Introduction:
The year 2019 brought a sense of hope and excitement to the Cystic
Fibrosis (CF) community with the approval of elexacaftor, tezacaftor,
ivacaftor (ETI) by the Food and Drug Administration (FDA) for patients
with at least one copy of F508del. The excitement was interrupted by the
world-wide challenge of the COVID-19 pandemic. For the CF community the
rules of masking and 6-feet apart were not novel or unusual, however,
the strain of the pandemic was still felt within our CF community.
Clinics shifted to telehealth, the North American CF Conference gathered
virtually, and usual care for research conduct was challenged. Despite
these difficulties, many papers were published throughout the year,
continuing to accelerate CF research.
CF is a multisystem disease which impacts multiple organ systems. This
review will cover research articles and case reports that were published
during the last year pertaining to diagnosis, mental health,
endocrinology, palliative care, epidemiology, delivery of clinical care,
women’s health, and more. It was humbling to review the great work that
has been done during this extraordinary year.
DIAGNOSIS
Diagnosis of CF is based on a positive newborn screen (NBS), family
history or clinical signs/symptoms and evidence of CF transmembrane
regulatory conductance (CFTR) dysfunction through abnormal sweat
chloride test or two disease causing mutations1.
Despite these guidelines, there are often complexities in diagnosis
where research published this year has allowed for some additional
clarity.
One less anticipated area of concern relates to the identification of
carriers for CF due to NBS. Farrell et al.2 conducted
interviews, following a structured script, of 288 parents of infants who
were found to be carriers for CF, to determine the communication and
understanding related to the NBS result. Miscommunication was observed,
as 2.4% of parents had no recollection of being informed of the NBS
results, 13% of those who recalled an explanation characterized it as
negative, and 7.8% felt their child may still get the disease.
Although overall anxiety levels were low at the time of the interview,
parents recalled higher anxiety at the time of reported NBS results. At
the time of the interviews, more than half (56.1%) were planning a
future pregnancy, with 84% planning on testing for themselves and
74.3% for their partner. Using the same parents, Farrell et
al.3 also measured parental perceptions of child
vulnerability, using the Vulnerable Baby Scale. Parental perceptions of
their child’s vulnerability were worse than expected compared to parents
screened at a well-baby visit in an urban/suburban clinic. The results
of these studies emphasize the need for continued understanding of the
adverse effects of NBS identification of carrier status and how to
mitigate these effects.
Interestingly, more information about the clinical effects for CF
carriers has also been reported. Colak
et al.4 genotyped over 100,000 Danish individuals from
the Copenhagen General Population Study for the F508del mutation. These
patients also completed a questionnaire and underwent an examination
(including pulmonary function test). In the 2,858 carriers, compared to
the general population, there was a 1.3-fold increased risk of chronic
bronchitis, a 1.9-fold risk of bronchiectasis, and a 1.5-fold risk of
lung cancer. No differences in mortality, airflow limitation or other
pulmonary, gastrointestinal, or reproductive complications were seen. In
a separate study from claims data, using a retrospective population
based matched cohort method, Miller et al.5 also
sought to determine if CF carriers are at risk for a range of CF-related
conditions. Each of the 19,802 CF carriers were matched with 5
controls. A higher prevalence of all 59 CF-related conditions examined
were identified in CF carriers compared to controls. Risk for certain
CF-related conditions was significantly increased in carriers including
pancreatitis, male infertility, and bronchiectasis. The authors
concluded that despite the individual risk being low, population level
morbidity related to carrier status is still high, therefore
identification of carrier status can lead to prevention, diagnosis and
treatment for these patients. In an editorial referencing the Colak and
Miller research, Martin and Burgel6 discussed an
evolving dogma that for a CF carrier there may be modifiable risk
factors such as smoke exposure, infections that can improve health.
Additionally, they indicate that possible CFTR modulator use for non-CF
pulmonary disease may show clinical benefit. Therefore, it may no longer
be appropriate to counsel carriers of a CF mutation (parents or infants
identified via NSB) that they are at no risk of disease and that there
is no potential treatment.
In infants who were diagnosed with CF via NBS, Schluter et
al.7 evaluated improvements in clinical outcomes and
the impact of NBS on reducing social inequities. Using the United
Kingdom CF registry, from 2000 to 2015, outcomes prior to and after NBS
implementation in 2007 showed improvements in weight, lung function and
chronic Pseudomonas aeruginosa in those diagnosed by NBS. Despite
these improvements, using the Index of Multiple Deprivation based on
postal code, no impact on social inequalities was seen in their
population, as the children who lived in the most deprived areas
continued to have worse nutritional and lung function status, despite
diagnosis via NBS.
Another diagnostic conundrum for clinicians is sweat chloride testing in
infants, as there can be difficulties obtaining enough sweat based on
current testing modality. Durc and
colleagues8 assessed the performance of a newly
developed skin wipe test (SWT) for diagnosis of CF, designed to be
simpler, noninvasive, less expensive, not reliant on pilocarpine
iontophoresis, and more likely to obtain results in very young patients
compared to traditional macroduct testing. The test analyzes multiple
ions collected on spontaneously generated sweat,obtained by a cotton
swab moistened with deionized water. Simultaneously collected SWT and
macroduct tests were compared in 114 patients with CF, 76 CF carriers,
and 58 controls. The authors explored several ion ratios. Sensitivity
was found to be 93.9% for chloride to potassium ratio and 99.1% for
chloride plus sodium to potassium ratio compared to 98.3% for macroduct
analysis. This preliminary data is of interest as a potential diagnostic
testing in resource limited countries.
The timing of the sweat test is also crucial to ensure the early
benefits of NBS and ensure adequate diagnosis. Unfortunately, inability
to obtain a sufficient quantity of sweat, leading to a quantity not
sufficient (QNS), can delay diagnosis. McColley and
colleagues9 used the CF Foundation Patient Registry
(CFFPR), from 2010-2018, to examine sweat testing. They compared 3
different spans of time (2010-2012, 2013-2015, and 2016-2018) to
evaluate impact of NBS on first attempt to sweat testing, finding the
median age for obtaining a sweat decreased from 32 days of age in
2010-2012 to 29 days in 2016-2018. Sadly, however, 23.8% of infants
still did not have a sweat test by 60 days of age. Younger age led to
higher QNS rates: a decrease in QNS rate was seen with every increasing
10-day increment of age, whereby at 0 to <10 days of life the
QNS rate was 16.4% while at 50 to 60 days of life it was 4.1%.
Additionally, preterm infants (<37-weeks gestation) were more
likely to have higher rates of QNS compared to term infants (19.5%
versus 6.6%, p<0.001). Despite the risk factors for QNS tests
in young infants and preterm infants, McColley and colleagues showed
that sweat testing is successful 83.6% of the time in infants as young
as 0 to <10 days of age. Therefore, this important diagnostic
test should not be delayed in infants with a positive NBS test for CF
for fear of a QNS result.
The final complexity in the diagnosis of CF explored in this year’s
published research relates to the many unanswered questions related to
CF-related metabolic syndrome (CRMS)/CF screen positive inconclusive
diagnosis (CFSPID). What is the progression to CF in this population?
How often and when should additional sweat testing be completed? How
long should they be followed in a specialized CF center? Munck et
al.10 sought to characterize the phenotypic expression
of children with CRMS/CFSPID and define the presence of disease and
prognosis. In a prospective, longitudinal multicenter study from
2002-2015, 63 patients with CRMS/CFSPID were matched to 63 patients with
CF. The patients were followed clinically through age 6-7 years. They
found that the CRMS/CFSPID cohort, overall, had lower immunoreactive
trypsinogen, sweat chloride values, delayed visits, less symptoms and
better nutritional status. When seen in follow-up at age 6-7 years, they
had fewer overall CF-related morbidities and lower chest radiograph
scores, higher pulmonary function test and improved nutrition leading to
reduced treatment burden, reduced hospitalizations and lessPseudomonas and MRSA identification. Progression to a diagnosis
of CF occurred in 44% (28/63) due to an elevation in sweat chloride
(16/28) or identification of a second mutation (20/28) or both (n=8).
Based on this data, the authors highlight the recommendation
that monitoring of CRMS/CFSPID infants should continue in a CF center
until the age of at least 6 years, at which time if no progression to CF
by genetics, sweat or clinical findings, discharge from care with
vigilance by primary physician could occur.
There is ambiguity in the diagnosis and care plan for children
identified through newborn screening who have less common mutations or
variations. In a letter to the editor, Rock11 argues
that patients do not “convert”, but were born with CF, and
additional diagnostic information should be obtained (such as more
comprehensive genetic analysis or expansion of the CF-causing mutation
list). He urges the CF community to come together to develop new
guidelines regarding the progression from CRMS/CFSPID to CF.
Exploring this further, Terlizzi et al.12 examined the
role of repeated sweat chloride testing in patients with mutations of
varying clinical consequences (MVCC) (with diagnosis of CF, CRMS/CFSPID
or CFTR related disorder). In an evaluation of 39 patients with MVCC,
after 4 years with sweat testing done every 6 months, 54.5% (18/33)
progressed to a diagnosis of CF, with 14 due to an elevation in sweat
chloride. Specifically, in the 18 CRMS/CFSPID patients, 14 (42.4%) had
sweat tests that became elevated after a mean follow up time of 3.1
years. The authors highlighted the need to continue to monitor sweat
chloride in the presence of one CF causing mutation located in trans
with an MVCC as there is risk of progression to CF diagnosis by
elevation of sweat chloride.
The research on CRMS/CFSPID that has emerged this year emphasizes the
challenge of this uncertain diagnosis. What seems to be clear from all
of the researchers, is that CRMS/CFSPID patients need to be monitored
for the development of morbidities associated with this diagnosis.
Further study of this patient population of CRMS/CFSPID is warranted to
better understand the pathophysiology and potential progression to CF.
Only then will we be able to have evidence-based guidelines on how to
monitor and manage patients with this CRMS/CFSPID.
MENTAL HEALTH
There is no physical health without mental health and wellness. Early
recognition of mental health concerns has been a priority of the US CF
Foundation (CFF) over the last several years. Establishing routine
screening is the first step in ensuring adequate mental health services
are provided to all persons with CF (PwCF) and their caregivers. Several
publications from this year describe the experience of mental health
screening (MHS) as it becomes more universally applied throughout CF
care centers worldwide. There were also publications examining the
impact of mental health on executive functioning and alcohol use. In
addition, several studies explored mechanisms to improve wellness
through the use of electronic applications on reducing social isolation,
building resilience, and even providing mental health services on a
virtual platform.
Mental health screening (MHS) is an important aspect of CF care. In
recent years, adoption of guidelines13 to integrate
MHS into CF care has significantly increased. Caregivers at Seattle
Children’s Hospital used quality improvement methods to improve their
MHS in eligible adolescent patients14. Their social
worker(s) performed a preclinical review of eligible patients,
administered screening on an electronic tablet and reviewed results with
the patient and family. This identification process led to 90% of
eligible patients receiving a MHS within the first year of
implementation of the MHS guidelines, creating a process that has been
successfully sustained in subsequent years. Quittner et
al.15 evaluated 84 programs across the United States
who received CFF grant funding to support the role of a mental health
coordinator (MHC). Using an internet-based survey (88% response rate),
41% of MHC were new to the team, with most being social workers
(54.1%) or psychologists (41.9%). MHS occurred in over 5000 PwCF and
over 1000 caregivers in the first year of implementation of MHC grant.
Collectively, these two articles highlight the possibility of
incorporating MHS into a busy, specialized clinic. MHS was facilitated
by universal uptake of screening tools, improved awareness and
detection, reduced stigma and positive feedback from patients and
families. Overall barriers were similar across both
studies14,15, including limited resources (such as
staff, time, space and logistics). One additional challenge highlighted
by Quittner et al.15, was screening for caregivers, as
parents are not the “identified patient”. This has brought up ethical
concerns about a CF center’s responsibility for documentation of
abnormal MHS in caregivers and oversight of appropriate referrals,
limiting caregiver screening in many pediatric CF centers.
Another area related to mental health is executive function (EF). EF can
be defined as a set of skills that allow for successful engagement in
goal-oriented behavior. Borschuk et al.16 had 19
children (6-18 years of age) with CF and their caregivers complete
several different questionnaires including the Barkley Deficits in
Executive Functioning scale, CF Questionnaire–Revised (CFQ-R), and
Treatment Adherence Rating Scale. Overall, children with CF did not have
a higher level of EF impairment compared to the general population.
However, a strong association was observed between poor family
communication/cohesion and worse EF in the children with CF. Outpatient
records revealed that those children with CF who had worse
EF demonstrated higher treatment burden, worse lung function, and poorer
adherence.
A risk factor for mood disorders is excessive alcohol use (EAU), which
is an unhealthy pattern of drinking including chronic heavy use and
binge drinking. Heavy alcohol use is defined as 8 or more drinks per
week (14 in men) and binge drinking is defined as 5 or more drinks on a
day or 4 drinks in a 2-hour period (5 in males). Lowery and
colleagues17 sought to understand alcohol use in
adults with CF. In an anonymous survey, 952 PwCF (>18
years), 77% of respondents use alcohol currently. Compared to the
general population, rates of heavy drinking (24% versus 6%) and binge
drinking (49% versus 25%) were higher in PwCF. Self-reported clinical
findings revealed that despite comorbidities, such as advanced lung
disease, transplant, CFLD, CFRD, and increased number of
hospitalizations, EAU still occurred. PwCF who were more likely to
develop EAU were younger, started drinking at a younger age, male, had a
high school or lower education, and were not married. The authors
conclude with a call to action to teams to increase awareness, use of
screening tools and interventions to work toward reduction in alcohol
consumption in this at-risk population.
Promotion of resilience is one mechanism to enhance well-being.
Toprak and colleagues18 sought to test the
acceptability and feasibility of the program, Promoting Resilience in
Stress Management (PRISM). PRISM is a skills-based intervention
targeting stress management, goal setting, cognitive reframing, and
meaning making, which is completed over 4 sessions. In 10 patients
(12-21 years of age) admitted to the hospital, PRISM was employed as a
means to mitigate the negative effects of hospitalization.
Resilience, distress and disease specific CFQ-R scores did not change
after PRISM intervention; however, it was found to be both feasible and
acceptable. Participants felt there would be increased benefit in a
younger CF population. This insight by the participants is poignant as
Amerio et al.19 highlights, in a letter to the editor,
an assertation that more attention needs to be paid to risk factors for
developing anxiety and depression. Use of PRISM at a younger age may
allow for primary prevention of mental health disorders and improvement
in the development of resilience that can positively impact medical
outcomes later in life.
PwCF are not alone in their need for enhanced well-being. Hente et
al.20 describes 24 CF health professionals who
completed 6 training sessions incorporating mindfulness, cognitive
therapy, and experiential exercises for processing feelings related to
stress and burnout. Significant improvements were seen for empathy,
perceived stress, depersonalization, anxiety, perspective taking,
resilience, and negative affect one month post training, compared to
baseline. Although improvements were seen for depressive symptoms,
fatigue, emotional exhaustion and positive affect, none were
statistically significant. Sleep was the only parameter with no
improvement. At 15 months follow up, positive effects were sustained
for empathy, perspective taking and depressive symptoms and 35% of
participants reported continued use of mindfulness skills. The authors a
call to health system management to encourage, incentivize, and have
available for these types of training as part of routine
responsibilities.
3.0 ENDOCRINE
3.1 Cystic Fibrosis Related Diabetes
The diagnosis of CF Related Diabetes (CFRD) is challenging for PwCF and
caregivers. As clinicians it is important to understand the epidemiology
of CFRD, mechanisms to screen, diagnose and upcoming novel treatment
options. The prevalence and risk factors for CFRD have changed over
years due in part to overall advances in care. In order to understand a
more recent cohort, the European CF Patient Registry was examined
between 2008 and 201521. The overall prevalence of
CFRD (defined as daily insulin use) was 9.7% in those 10-19 year of
age, 24.1% in 20-29 years, and 32.7% in PwCF 30 years. Females were
found to have a higher
prevalence at all ages under 30 years (11.6% females versus 8.1% males
for 10–19 year old; 27.8 versus 21.2% for 20–29 year old, p
< 0.0001). CFRD was more likely in those with severe CF
mutations (defined as both mutations being class I-III) (OR = 3.11, 95%
CI: 2.77–3.48), PI (OR = 1.46, 95% CI: 1.39–1.53), lung function FEV1
percent predicted <40% (OR = 1.82, 95% CI: 1.70–1.94), BMI
z-score of ≤ -2 (OR = 1.24, 95% CI: 1.15–1.34) and higher rate of
chronic infection with Pseudomonas aeruginosa , Burkholderia
cepacia or Stenotrophomonas maltophilia.
In a pilot study of 11 children with CF <10 years of age
(median age at study entry of 3.8 (±2.5) years), Prentice et
al.22 used continuous glucose monitoring (CGM) over 3
days, with repeated CGM after 12 and 24 months. Normal glucose at all
time points was only seen in 27% (n=3). Impaired glucose levels
(defined as ≥104 mg/dL/7.8mmol/L for >4.5% of the time)
were seen in 73% (n=8) compared to 2% in children without CF. Of those
8 patients, 5 had impaired values at more than one test and two had
impaired glucose at all time points. Peak glucoses (≥200mg/dL/11.1
mmol/L) were seen in 64% (n=7) at any time point, while this is not
reported in children without CF. The authors conclude this variation
could be based on alteration in dietary intake during CGM monitoring,
evolving exacerbation, or variable insulin resistance. The study
provides further support that glucose abnormalities begin early in life
for patients with CF and suggests that CGM may be the appropriate test
to detect glucose abnormalities in this age. In an editorial,
Chan23 emphasized the challenge of screening and the
need to consider other methods, acknowledging that CGM has limitations
and is not ready to replace or even compliment OGTT yet.
Another outcome of screening for CFRD, can be the appearance of
post-prandial or OGTT-related hypoglycemia. While the mechanism remains
unclear, it is speculated to be related to derangement in glucose
homeostasis involving both insulin and glucagon24,25.
Kilberg et al.24 used a mixed meal tolerance test
(MMTT) in 34 nondiabetic adolescents and young adults with pancreatic
insufficiency, finding 26% (9/34) with hypoglycemia. Those with
hypoglycemia, had a higher peak glucose (215 ± 21 versus 168 ±33 mg/dL,
p<0.01) and had a later peak phase of insulin, defined by peak
after 60 minutes, (89% versus 48%, p=0.03). The authors concluded that
a delayed but overly robust insulin secretion led to hypoglycemia.
Further study of hypoglycemia was done by Armaghanian et
al.25 using a 3-hour glucose tolerance test in 24
patients (7 normal glucose tolerance, 12 abnormal glucose tolerance and
5 CFRD). None of the patients with CFRD had hypoglycemia, while 79%
(15/19) of the remaining subjects showed hypoglycemia at the 3-hour time
point, with 5 being symptomatic (sweaty, clammy hands and dizzy).
Similar to the study by Kilberg et al.24, those with
hypoglycemia had a higher peak glucose and delayed and higher insulin
release25. Incretins, hormones produced by the
intestines that signal insulin secretion after eating, were not
different between groups, and there was no change in the counter
regulatory glucagon response. Together the two articles help to better
outline the potential mechanisms for post prandial/post OGTT
hypoglycemia.
Beyond accurate diagnosis, partnership with an endocrinologist can be
helpful as treatment modalities broaden. A small study by Sherwood et
al.26 looked at use of a bionic pancreas (BP) in
management of CFRD. A bionic pancreas can have two different mechanisms,
a bihormonal BP (BHBP) providing both insulin and glucagon or an insulin
only BP (IOBP). In a three-arm crossover pilot study of BHBP, IOBP and
usual care, with one week study periods, 3 females with CFRD were
assessed. CGM monitoring revealed nominally lower glucose levels with BP
(BHBP 139 ± 15 mg/dL, IOBP 149 ± 10 mg/dL versus usual care at 159 ± 35
mg/dL). Other measures of glucose control were also improved/shown to be
equivalent to usual care. BP is an interesting new technology that
deserves additional exploration for CFRD.
3.2 Bone Disease
Multiple factors can contribute to low bone mineral density (BMD) in
patients with CF. A prospective, single center study evaluated 40
patients (>age 7 years) with CF to help determine clinical
factors likely to contribute to BMD27. Osteopenia was
seen in 37.5% (15/40) and 27.5% (11/40) had osteoporosis, with no
differences seen between PS or PI patients. BMD did however correlate
with FVC, FEV1, lean arm mass, fat free mass, hand grip strength,
modified Shwachman‐Kulczycki (SK) score (composite of general activity,
physical findings, and nutritional status) and quality of life. The SK
score was found to be the highest predictor of BMD. The authors conclude
that use of the SK score, which can be easily obtained, may help with
early identification of patients in need of further evaluation.
4.0 PALLIATIVE CARE
While life expectancy has improved in CF over the last several decades,
CF continues to plague patients with significant morbidity and
mortality, making palliative care an essential aspect of the services
provided to PwCF and their caregivers/families. Palliative care is a
comprehensive and holistic approach to care of patients and families
aimed at improving the quality of life and reducing the emotional toll
of illness. Traditionally palliative care is used at the end of life,
but more recently, utilized in the setting of major life and death
treatment decisions, such as transplant. A survey completed by 164 adult
patients at one center identified that 78% of participants reported at
least one unmet palliative care need28. Specifically,
one or more unmet needs were seen in the following domains: physical
such as symptom burden (72%), psychological needs such as anxiety
surrounding worsening disease (66%), health system and information
(41%), patient care and support (30%) and sexuality (20%). When
looking at specific needs, more than half of respondents indicated unmet
needs due to “lack of energy/tiredness” (65%), “feeling unwell a lot
of the time” (52%) and “fears about my CF getting worse” (50%).
While lower FEV1 values were found to correlate with increased treatment
and symptom burden, there was not a correlation seen between lower FEV1
and more unmet needs. The authors conclude that identification of this
large unmet need justifies the use of palliative care services and
underscores the importance of systematic screening using patient
reported outcomes versus clinical factors such as FEV1 since not
strongly associated with these unmet needs.
Trandel et al.29 also surveyed clinicians (n=350),
adults with CF (n=70) and CF caregivers (n=100) to understand
perceptions of palliative care. The majority of adults with CF (64%)
and caregivers (74%) were unaware if their center had palliative care
programs, while only 14% of adult and 23% of pediatric clinicians were
unaware. Clinicians perceived confidence in their ability to provide
both primary (basic symptom management and initial discussion of
prognosis and goals) and advanced palliative care skills (advanced
symptom management provided by fellowship trained palliative care
physicians). Patients and caregivers reported their CF clinicians as
“very good” in the basic assessment of pain and “good” at discussing
prognostic uncertainties, both important skills of primary palliative
care, but did not rate clinicians as highly regarding advanced
palliative care including specifically transplant, hospice care, and
end-of-life care. The results for this survey call to attention the need
for increased awareness and knowledge regarding palliative care. In
fact, as Waldman and Quinn30 note in their editorial,
there need to be opportunities for improving palliative care skills
among CF clinicians, and improving partnering and integration with
existing palliative care specialty services.
5.0 POPULATION
As part of the Lancet Respiratory Medicine Commission on the future of
cystic fibrosis care, Bell et al.31 beautifully
summarized the understanding of CF pathophysiology, diagnosis, care
model, and therapeutic advancements in their very thorough article,
“The future of CF: a global perspective”. While discussing the amazing
advancements that have been made over the last 6 decades, the article
also takes a real look at the changing epidemiology of CF disease within
non-European descents across the globe and challenges specific to
low-income and middle-income countries (LMIC). The Commission focused on
five key areas, 1) the changing epidemiology of CF, 2) future
challenges of clinical care and its delivery, 3) the building of CF care
globally, 4) novel therapeutics, and 5) patient engagement. The article
delves into each key area providing historical perspective, current
state of affairs, and a look into how to improve the future of CF care.
Bell’s article is a must read, especially for those new to the field of
CF, including medical students and residents.
Several publications from this year expanded on themes presented in
Bell’s executive summary, describing the experience with CF in specific
ethnic populations to create a better understanding of the
similarities/differences and struggles across the globe. Dogru et
al.32 described the data of the CF registry in Turkey
from 2017. As a LMIC, the authors conclude there are still gaps in
knowledge leading to low diagnosis, thus low inclusion in the registry
(only ~30% of the total Turkish CF population is
included). Significant advances were made when NBS started in 2015, such
that 81.9% of those under 3 years of age were diagnosed via NBS. Sweat
testing and genetic testing occurred in the majority, however, 19.7%
only had one mutation identified and 25.2% had no mutations identified.
Additionally, the heterogeneity of the population is reflected in the
most common mutation being F508del, however, only at an allelic
frequency of 28%. Based on the 2017 registry data, 8.8% of the
population was homozygous F508del and 12.9% were heterozygous. Clinical
care differs due to availability of resources, with dornase alpha and
pancreatic enzymes/vitamin supplements being commonly used (86.7%) but
very low percentages of patients using other medications/therapies and
no access to modulators. Outcomes were poor; as an example, FEV1pp was
82 ±28.7% between 15-19 years of age and all patients having Z scores
for weight, height and BMI less than zero. Mortality was at a young age
with median age at death of 13.5± 9.9 years. Complication rates varied
with only 20.9% having chronic Pseudomonas , although culture
frequency was not included. The most common complication reported was
Pseudo-Bartter syndrome (PBS) (acute exacerbation of hyponatremic,
hypochloremia dehydration with metabolic alkalosis without kidney
pathology) seen in 10.2% despite recommendations for routine salt
supplementation. This snapshot of care in Turkey is enlightening to
provide perspectives regarding care in other countries.
Shi et al.33 provided insight into the demographics
and common clinical characteristics for PwCF in China. Of the 113
patients included, 78 were diagnosed within the last five years showing
an increase in knowledge and awareness amongst providers. The median age
of diagnosis was 8.7 years, with the majority (68%) diagnosed in the
first year of life (not including 5 diagnosed in the neonatal period).
Only 8% of infants were found to have meconium ileus (MI). Sweat tests
were only reported in 79 patients and genetic testing revealed the most
common mutation to be c.2909G>A (9.15%). Only one patient
in China has been reported to have a mutation in F508del. Outcomes
presented included normal FEV1pp in 13.3% however the authors do not
mention nutritional outcomes. Median age of death was not provided, but
20/113 patients died, between the ages of 3 months and 24 years of age.
Complications included pancreatic disease (defined by authors as
pancreatitis or PI) in 12.4% and 8.8% with PBS.
Both studies33,34 from Turkey and China report on the
complication of PBS, which was further characterized in two additional
studies. Shen et al.35 described 12 cases of PBS at
Beijing’s Children’s Hospital over the last 10 years. The median age of
PBS diagnoses was 4 ±1.7 months and subsequent diagnosis of CF occurred
at median age of 28.6 ±37.5 months. The patients had comorbidities at
time of PBS diagnosis that included recurrent or persistent pneumonias
(91.7%), pancreatitis (83.3%), vomiting/diarrhea (66.7%), liver
disease (58.3%) and severe failure to thrive (58.3%). In comparison,
the Turkish registry from 2017 was used to evaluate patients with CF
with or without PBS36. Those with PBS were younger,
more likely to have been diagnosed at an earlier age, but less likely
via NBS, and had lower second sweat chloride test values. Compared to
age and gender matched patients with CF, there were no differences found
in any parameters. Both authors conclude that PBS is a common
complication in warmer countries and reinforce the importance of
recognition of PBS as an early clue for
diagnosis35,36.
In an exploration of racial disparities in CF in South Africa, 34 black
patients with CF (defined as at least two sweat conductivity tests
>80mmol/L in the presence of phenotypic manifestation
compatible with CF) were compared to 34 Caucasian homozygous F508del
patients37. The most common mutation in the Black
African patients with CF was the 3120+1G>A and none had a
F508del mutation. The 3120+1G>A mutation had an allele
frequency of 81%, 23 (67.6%) were homozygous and 6 (17.6%) were
heterozygous. Median age at diagnosis was similar (5.0 (2.0-15.0) months
for cases, 6.0 (3.0-15.0) months for controls), as was percent with
pancreatic insufficiency (88.2% for cases, 85.3% for controls). Black
African children were found to be more malnourished at diagnosis and
less likely to be diagnosed with neonatal bowel obstruction (5.9%
versus 31.3%, p = 0.03). By three years of age, no differences were
seen in nutritional status between the two groups. No significant
differences were seen in regard to change in FEV1 over time (at 6, 10
and 14 years of age), age of first Pseudomonas infection, or
prevalence of Pseudomonas . Three Black patients died early (8.8%
compared to only one Caucasian patient [2.9%]). The authors
conclude that despite differences in presentation and genetics, there
were comparable outcomes regardless of race, and encourage a high index
of suspicion should be maintained for black African infants who present
with symptoms consistent with CF.
Fitzgerald et al.38 evaluated the effect on clinical
outcomes after establishment of NBS in Ireland comparing pre-NBS
(2008-2011) to post-NBS (2011-2016). Not surprisingly, NBS infants were
diagnosed earlier (0.69 months versus 10.22 months, p=0.001). Children
diagnosed by NBS were more likely to be on prophylactic antibiotics and
less likely to have other siblings with CF or a mother whose nationality
was Irish. Those diagnosed clinically had an odds ratio of 2.80 (95% CI
1.24-6.29) of hospitalization for pulmonary exacerbation in the first 3
years of life. Time from diagnosis to age of first acquisition ofPseudomonas was longer in the NBS cohort. Nutritional outcomes of
weight and length/height were better in the NBS cohort at ages 6 and 12
months. This study highlights the importance of NBS in improving
outcomes for patients through earlier diagnosis and treatment.
Greenland, as part of the Danish Kingdom, started NBS in 2016. The first
known case in an infant of Inuit (defined as being born in Greenland)
origin diagnosed via NBS was published (F508/c.3000_3014del, sweat
chloride 116 mmol/L, fecal elastase <15
mcg/g)39. Interestingly, the infant’s ancestry was
traced to Danish descent, which has one of the highest frequencies of
the classic F508del mutation with approximately 96% of patients with CF
having the mutation on at least one allele. The authors concluded that
although a population may not have genetic predisposition to a
particular disease, it can be introduced by ancestors, thus further
expanding the rationale for universal NBS.
Pasterkamp et al.40 used the Canadian CF Registry to
describe a population of 92 Hutterite Brethren, a communal group of
Anabaptists (which also included the Mennonites and Amish), who live in
Western Canada, to Canadian homozygous F508del controls. The Hutterites
have a high incidence of CF (1:467) and almost exclusively carry the
F508 and M1101K mutations (due to founder effect). The Hutterite group
had no difference in age at diagnosis compared to the Canadian
homozygous F508del patients. As the M1101K mutation is associated with
PS, diagnosis consisted of less gastrointestinal presentation and better
nutritional outcomes in the Hutterites. Lung function was lower in
Hutterite children, with no difference found later on in adulthood. The
only microbiological difference of statistical significance was the
Hutterites had an increased incidence of Staphylococcus aureus .
The Hutterites also had socio economic instability and minimal exposure
to SHSe due to communal practices of the population. Hutterites had a
lower median age of death (17.5 ± 11.5 versus 28.2 ± 10.8 years, p
<0.0001) compared to the Canadian homozygous F508del controls.
In Poland, Zybert et al.41 studied 13 infants with CF
born between September 2006 and May 2019 (11 diagnosed via NBS and 2
with symptoms and subsequent diagnosis), who had at least one allele
with a rare or mutation of unknown consequence. All infants had elevated
sweat chloride tests (>60 mmol/L) and at least 2 CFTR
mutations detected and compared clinical information for the infants to
partner with their genetics. The authors identified three novel
pathogenic mutations (A1217E, E33X, and dup16,17A). Given their
experience, they encouraged clinicians to ensure adequate attentive
follow up of any infants with rare/novel mutations in order to elucidate
the clinical effect.
6.0 PARTNERSHIPS IN CARE
In 2018 and 2019, the James Lind Alliance Priority Setting Partnership
in CF and the CF Foundation, respectively, queried the CF community
regarding research priorities, including burden of care for
CF42,43. A follow-up survey was developed by Davies et
al.44 to better understand the size and diversity of
the treatment burden in PwCF. A summary of the 941 responses (20% PwCF,
48% relatives/friends of PwCF, 32% health professionals) from 21
countries, described the most important and burdensome treatment areas.
There was confirmation of the high burden and concordance between lay
and professional perceptions. The top 5 most important treatments were
identified as pancreatic enzyme, airway clearance, CFTR modulators,
exercise and physical activity, and long-term nebulized antibiotics and
the top 2 burdensome treatments were identified as airway clearance and
long-term nebulized antibiotics. Themes related to simplifying treatment
burden were prioritized as research questions including the development
of interventions that engage both patients and caregivers in shared
decision-making and goal setting to continue to improve the quality of
life for PwCF.
The relationship between PwCF, caregivers and CF care teams allows for
productive shared decision-making, however, communication barriers can
lead to difficulties. Therefore, Cooley et al.45evaluated communication skills at 5 US CF Centers through observation of
clinical visits, 1:1 interview, and focus groups with CF team members,
PwCF, and caregivers. Four main themes emerged 1) eliciting psychosocial
concerns, 2) addressing childhood development and transition, 3)
negotiating agendas and sharing decision-making and 4) educating to
enhance CF conversations. All participants including PwCF, caregivers
and CF clinicians who participated in the study expressed the desire for
additional resources to facilitate improved conversations. Development
of advanced communications skills including open communication,
trust-building and active listening will allow all care team members,
PwCF, caregivers and CF clinicians to better partner in shared
decision-making and goal setting.
The ties between PwCF and their care teams often blur the lines of
primary care and specialty care. As adults with CF are living longer,
they are in need of routine health screening. Haywood et
al.46 evaluated 92 charts of adult CF patients, at the
University of North Carolina at Chapel Hill and found no identified
primary care provider in 59%. Routine preventive care was poorly
documented for non-CF priorities such as mammography (22%), cervical
cancer screening (12%), and sexually transmitted infection (STI)
screening (20%). In contrast, higher rates were seen for CF priorities
including colorectal cancer screening (48%), osteoporosis (66%),
diabetes (96%), and mental health issues (92%). The authors concluded
that pulmonologists should encourage adults with CF to seek appropriate
primary care. If the pulmonologist chooses to serve as the primary care
physician, then they must stay up to date on general preventive adult
care.
Douglas et al.47 evaluated the impact of participating
in AREST-CF (Australian Respiratory Early Surveillance Team for CF), a
longitudinal study (over two decades) looking at key drivers of lung
disease in early life. Specifically, the impact of additional intensive
early diagnostic testing embedded in clinical care on families in terms
of providing reassurance about their children’s health or creating
anxiety was studied. This study brings attention to the hidden cost of
doing research, adding to the stress that families with children with CF
experience in “monitoring” disease progression even when children are
seemingly doing well79. Several themes emerged: 1) a
degree of uncertainty regarding what to expect, which became easier with
time, 2) optimism (via control due to increased knowledge regarding
disease progression leading to a sense of power and gratitude), 3)
pessimism (through anticipation of disease progression and reduced life
expectancy) and 4) feelings of helplessness and lack of control (a
feeling of “studying for an exam”). The results of the intensive
additional testing led to disparate impact. If results were positive,
parents had increased confidence and self-esteem in their role as
caregiver, however negative results led to feelings of accountability
and self-blame. Similarly, emotional ambivalence was seen when
contrasting the best interest of the child with the risk and discomfort
involved. The authors concluded their research supports the inclusion of
psychosocial support when using sensitive measures of lung disease. The
same approach should be extrapolated to other studies of monitoring
progression of other challenging comorbidities of CF.
Oates et al.48 set out to understand how to partner
with caregivers and CF care teams to limit exposure of SHSe for children
with CF by using the PRECEDE model to identify predisposing, reinforcing
and enabling factors. Semi-structured interviews of 8 caregivers who
were current or former smokers and 9 clinical team members focused on
how to facilitate discussion between caregivers and clinicians focused
on smoking cessation, not limiting exposure. The authors concluded the
need for a multi-level intervention including professional cessation
counselor support, nonjudgmental support from CF team and support from
families partnered with nicotine replacement. The lack of CF specific
resources focusing on the specifics of how smoke impacts the lungs of
children with CF was identified. The authors concluded that the study
identified a need for a family-centered and health system interaction to
develop a program that includes family education emphasizing harms to
children with CF, screening for smoking with biochemical confirmation,
access to tobacco cessation counselors, access to free and low-cost
pharmacotherapy, and outpatient follow-up.
Medication access is a challenging and frustrating issue for PwCF,
caregivers and clinicians alike. Zobell et al.49studied the impact of adding both a specialty pharmacy (SP) technician
and a clinic-based pharmacy (CB) technician at Intermountain Primary
Children’s Hospital in Salt Lake City, Utah. The SP technician works
within the hospital special pharmacy on behalf of CF patients, while the
CB technician works in the CF clinic verifying medications, obtaining
insurance coverage and is an active part of the CF quality improvement
(QI) team. Addition of the SP technician led to faster delivery of
dornase alpha, decreasing from 8 days to 3 days (p<0.00001).
Addition of the CB technician reduced the need for multiple pharmacies,
increasing use of only one pharmacy from 8% to 38% (p=0.005) and
reducing use of three pharmacies from 25% to 2% (p=0.003). Both models
improved medication access for patients with CF and increased the
efficiency of CF care teams.
7.0 WOMEN’S HEALTH
With PwCF living healthier lives into adulthood, the topic of
reproduction and preimplantation genetic diagnosis becomes more
relevant. Based on the large variability in mutations for CF, many
couples can still be left with an increased risk for CF transmission
with current preimplantation genetic screening.
For women with CF who proceeded with pregnancy, the effect on pulmonary
status was evaluated by Reynaud et al.50 using the
French CF Registry between 2000-2012 in 36 women with FEV1≤50% and 113
women with FEV1> 50%. The women were followed over four
years, one year prior to pregnancy and two years after pregnancy. Not
unexpectedly, the women with lower FEV1 had lower BMI and more IV
antibiotics at baseline. Rates of medically assisted conception were
similar in both groups. Women with lower lung function more commonly had
cesarean sections (43.7% versus 21.2%, p=0.01). There was no
difference in the frequency of prematurity, however, those with lower
lung function were more likely to have infants with lower birth weights
(median 2705 grams [range 650-3700 grams] versus 3044 grams [range
1590-3860 grams], p=0.003). Maternal mean FEV1 change per year over
the time studied was -0.9% (95% CI -2.5 to 0.8) in the low lung
function women while the women with higher lung function decreased by
-2.3% (95% CI -3.3 to 0.6). No significant changes in BMI occurred.
The authors concluded that pre-pregnancy lung function did not influence
pulmonary or nutritional status of the mothers in the 2 years after
delivery.
8.0 EAR, NOSE, THROAT (ENT)
Ototoxicity is a concern for individuals who require repeated doses of
aminoglycosides for pulmonary infections. Vijayasingam et
al.51 compared the standard of sound booth audiometry
to a web-based hearing test, a tablet-based audiometry, and various
validated questionnaires (Hearing Handicap Inventory for Adults, Vertigo
Handicap Questionnaire, and Tinnitus Handicap Questionnaire). All
interventions were completed by each participant, in a multi-center,
cross sectional evaluation of 126 adult patients with CF. Similar to
other studies, increased age and more days of IV antibiotics increased
risk of abnormal audiometry. Specifically, for each year of age older, a
patient would have a 12.8% increased risk of abnormal sound booth
audiometry (OR 1.127, 95% CI 1.074 to 1.182, p<0.0001). After
adjustment for age, there was a 6.7% (OR 1.067, 95% CI 1.028 to 1.966)
increase in the probability of abnormal sound booth audiometry for each
14-day course of IV antibiotics. Vestibular toxicity (9.5%) and
tinnitus (7.1%) were also seen in this cohort. Tablet based screening
had high sensitivity, specificity, and negative predictive value, thus
the authors concluded that screening with tablet and questionnaires can
be easily done in clinic and if any abnormalities, refer for formal
audio booth screening.