that 14.7% (926 individuals)
of adults in the CF registry were diagnosed on or after their 16th birthday, including
20 new diagnoses in that age group in 2021.
Clinical Phenotype of Individuals with a Late Diagnosis of Cystic Fibrosis
Clinical Phenotype of Individuals with a Late Diagnosis of Cystic Fibrosis
The identification of individuals with a possible diagnosis of CF requires that clinicians
not specialized in the area are aware of the possibility of a later presentation.
It is also necessary to be aware of the multisystem nature of CF disease. Although
often believed to be a respiratory disease with recurrent respiratory tract infections
and the development of (usually) upper-lobe predominant bronchiectasis, several other
presentations can be attributed to CF in adulthood, including infertility in males,
severe sinusitis, or pancreatitis. Many may not have been reviewed by respiratory
specialists and will present to other services.
The clinical presentation of patients with a late diagnosis of CF has been studied
for several decades including in the era prior to NBS. [Table 1 ] summarizes several case series describing the most common presenting features at
diagnosis. A 1995 Dutch study described a cohort of 25 patients attending a single
adult CF center who were diagnosed after their 16th birthday, comprising 20% of their
overall CF clinic attendees.[13 ] Clinical characteristics of these 25 individuals were compared with 118 individuals
with an earlier diagnosis. In the later diagnosis group, 92% presented with recurrent
respiratory tract infections. Gastrointestinal symptoms, male infertility, and esophageal
varices were the other reasons for presentation. In almost one quarter, the diagnosis
was made because of a sibling having CF. Lung function was relatively better preserved
in the later diagnosed cohort with a mean forced expiratory volume in 1 second (FEV1 ) of 72.5% predicted and these individuals had less than half the rate of annual lung
function decline than their earlier diagnosed peers. Infection with Pseudomonas aeruginosa was also less common at 24% compared with 70% in the early diagnosed group. Typical
extrapulmonary manifestations of CF such as pancreatic insufficiency (12%) and diabetes
(8%) were relatively uncommon in the later diagnosed cohort. A more contemporary study
from the United States reported similar findings but highlighted that late diagnosis
(with an age range from 24 to 72.8 years) defined an important subgroup of pwCF, characterized
by better lung function, more pancreatic sufficiency, and, interestingly, more nontuberculous
mycobacteria.[6 ]
Table 1
Presenting features of CF in patients diagnosed in adulthood from published studies
and registry reports (the United Kingdom Cystic Fibrosis Registry Report 2021[12 ])
Gan et al[13 ]
Widerman et al[14 ]
Farley et al[15 ]
Padoan et al[16 ]
The United Kingdom CF Registry
Country
The Netherlands
The United States
The United Kingdom
Italy
United Kingdom
Year
1995
1996
2002–2020
2012–2018
1995–2020
Number of pwCF diagnosed in adulthood
25
786
38
204
926
Lower age at diagnosis (years)
16
18
19
18
16
Mean/Median age at diagnosis (years)
27.7
27
38
36.2
NR
FEV1 (% pred)
72.5%[a ]
59.45%[a ]
60.8%
90.8%
NR
Pseudomonas aeruginosa colonization (%)
24%
66.7%[a ]
37%
17%
NR
Pancreatic insufficiency (%)
12%
67.8%[a ]
[b ]
26%
12.2%
NR
Presenting symptoms
Recurrent or chronic respiratory tract symptoms
92%
81.6%
100%
NR (70% CF-like symptoms)
53.9%
Abnormal stool/GI presentation
8%
18.5%
21% pancreatitis
NR
5.6%
ENT—nasal polyps or sinusitis
NR
11.1%
32%
NR
7.1%
Male infertility
4%
NR
90% of males were infertile
45.9% of males
5.1%
Genetic testing (FHx or other reason)
NR
3.82%
NR
30%
23.8%
Abbreviations: % pred, percent predicted; CF, cystic fibrosis; ENT, ear–nose–throat;
FHx, family history; GI, gastrointestinal; NR, not reported; pwCF, people with cystic
fibrosis.
a Cross-sectional data and not at the time of presentation.
b Pancreatic enzyme use as surrogate for pancreatic insufficiency.
Widerman and colleagues also reported distinct differences between patients diagnosed
in adulthood and those with an earlier diagnosis by examining data from the 1996 U.S.
CF Patient Registry.[14 ] There were significant differences in the presenting symptoms suggesting diagnosis
with respiratory symptoms and nasal polyposis being significantly more common in the
later diagnosed group, and gastrointestinal symptoms such as malabsorption, malnutrition,
and bowel obstruction being significantly less common.
A single-center study from Oxford in the United Kingdom examined 38 patients who were
diagnosed in adulthood.[15 ] They also describe that by far the most common presenting feature was of recurrent
and chronic pulmonary symptoms, with bronchiectasis seen in 94% of those who had a
CT at baseline. Spirometry was more impaired in this cohort than has been previously
described, with a presenting FEV1 of 61% predicted. Mean body mass index was 22 kg/m2 , consistent with those of patients diagnosed later in life presenting without nutritional
depletion. Data from the Italian CF Registry have been published looking at clinical
characteristics of 204 patients diagnosed as adults from 2012 to 2018.[16 ] They similarly found that patients presented with better nutritional status with
only 4.1% of males and 9.4% of females being considered underweight, undoubtedly resulting
from a low prevalence of exocrine pancreatic insufficiency of 12.2% in comparison
to an estimate of approximately 85% in the overall CF population.
The aforementioned UK CF Registry report also provides information comparing those
at an older age of diagnosis to younger presentations who were not identified by NBS.[12 ] It is interesting to note that the main mode of presentation for older individuals
was persistent or acute respiratory infection (53.9%) with an additional 10% presenting
with bronchiectasis, highlighting again a key need to further investigate individuals
with chronic respiratory symptoms. Nasal polyposis was the presenting feature in 66
people representing 7.1% of the late-diagnosed cohort. Other systemic manifestations
of CF such as pancreatitis (1.6%) or fertility issues in men (5.1%) were less common,
although this may represent an underestimate as diagnosis secondary to genotype was
relatively high at 23.8%, but indication for genetic testing is not clear.
It is apparent therefore that adult-diagnosed patients may present with an altered
clinical phenotype in comparison to that seen in the overall CF population.[7 ] This modified clinical phenotype undoubtedly contributes to the later age at diagnosis.
It likely results from a high prevalence of genetic variants which confer some residual
protein activity making organs such as the pancreas, which are less sensitive to reductions
in CFTR protein activity, less affected early in the course of the disease. It is
important to note, however, that the majority of individuals from the studies outlined
earlier presented with chronic symptoms which would have seen them present to multiple
and diverse medical services. It directly follows therefore that there were likely
missed opportunities at achieving a more timely diagnosis. Greater efforts are required
among the CF medical community to disseminate this message and ensure that colleagues
in pulmonology and across other medical specialties are mindful of CF as a differential
diagnosis across a range of multisystem presentations. Work to improve this knowledge
and inform the wider medical community is underway by the European CF Society Diagnostic
Network Working Group and its CFTR-related disorders (CFTR-RDs) committee.[17 ]
Does Late Diagnosis Matter?
Does Late Diagnosis Matter?
Accurate diagnosis is crucial to ensure pwCF are given access to the correct treatment
and support which CF care centers can provide. An analysis of the adult-diagnosed
CF population in the Canadian CF Registry revealed that a more timely diagnosis may
also have a prognostic impact.[18 ] Older age at diagnosis was an independent risk factor for death or transplantation
in a multivariate model. Moreover, a large study using data from the U.S. CF Foundation
Patient Registry showed significant improvements in health parameters when adults
diagnosed with CF older than 40 years received CF-specific healthcare interventions.[19 ]
Diagnostic certainty for individuals can be greatly helpful as many will have suffered
symptoms for long periods before a definitive diagnosis has been made, as suggested
by the high rates of chronic respiratory symptoms at diagnosis. CF care models are
based on multidisciplinary care teams with expertise in different aspects of CF care.
A diagnosis of CF provides individuals with access to this expertise and support from
medical, nursing, and psychological services, which can be profoundly helpful at these
times.
A formal diagnosis of CF can also enable better access to therapies. More treatments
and in particular nebulized antibiotics are licensed for the treatment of CF-related
bronchiectasis than non-CF bronchiectasis.[20 ]
[21 ]
[22 ] The recent development of CFTR modulator therapies has increased the importance
of a correct diagnosis.[10 ]
[11 ] Through three generations of compounds, CFTR modulators are now indicated for more
than 90% of pwCF. Clinical trial results suggest that in many they can have transformative
effects in terms of pulmonary function, risk of infection, and quality of life. This
appears to be the case even for those with a milder phenotype with clinical trials
suggesting significant benefit with dual CFTR modulator therapy for those individuals
heterozygote for the most common variant Phe508del and a variant associated with residual function (commonly termed “residual function
variants”).[23 ] More recently, the combination of three therapies, elexacaftor, tezacaftor, and
ivacaftor (ELX/TEZ/IVA), has confirmed additional benefit over and above dual therapy.[24 ] CFTR modulator use has also been shown to reduce admissions with acute pancreatitis
for pwCF, suggesting a possible further benefit for patients diagnosed later in life,
although the evidence for this is still conflicted, as some patients may also have
a worsening of symptoms.[25 ]
[26 ]
[27 ]
Current Diagnostic Pathways
Current Diagnostic Pathways
The diagnosis of CF can be firmly established when a reliable biomarker of CFTR protein
activity shows aberrant protein function and is associated with compatible gene variants
situated in trans in each of the individual's CFTR alleles. With greater elucidation of the functional consequences of individual CFTR gene variants, there is a greater appreciation that although for most the diagnosis
is clear and can be established at an earlier age, for others it can be more challenging.[28 ] The CF community has made great efforts to characterize individual genetic variants
and thereby determine the potential disease liability afforded to each.[29 ] Currently, there are more than 2,000 reported CFTR variants, some of which are classified as not CF disease causing, as CFTR function
is not diminished enough to cause CF. CFTR protein dysfunction exists on a continuum
and for some with variants which alter protein activity, the reduction in activity
may not be sufficient to lead to multiorgan dysfunction; for others whose variants
confer no residual protein activity, the consequences lead to the systemic consequences
of a “full” CF diagnosis. A further complexity occurs when a variant of varying clinical
consequence (VCC) is identified. In this situation, reduction in protein function
can be variable and disease liability will be affected by penetrance and expressivity,
in addition to the functional consequences of the gene variant carried on the second
allele. The current CF diagnostic guidelines were revised in 2017 and embrace some
of these nuances.[30 ]
These guidelines provide a robust diagnostic algorithm for the diagnosis of CF (see
[Fig. 1 ]). The algorithm begins with a statement that an individual has to have a clinical
presentation of the disease and evidence of CFTR dysfunction. Clinical presentation
of the disease is defined as signs/symptoms, a positive NBS, or a family history.
The first level of CFTR protein testing is the sweat test indicating how well this
test has stood the test of time with levels of ≥60 mmol/L consistent with a diagnosis
of CF, 30 to 59 mmol/L being designated borderline and <30 mmol/L deemed normal, whereby
a CF diagnosis is unlikely (although in rare cases it is still possible as some variants
are associated with borderline or even normal sweat chloride values).[31 ] Further strata of testing are then suggested with CFTR genetic analysis and then
additional functional CFTR testing using nasal potential difference (NPD) or intestinal
current measurements (ICMs) to reach a more conclusive diagnosis, if indicated.
Fig. 1 Current diagnostic algorithm for cystic fibrosis (CF). CFTR, cystic fibrosis transmembrane
conductance regulator; ICM, intestinal current measurement; NBS, newborn screening;
NPD, nasal potential difference. (Reprinted from Farrell et al,[30 ] with permission from Elsevier.)
This approach remains the standard of care for diagnosing adults with CF. The subtleties
of diagnosis are alluded to at the end of the algorithm, with the final outcomes categorized
as CF diagnosis, CF unlikely, and finally CF diagnosis not resolved. In some cases,
individuals under investigation will be determined to fit better into the diagnostic
category of CFTR-RD, a diagnosis more common in adults than in children. The term
CF screen positive inconclusive diagnosis (CFSPID) is exclusively used for asymptomatic
babies who have a positive NBS but in whom the diagnosis of CF is not confirmed; so,
it is not relevant to adult diagnosis. CFTR-RDs are clinical conditions associated
with CFTR dysfunction but do not meet the full diagnostic criteria for CF.[32 ] Classical examples of these presentations include congenital bilateral absence of
the vas deferens (CBAVD), recurrent acute or chronic pancreatitis, and diffuse bronchiectasis.
While these are still the most common presentations of CFTR-RD, recent updated published
guidelines highlight that a more diverse clinical spectrum is feasible, including
the possibility of polyorgan (and symptomatic) involvement.[17 ] Accurate separation between CFTR-RD and CF can be particularly challenging and should
be conducted in specialist centers, as the diagnosis of CF may carry with it important
psychological and financial consequences potentially influencing an individual's ability
to secure life insurance or indeed a mortgage.
Diagnostic Tools in Cystic Fibrosis
Diagnostic Tools in Cystic Fibrosis
Sweat Test
The sweat test is the oldest and most widely applied and available test of CFTR protein
function. The sweat test relies on the role of CFTR protein in reabsorbing chloride
ions from sweat into the cells of the sweat duct. Dysfunction of CFTR protein leads
to elevated levels of chloride in sweat with agreed threshold values as outlined earlier.
It is recommended that sweat testing is performed on more than one occasion to achieve
two measurements before a diagnosis can be confirmed in the correct context. Borderline
sweat chloride values can also lead to a diagnosis of CF in the right clinical context
if accompanied by two variants in the CFTR gene known to be CF causing. As outlined earlier, as certain CFTR variants associated with disease can be associated with normal or borderline sweat
chloride values (such as D1152H and 3849 + 10 kb C > T),[31 ]
[33 ] it is advisable to pursue further testing and not resolve a diagnostic quandary
based on sweat chloride values alone.
Genetic Testing
The next step in the diagnostic pathway involves genetic testing to identify variants
within the CFTR gene which may lead to a disruption or loss of function of the CFTR protein. Genetic
testing for variants in CFTR is usually a multilevel process with the initial screen using a polymerase chain
reaction (PCR) analysis to identify the most common pathogenic variants identified
in a specific population. As variant frequency varies according to geographical region,
it is essential that the ethnicity of the person being tested is known to permit targeted
variant analysis for the most relevant variants for them. In the United Kingdom, the
most common panels cover 36 to 50 variants for initial testing, which is approximately
90 to 95% of alleles in British Caucasians.
Further testing, however, may be required in isolated cases and this may be more common
in those with a later diagnosis. It is a relatively common misconception that a negative
initial screen by itself is sufficient to rule out a diagnosis of CF. In the context
of adult diagnosis, for patients presenting to secondary respiratory services or other
medical specialties, the sole use of an initial PCR test can lead to false reassurance,
particularly due to the limited availability of specific functional CFTR testing,
including sweat chloride, outside of a pediatric setting. In the correct clinical
context, functional CFTR testing should always be performed and if clinical suspicion
is high, a more thorough evaluation of the CFTR gene is indicated. Usually, this includes exon sequencing and multiple ligation probe
amplification to look for large deletions and duplications in the 27 coding exons
of the CFTR gene. However, whole gene sequencing may be more appropriate in select cases, as
demonstrated by a recent publication by Morris-Rosendahl and colleagues from a large
adult center in the United Kingdom, as they identified a disease-causing deep intronic
variant by next-generation sequencing, which would not be identified by the aforementioned
methods.[34 ] In cases of diagnostic uncertainty, the surveillance of noncoding regions of the
CFTR gene may be necessary to facilitate an accurate diagnosis.
Interpretation of Genetic Variants
Interpretation of Genetic Variants
The detection of rarer variants is accompanied by distinct challenges of its own.
Little may be known or published regarding the functional consequences of individual
variants and accurate genotype–phenotype correlations may be challenging. The online
resource CFTR2.org provides invaluable assistance in this context by examining the
disease liability of variants in CFTR .[35 ] By utilizing clinical, laboratory, and epidemiological data provided by CF registries
worldwide they have adjudicated on the likely pathogenicity of more than 480 variants.
At the time of writing this article, 82.7% of these variants have been determined
to be CF-causing, 4.9% thought to be non–CF-causing, 10.1% are variants of VCC, and
2.3% are of unknown significance. In individuals with two variants identified, utilization
of this resource can be invaluable in determining accurate disease classification.
Providing a diagnosis of CF is clear in those with two known CF-causing variants and
a compatible clinical phenotype. As CF is biallelic, the disease-causing propensity
of each individual variant an individual harbors has to be evaluated. In those with
milder phenotypes, interpretation of results remains a challenge in some instances.
In the vast majority of cases, individuals with two variants of VCC, residual function
of the mutated CFTR protein is unlikely to lead to the multisystem consequences of
classic CF. This is not universal; so, clinical phenotype and functional CFTR testing
are essential for accurate diagnosis. Similarly, in those harboring one CF-causing
variant and a second variant of VCC, a combined approach is necessary.
Genetics of Patients with an Adult Diagnosis of Cystic Fibrosis
Genetics of Patients with an Adult Diagnosis of Cystic Fibrosis
The specific genotype of those with a late diagnosis will vary according to geographical
location. In Western countries where homozygosity for Phe508del is the most common genotype among CF patients diagnosed at any age (47.7% population
of the United Kingdom),[12 ] it is markedly less common (proportionately) in later diagnosed patients due to
the severity of this genotype and likely early clinical manifestations. Later diagnosed
patients are more likely to harbor residual function variants, including variants
of VCC, in combination with a CF-causing variant. An Italian study looking at the
characteristics of 204 adult-diagnosed patients in the period 2012 to 2018 revealed
Phe508del to be the most common genetic variant, but only 3 (1.5%) of the patients were homozygous.[16 ] In 35% of cases, the genotype combination was CF-causing/CF-causing, but slightly
more common was the genotype CF-causing/variant of VCC (36%). In almost 18% of causes,
the pathogenicity of the second allele was unknown. These data again highlight the
difficulty in diagnosing some adults and the need for additional testing in many cases.
The ability of individuals to benefit from variant-specific treatment such as CFTR
modulators is a key consideration given the benefits reported in clinical trials.
Farley and colleagues described that 84% of their 38 adult-diagnosed patients would
qualify for CFTR modulator therapy under a European license with the figure increasing
to 89% if U.S. licensing was used.[15 ] Most published case series represent data from Europe or North America where the
majority of adult-diagnosed patients are heterozygous for Phe508del , which is the licensed indication for the combination therapy ELX/TEZ/IVA. This may
not be the case in other jurisdictions where Phe508del is a less common variant.
Other Tests of Cystic Fibrosis Transmembrane Conductance Regulator Function
Other Tests of Cystic Fibrosis Transmembrane Conductance Regulator Function
As highlighted earlier, in select cases, the diagnosis of an adult with CF can be
challenging. Initial sweat testing may be in the borderline (or even low) range and
the disease-causing potential of identified variants may be unknown or variable. Therefore,
if the diagnosis remains unresolved, further evaluation of CFTR function should be
undertaken. As outlined earlier, the two principal tests with clinical utility in
this context are NPD and ICM.
Nasal Potential Difference
The role of NPD in assessing a CF diagnosis has been elevated over recent iterations
of diagnostic guidelines.[30 ] In cases where there continues to be ambiguity, further electrophysiological measurements
are recommended. Testing of NPD and ICM is the best evidenced next step. A full review
of NPD is beyond the scope of this article and it is covered in depth in other review
articles.[36 ]
[37 ] Briefly, NPD assesses CFTR and the epithelial sodium channel (ENaC) function by
measuring the change in voltage across the nasal epithelium in the presence of solutions
that will modify ion channel activity. This is done by measuring the potential difference
between the subcutaneous compartment and the nasal epithelium (under the inferior
turbinate where epithelium becomes ciliated pseudocolumnar epithelium). As CFTR is
an ion channel, its function can be assessed by the sequential perfusion of solutions
that inhibit ENaC (amiloride) and induce CFTR activity (chloride-free solution and
isoprenaline) giving rise to characteristic traces separating CF patients from healthy
controls ([Fig. 2 ]). Due to the technical nature of the procedure, the need for precise conditions,
and the relatively low proportion of patients requiring the test, it is recommended
that these procedures are conducted only in expert centers, with a critical mass of
expertise and throughput. In the correct setting, NPD measurements have been shown
to be reproducible and effective in discriminating between CF and non-CF.[38 ]
[39 ]
[40 ]
[41 ] Furthermore, NPD measurements may provide useful information on patients who are
at higher risk of CF complications and potentially select individuals who may need
more intensive follow-up.[42 ]
[43 ]
Fig. 2 (A ) An abnormal nasal potential difference tracing from a patient with the Phe508del/Asp1152His genotype. Although basal sodium secretion is normal, there is an absence of chloride
secretion. The abnormal NPD trace is contrasted with a healthy control (B ), showing a normal basal reading and excellent chloride secretion; well above the
diagnostic threshold of ≥5 mV). NPD, nasal potential difference.
Intestinal Current Measurements
ICM is an ex vivo method of examining CFTR protein function on rectal biopsies from
patients suspected as having CF. Freshly obtained rectal biopsies are tested in a
Ussing chamber for electrical responses to a series of secretagogues. By examining
differential responses determined by the level of CFTR protein function, discrimination
can be made between healthy controls, CFTR-RDs, and CF. ICM shares many of the challenges
of NPD measurements (such as specialist equipment and highly skilled operators) but
requires the additional step of obtaining rectal biopsies from patients. This procedure
is conducted in a limited number of CF centers worldwide and availability of testing
can represent a challenge in certain jurisdictions. Evidence to date suggests that
it is at least as effective as NPD in accurately diagnosing patients and has the added
advantage of not being affected by epithelial inflammation, which can reduce the accuracy
of NPD, particularly when severe nasal polys and/or rhinitis is present.[44 ]
[45 ]
[46 ]
Other diagnostic tools are under development, including the β-adrenergic sweat stimulation
test and, more recently, the use of patient-derived rectal organoids.[47 ]
[48 ] Organoids are three-dimensional structures derived from stem cells commonly generated
from an intestinal tissue sample. Work has been performed assessing the response of
rectal organoids to CFTR modulator drugs and an ongoing EU-funded project is examining
their utility as individual responsiveness biomarkers to assess novel medications
aimed at improving CFTR function.[49 ] However, more recently, their diagnostic capabilities have been investigated; in
a recent publication by the Belgian Organoid Project, morphology analysis of rectal
organoids was performed to investigate the potential utility of this technology as
a diagnostic tool.[50 ] By examining the presence or absence of a central lumen and the roundness of the
organoid structures, this analysis was able to discriminate between patients with
CF (including those with milder phenotypes) and healthy controls. This technology,
however, is early in development and further validation will be required before it
can be introduced into clinical practice.
The Diagnosis: Where Are Individuals with a Potential Diagnosis of Cystic Fibrosis
Identified?
The Diagnosis: Where Are Individuals with a Potential Diagnosis of Cystic Fibrosis
Identified?
There are many sources of adult referrals to CF centers for the purpose of further
diagnostic assessment. Male subjects may be referred as a result of infertility investigations
which have identified azoospermia and CBAVD. However, one of the most common sources
of referral is still via the respiratory specialist as recurrent respiratory tract
infection and the identification of bronchiectasis should be potential triggers for
further investigation. Ear, nose, and throat specialists may be alerted to the possibility
of a diagnosis of CF due to the degree of nasal polyposis present. Other presentations
yielding further investigation include recurrent pancreatitis and some individuals
will present due to known or a recently discovered family history. In rare situations,
dermatologists may consider the diagnosis as aquagenic wrinkling of the hands is a
known rare association of CFTR gene variants.[51 ]
Illustrative Case
A 63-year-old white female presented with a history of bronchiectasis since early
adulthood. Test results at that time were “inconclusive” for CF; so, she stayed in
a general respiratory service. Her airways became chronically infected with P. aeruginosa and her FEV1 deteriorated to 38% predicted; so, she was referred for further CF investigations.
She was found to have a normal/borderline sweat (chloride) test of 24 and 30 mmol/L.
Genetic analysis identified Phe508del and Asp1152His , the latter being a variant of VCC. She underwent NPD measurements ([Fig. 2 ])—despite showing a normal basal (sodium) value, there was no chloride secretion,
thus confirming the diagnosis of CF. Confirming CF brought significant improvements
to her health with CF multidisciplinary team input and access to effective CF therapies
such as dornase alfa and inhaled antibiotics. Importantly, the CFTR modulator ELX/TEZ/IVA
is indicated for this genotype.
Key Factors that May Suggest Cystic Fibrosis as a Possible Diagnosis
Key Factors that May Suggest Cystic Fibrosis as a Possible Diagnosis
As CF is a multisystem disease, the recognition of a combination of symptoms, signs,
or past illnesses is crucial to alerting the treating clinician. A history of recurrent
or chronic pancreatitis or recurrent respiratory symptoms, or in males a history of
infertility, should initiate the consideration of a systemic problem. Adult diagnosis
of CF can result from a failure to identify these patterns earlier in life and thus
can lead to excess patient morbidity, frustration, and a lack of faith in medical
professionals.
Pasteur and colleagues published a case series of 150 patients with bronchiectasis
who were further investigated in a large center in the United Kingdom.[52 ] A total of 142 of the referrals were from respiratory physicians, 4 from a lung
transplantation unit, and 4 from family doctors. In 11 of these subjects, using a
limited genetic panel covering only 86% of local mutant CFTR alleles, at least one CFTR variant was found. Although the authors state that CF
was ultimately diagnosed in only 4 patients, 8 of the 9 patients who had sweat testing
performed had a sweat chloride level of ≥60 mmol/L consistent with a CF diagnosis.
It is notable that these investigations were not pursued prior to tertiary referral
even among pulmonary specialists, highlighting that awareness of a late presentation
is a significant issue. The development of more effective treatments since this publication
clearly highlights that failure of diagnosis may lead to unnecessary morbidity.
Key features that should alert pulmonary physicians to the possibility of CF are recurrent
infections without an underlying cause. Patients may have been mislabeled as asthmatics
for many years prior to diagnosis and a thorough assessment for those with recurrent
infections is indicated. The isolation of certain pathogens may also alert the treating
physician.[53 ] Certain pathogens such as Staphylococcus aureus and P. aeruginosa are commonly seen in other respiratory conditions. However, the identification of
other pathogens such as Stenotrophomonas maltophilia and Achromobacter species, in addition to atypical species such as Pandoraea , Ralstonia , Serratia , and Burkholderia , would be considered unusual and merit further exploration in the correct clinical
context. Similarly, the identification of predominantly upper lobe bronchiectasis,
allergic bronchopulmonary aspergillosis (in the absence of asthma), hemoptysis, and
clubbing may provide clues that a systemic pathology is the underlying cause.
Communicating the Diagnosis
Communicating the Diagnosis
Making a diagnosis of CF is a significant life event for each patient. Many have had
a long history of symptoms which have not been fully addressed; so, an accurate diagnosis
may come as a relief initially as they envisage a clear treatment pathway. The diagnosis
can also be unexpected and result from potentially minimally symptomatic disease.
In a growing age of medical information being widely available on the internet, the
diagnosis of CF can be worrying for them as most sources will describe it as a life-limiting
or lethal condition. In spite of best advice, most people newly diagnosed will carry
out their own additional research. Although accurate prognostication can be very challenging,
it is likely that their disease trajectory will differ from that reported for the
majority of CF patients, with better survival[54 ]
[55 ]; so, these nuances should be carefully explained to them.
The diagnosis of a genetic condition can lead to significant worry about the patient's
own family and offspring. The realization that they now are diagnosed with an incurable
chronic condition can be exceptionally harrowing and confusing. Adjustment to living
with a lifelong condition that may lead to premature death takes time and the support
of the CF medical and nursing teams is crucial. Many benefit from the input of CF
psychology services during this period of adjustment. The diagnosis may also have
financial implications with many employers unaware of precautions that may need to
be taken to accommodate pwCF and the need for recurrent hospital appointments. Patients
may find it difficult to secure life insurance or mortgages which adds additional
burden. Sensitivity and empathy from the CF care team can be crucial in helping newly
diagnosed patients adjust to a changing future.
Cystic Fibrosis Transmembrane Conductance Regulator–Related Disorders and Unresolved
Cases
Cystic Fibrosis Transmembrane Conductance Regulator–Related Disorders and Unresolved
Cases
After thorough evaluation, the diagnosis of CFTR-RD—not CF—may be more appropriate
for some individuals. Patients with this diagnosis should be followed up longitudinally
to manage their symptoms appropriately and to monitor for the development of more
CFTR-related complications in the future as their diagnostic label could change to
a more formal diagnosis of CF. Long-term management and follow-up is discussed in
recent published guidelines, but essentially CF center (or centers with a specialist
interest in CF/CFTR-RD) follow-up is advised, but usually on a less intensive basis
than CF standards of care.[17 ]
When no evidence of CFTR dysfunction or CFTR-associated disease is identified, the
individual can be discharged back to their referring team. In a minority of cases,
the situation may remain unresolved; there may be suspicion of another channel defect
(e.g., ENaC),[56 ] but the evidence remains unclear. Follow-up in this situation will depend on the
level of disease and at the discretion of the clinician and patient.
Ongoing Challenges for Adults Diagnosed with Cystic Fibrosis
Ongoing Challenges for Adults Diagnosed with Cystic Fibrosis
There are several ongoing challenges in this field. The greatest initial challenge
is increasing the awareness of the spectrum of CF and late diagnosis among the medical
community; experience in CF centers should be an essential requirement for all pulmonology
trainees. Increasing education across medical specialties is also necessary as presentations
may be subtle and easily missed, particularly if each pathology is considered in isolation.
The diagnostic entities of CF and CFTR-RD are not always easy to separate and are
somewhat fluid. There is also a gender discrepancy among CF/CFTR-RD as males have
the additional diagnostic entity of CBAVD. For example, should a female and a male
both present with chronic pancreatitis in their 30s with identical genetic variants
and physiological testing, the male would be considered to have more systemic disease
and likely diagnosed with CF, whereas the female may receive the diagnosis of CFTR-RD.
In equivocal cases, it can be a matter of interpretation whether one attributes symptoms
such as nasal polyposis, sinusitis, or a cough in the absence of bronchiectasis to
CFTR dysfunction and these subtleties may lead to inconsistent diagnoses between physicians.
For the identification of bronchiectasis, high-resolution CT thorax remains the gold
standard and is often utilized to rule out bronchiectasis. However, we know from infant
studies that inflammatory changes and ventilation abnormalities can occur in CF that
precede the development of bronchiectasis.[57 ] In adults, questions remain unanswered in this area: Should we consider the use
of more sensitive techniques, such as lung clearance index, to identify pulmonary
involvement in someone without bronchiectasis, when the diagnosis of CF or CFTR-RD
has been confirmed? The CF community has recently published guidelines to try to improve
this situation and increase consistency, producing updated recommendations on the
use of diagnostic biomarkers, diagnosis and management of CFTR-RD, to help clinical
teams and improve information for patients.[17 ]
[58 ]
Conclusion
Diagnosing CF in adults is not a rare occurrence for CF centers—delays in the diagnosis
have a meaningful impact on an individuals' well-being, something that will extend
further in the new era of CFTR modulation therapy. Patients diagnosed later in life
largely represent a cohort of individuals with variable clinical presentations, but
one that is progressive and requires long-term care in a CF center. Improving the
awareness of this issue is essential to ensure a prompt and accurate diagnosis, so
that outcomes for all people affected can be optimized for the long term.
