Received: 7 November 2019 | Revised: 9 December 2019 | Accepted: 2 January 2020

DOI: 10.1111/apa.15155

REVIEW ARTICLE

Cystic fibrosis in the year 2020: A disease with a new face

Kris De Boeck

Pediatric Pulmonology, University Hospitals

of Leuven, University of Leuven, Leuven, Abstract
Belgium The autosomal recessive disease cystic fibrosis (CF) was once untreatable and deadly
Correspondence in childhood, but now most patients survive to adulthood. Many countries have insti-
Kris De Boeck, Department of Pediatrics, tuted CF newborn screening because early diagnosis improves outcome. CF research
Pediatric Pulmonology, University Hospitals
of Leuven, Herestraat 49, 3000 Leuven, has greatly intensified following the discovery of the CF transmembrane conduct-
Belgium. ance regulator (CFTR) gene, which has more than 2000 different mutations. For pa-
Email: Christiane.deboeck@uzleuven.be
tients with common mutations like F508del, CFTR modulators are life transforming
and may even prevent major complications if started early in childhood. For some
patients with rare CFTR mutations, a treatment path still needs to be developed.
Conclusion: This review provides a general update on CF, including screening and
current and future treatment.

KEYWORDS

cystic fibrosis, diagnosis, early screening, genetic mutations, survival rates

pathogens like Burkholderia cepacia, Achromobacter xylosoxidans,

1 | I NTRO D U C TI O N Stenotrophomonas maltophilia and mycobacteria. However, compli-
cations can occur in nearly every organ and increase with age, in-
Cystic fibrosis (CF) is the most common autosomal recessive disease cluding: liver disease, CF-related diabetes, nasal polyps, intestinal
in the Caucasian population, occurring in approximately 1/3500 obstructions, haemoptysis and allergic bronchopulmonary aspergil-
births.1 Most patients become symptomatic at birth or soon after losis and many more.4
birth and respiratory infections and poor weight gain are the most Since 1989, we have known that CF is caused by mutations in the
2,3
frequent presentation. This combination of recurrent respiratory cystic fibrosis transmembrane conductance regulator (CFTR) gene
infections and pancreatic insufficiency should prompt the diagno- that encodes the CFTR protein.5 This anion channel, which conducts
sis of CF. But prior to CF newborn screening, a diagnostic odyssey conducting chloride and bicarbonate at the apical membrane of dif-
usually preceded the eventual diagnosis with a sweat test. Indeed, ferent epithelia, regulates water and ion transport and maintains ep-
a sweat chloride concentration above 60 mmol/L is diagnostic for ithelial surface hydration.6 The bicarbonate release in the airway is
CF. Other classic disease manifestations are excessive salt loss via important for the proper unfolding of mucins7 and defending against
sweat and male infertility. Respiratory disease is the most severe bacteria.8 In the intestine, bicarbonate release is needed to buffer
manifestation and the most frequent cause of death or lung trans- gastric acidity and enable the activation of pancreatic enzymes.9
plant in early adult life. They also include chronic lung infections So far, over 2000 different CFTR mutations have been reported
with specific pathogens and excessive inflammation that leads to and F508del is by far the most common.10 In Europe, 82.4% of pa-
bronchiectasis, declining lung function and eventually respiratory tients have at least one F508del mutation, but the frequency of
insufficiency.3 Prevalent CF pathogens include Staphylococcus au- F508del is higher in Northern Europe than in Southern Europe, for
reus and Pseudomonas aeruginosa; later in the disease course, some example 83% in Denmark vs 40%-60% in Spain, Italy and Greece.
patients become infected with more unusual and difficult to treat All other mutations are only present in maximum a few per cent of

Abbreviations: CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance

European patients with CF. However, the frequency of a specific mu-
regulator; FEV1, forced expiratory volume in one second. tation may be up to 10%-15% in a specific region.4

Acta Paediatrica. 2020;109:893–899. wileyonlinelibrary.com/journal/apa© 2020 Foundation Acta Pædiatrica. | 893

Published by John Wiley & Sons Ltd
894 | DE BOECK

2 | FRO M A D I S E A S E I N C H I LD R E N TO A
D I S E A S E I N C H I LD R E N A N D A D U LT S Key notes

When CF was first described in 1935, it was a universally fatal dis- • Most patients with cystic fibrosis (CF) now survive to
ease in early childhood. Establishing CF registries that describe CF's adulthood, and many countries have instituted CF
natural history has been crucial in the fight against the disease. By newborn screening because early diagnosis improves
identifying major associations with outcome, progressively better outcome.
treatments have been established. Combining these with intensive • The discovery of the CF transmembrane conductance
follow-up has led to improved survival (Figure 1). regulator (CFTR) gene has transformed the lives of pa-
Early on, children died from malnutrition due to pancreatic insuf- tients with CF, by leading to treatment that may prevent
ficiency. That is why pancreatic enzyme supplementation to improve major complications if started early in childhood.
digestion and nutritional status was the first major step forward. Later • This review provides a general update on CF, including
on, the association between a high-fat diet and improved outcome led screening and current and future treatment.
to adopting this practice. Nutritional status still has a major impact on
outcome,11 and continuously striving for optimal nutritional status is
a major treatment goal in every individual patient. After malabsorp- as a parameter of the quality of care. Unfortunately, poorly resourced
tion was improved, it became clear that children died from chronic re- areas like Eastern European countries still have a low proportion of
spiratory infections, first with Staphylococcus aureus and later on also adults with CF. The number of adults with CF is anticipated to increase
with Pseudomonas aeruginosa. It took several decades to find ways to further and warrants development of more adult patient services.19
combat lung disease by clearing the airways using systemic and inhaled The discovery of the CFTR gene also uncovered that CF has a wide
antibiotics and drugs to counteract viscous secretions and excessive disease spectrum. Some patients have late onset of symptoms, or only
inflammation. But increasing treatment intensity12 and centralising mono-symptomatic disease, such as bronchiectasis, liver disease or
and standardising patient follow-up13 improved outcomes further. We male infertility, but still have two CFTR mutations and at times only a
currently have consensus on most aspects of symptomatic CF treat- mildly raised sweat chloride value of between 30 and 60 mmol/L. This
ment,14 but registries continue to point out ongoing challenges. These means that the diagnosis of CF is increasingly made during adulthood.
include the disadvantages females have with regard to survival, possi- It is important to diagnose these subjects. Although they present later,
bly linked to hormonal status.15 Then, there is the faster lung function they can go on to develop respiratory insufficiency and symptomatic
decline during adolescence,16 the progressive loss of lung function at CF treatment greatly improves outcome.20,21
times of pulmonary exacerbations17 and the often asymptomatic in-
fections and inflammation that lead to bronchiectasis as early as during
the preschool years.18 3 | FRO M D I AG N OS I S V I A S Y M P TO M S TO
Intensive follow-up and treatment have allowed most children to CF NEWBORN SCREENING
survive until adulthood. In western European countries, adults with CF
now outnumber children4 and the proportion of adults with CF is used If CF goes undiagnosed and untreated in early life, severe bronchi-
ectasis can already be present at diagnosis. Despite symptoms like
chronic coughs, poor weight gain or complications due to malnutri-
tion, the median age at diagnosis ranges from a few months to several
years.4 Making the diagnosis after a few weeks of life is already too
late for optimal outcomes.22 In CF, prevention of lung disease progres-
sion and complications is key, but it still took many decades to prove
that CF was a disease that fitted the criteria for newborn screening.
We now know that the benefits of CF newborn screening outweigh
the harm and that CF newborn screening leads to better survival.23
Cystic fibrosis newborn screening started with measuring serum
immunoreactive trypsinogen in a dry blood spot. But this strategy
had a low positive predictive value, of around 10%, and patients
had to be recalled for a second test. Adding detection of the most
frequent CFTR mutations to the immunoreactive trypsinogen mea-
surement has improved the positive predictive value of CF newborn
screening, and this is now the preferred strategy in most countries. 24
A positive screening test must be followed by proving the diagnosis
F I G U R E 1 Over the six decades, symptomatic treatments
have greatly improved the survival of patients with cystic fibrosis. via a positive sweat test (sweat chloride >60 mmol/L) or the pres-
Reproduced with permission of the ERS© 2019. Elborn57 ence of two mutations that cause CF. 2
DE BOECK | 895

At present, nationwide CF newborn screening has been im- these regions to better understand the full impact of the CF. At pre-
plemented in nearly all European countries, in the United States, sent, our information is provided by CFTR2, 28 a database that reports
Canada, Australia and even in Russia, Turkey and Brazil. Some cases the occurrence of symptoms and CFTR function results for different
are missed by CF newborn screening. Algorithms should strive for a CFTR mutations and this is skewed towards the western population.
sensitivity above 95% and a positive predictive value above 30%. 25 There may, indeed, be differences in disease expression and diagnos-
The major side effect of CF newborn screening is detecting infants in tic test results in these other populations. This was proven by a study
whom the diagnosis CF cannot be made or excluded with certainty. of patients with CF of Asian descent that found that they were more
These children, designated as having a CF screen positive inconclu- likely to be pancreatic sufficient and have, on average, a lower sweat
sive diagnosis, are asymptomatic but follow-up is needed to detect chloride value, even if homozygous for F508del. 29
26
the minority who will develop CF symptoms, which is about 10%. Outcomes for patients with CF are also usually less favourable in
In regions with a long-standing history of CF newborn screening these poorly resourced areas. Increased awareness, the availability
linked to carrier detection, the incidence of CF is decreasing due to of diagnostic tools and allocating health resources to CF will hope-
cascade screening in relatives and preconception counselling. 27 fully reverse this situation.30

4 | FRO M A C AU C A S I A N D I S E A S E TO 5 | FRO M TR E ATI N G S Y M P TO M S TO

R E A LI S I N G TH AT C F O CCU R S WO R LDW I D E TR E ATI N G TH E U N D E R LY I N G D E FEC T

Older publications stressed the fact that CF was typical in Caucasian Cystic fibrosis transmembrane conductance regulator mutations are
populations. But increasing reports from South America, Africa, classified into groups according to how they decrease CFTR protein
Turkey, the Middle East and Asia prove that CF is not so uncommon in synthesis, function or stability (Figure 2). This has been instrumental
these regions. In regions with a high prevalence of tuberculosis, mal- in developing small molecule therapies to treat underlying defects.31
nutrition or the human immunodeficiency virus and high childhood Class I mutations lead to the near absence of the CFTR pro-
mortality, the diagnosis of CF is often not considered and children tein. They are mainly stop codon mutations and frameshift muta-
may die undiagnosed. We need information on the CFTR mutations tions leading to a premature termination codon. Class II mutations
in these regions and diagnostic tests should be adapted to suit the lead to defective processing and trafficking of the CFTR protein,
local population. We badly need reports and CF registry results from which is mostly degraded in the proteasome. The amount of CFTR

F I G U R E 2 Classes of CFTR mutations and their respective therapeutic strategies. CFTR mutations are grouped into seven functional
classes, with the expectation that the same type of modulator will be applicable to all the defects in one class. Class VII mutations are
not expected to be rescuable by a modulator. A therapeutic strategy for Class VII mutations could be stimulation of alternative chloride
channels, gene therapy, gene editing or the addition of messenger ribonucleic acid. rPhe508del = rescued Phe508del
896 | DE BOECK

protein at the apical membrane is severely reduced. Class III mu- in vivo CFTR function, decreased from a mean of 100 mmol/L to an
tations lead to CFTR protein at the cell membrane, but defective average of 50 mmol/L. Patients had less pulmonary exacerbations.
regulation of CFTR gating severely disturbs the channel opening. The improvement had a fast onset and was sustained for months or
Class IV mutations cause impaired conductance of the CFTR chan- years. In real life, this translated to better survival, a lower need for
nel, with fewer ions passing through the open channel pore. Class lung transplants and less complications.37 The lives of these patients
V mutations, often alternative splice mutations, lead to a reduced were really transformed. Another drug benefit is improved glucose
amount of normal CFTR protein. Class VI mutations lead to un- tolerance, as CFTR seems involved in insulin secretion. Unfortunately
stable CFTR protein that is prematurely recycled from the apical only around 3%-5% of patients have a class III mutation.38 In patients
membrane and degraded in lysosomes. Since the CFTR modulator with a class III mutation, ivacaftor has further been assessed in
era, a seventh class has been added that groups large deletions open-label trials down to the age of 12 months.39,40 The drug is gen-
and frameshift mutations that are not easily amenable to phar- erally well tolerated, although rises in liver function tests, which are
macotherapy. 31 Although helpful, the mutation classification is an usually reversible, are seen in up to 30% of patients.39,40 But more
oversimplification because most mutations cannot be strictly con- importantly, reversion of pancreatic insufficiency, as measured by
fined to one class. For example, the class II mutation F508del also stool elastase, is seen in 50% or more of toddlers.40 Therefore, there
32
has characteristics of classes III and VI. is hope that effective CFTR modulators, if started in good time, will
On average, patients with at least one mutation of class IV or transform the disease and prevent major complications. Ivacaftor
V have later onset of disease, lower sweat chloride values, slower provides a moderate benefit, namely an average 5% increase in FEV1
decline in lung function, less chronic Pseudomonas aeruginosa in- in adults with the class IV mutation R117H,41 and in subjects with
33,34
fections, less CF-related diabetes and lower treatment burden. selected residual function mutations, thus leading to treatment for
Together, these mutations are called residual function mutations, in another few percentages of the entire patient cohort.38
contrast to mutations that confer no, or hardly any, CFTR function, Ivacaftor plus lumacaftor or tezacaftor provides a modest but
which are jointly called minimal function mutations. sustained benefit, of a 3% to 4% improvement in FEV1, for patients
At present, three oral drugs have been approved by the European homozygous for F508del, which account for 45%-50% of all pa-
Medicines Agency to treat the underlying defect in CF: ivacaftor tients.42,43 Tezacaftor is better tolerated than lumacaftor and also
(Kalydeco), lumacaftor plus ivacaftor (Orkambi) and tezacaftor plus poses less problems with drug-drug interactions.
ivacaftor (Symdeko) (Table 1). These drugs are called CFTR modula- By adding a second corrector to the tezacaftor plus lumacaftor
tors (Figure 3). Ivacaftor, which is a potentiator, improves the CFTR combination, we come to triple therapy and this greatly improves
channel opening so that more ions flow through the pore. Tezacaftor the efficiency of CFTR rescue. Results from phase 2 trials showed
and lumacaftor, which are correctors, improve CFTR protein folding a further increase in lung function, namely a 10% improvement in
and trafficking so that more mature CFTR protein appears at the cell FEV1, when the second corrector elexacaftor, VX-445 or VX-651,
membrane. They are examples of mutation-specific therapies. was added to the tezacaftor-ivacaftor combination in homozy-
In randomised controlled trials, ivacaftor majorly improved lung gous F508del subjects.44,45 Even more importantly, the same tri-
function, with an average increase in forced expiratory volume ple drug combination also provided an average 14% increase in
(FEV1) of 10%, weight gain and improved quality of life in patients FEV1 in subjects who had one F508del mutation plus one of class
with a class III mutation.35,36 The sweat chloride value, a reflection of I or class II minimal function mutation. In both populations, the

TA B L E 1 CFTR modulators approval

CFTR modulator Mutations From age of
status by the European Medicines Agency
Kalydeco (ivacaftor) 9 class III mutations: 12 mo
G551D, G1244E, G1349D, G178R, G551S,
S1251N, S1255P, S549N and S549R
R117H 18 y
Orkambi F508del homozygous 2y
(lumacaftor + ivacaftor)
Symkevi, Symdeko F508del homozygous 12 y
(tezacaftor + ivacaftor) Patients heterozygous for F508del and one of the 12 y
following mutations:
P67L, R117C, L206W, R352Q, A455E, D579G,
711 + 3A>G, S945L, S977F, R1070W,
D1152H, 2789 + 5G>A, 3272 26A > G, OR
3849 + 10kbC>T

Sources: https​://www.ema.europa.eu/en/medic​ines/human/​EPAR/kalydeco, https​://www.ema.

europa.eu/en/medic​ines/human/​EPAR/orkambi, https​://www.ema.europa.eu/en/medic​ines/
human/​EPAR/symkevi.
DE BOECK | 897

FIGURE 3 Site and mechanism of action of different CFTR modulator drugs

quality of life estimated by a CF specific and validated score in- treatment, if access to the drug can be guaranteed. Given the enor-
44,45
creased dramatically. mous efficacy seen in trials, triple combination treatment is expected
Phase 3 trials on the triple combination of elexacaftor, tezacaftor to majorly change the lives of most patients with CF.
and ivacaftor were performed in patients from the age of 12 years Patients with very rare CFTR mutations pose a particular chal-
onwards and the results confirmed the phase 2 results. After lenge. Their number is too low for proper clinical trials. For these
24 weeks of treatment with the triple combination rather than the patients, the development of intestinal organoids has been a major
placebo, F508del/MF heterozygous patients showed improvements: step forward.48 This allows quantifying CFTR function and its res-
FEV1 increased by 14.3% predicted, the rate of pulmonary exacer- cue by CFTR modulators in vitro in patient-specific material via the
bations decreased by 63% and the Cystic Fibrosis Questionnaire- forskolin-induced swelling assay: more function equals more swell-
Revised scores improved by 20.2 points. Sweat chloride decreased ing. The validity of this method can be proven as the mean improve-
by 41.8 mmol/L.46 After F508del homozygous patients received ments in sweat chloride, and FEV1 reported by different clinical trials
four weeks of treatment with the triple combination rather than have correlated strongly with mean improvements in CFTR function.
tezacaftor plus ivacaftor, FEV1 increased by 10.0% predicted and the These were induced by the same CFTR modulators in organoids from
Questionnaire scores improved by 17.4 points. Sweat chloride de- patients carrying the trialled mutations.49 Testing CFTR function in
47
creased by 45.1 mmol/L. These improvements are very impressive. intestinal organoids can thus be used for personalised medicine:
Such increases in the Questionnaire scores had never been seen be- to select candidates for treatment with CFTR modulators. Several
fore. The fact that heterozygous subjects benefitted to the same ex- patients with rare mutations have obtained specific treatment and
tent as homozygous subjects was surprising. It may indicate that close derived major benefit from this method.
to full correction of the F508del allele had been achieved, as carriers There is one downside to CFTR modulator therapy. Currently,
do not have the disease, or that the maximal possible acute correction the cost of CFTR modulators is huge, at around 150 000 to 250 000
of CFTR function had been reached. The triple combination treatment Euro per patient per year. For that reason, although three drugs have
was tolerated with limited side effects, and no new safety concerns been approved by European Medicines Agency, drug reimbursement
were reported, except those known for the tezacaftor and ivacaftor lags behind in many countries. Even Kalydeco, which provides enor-
combination. In October 2019, the elexacaftor, ivacaftor, tezacaftor mous benefits to patients with a class III mutation are not funded by
(Trikafta) triple combination was approved by the American Food health systems in Portugal, most of Eastern European countries and
and Drug Administration for patients over 12 years who are homo- even New Zealand. As the benefit and cost ratio increases for the tri-
zygous for F508del or heterozygous for F508del and has a minimal ple combination, the cost discussion may become easier. In addition,
function mutation. European Medicine Agency approval is expected since several companies have CFTR modulators in the pipeline, drug
in 2020. Around 85%-90% of patients with CF could benefit from this cost is likely to decrease.
898 | DE BOECK

6 | TH E FU T U R E specific tissue opens up the pathway to personalised therapy. Other

mutation aspecific corrective therapies are in the longer term pipe-
A large number of alternative CFTR potentiators and correctors are line. Although the cost of medicine is a worry, the future has never
being developed by different pharmaceutical companies.50 In ad- looked better for patients with CF.
dition, CFTR modulators with different mechanisms of action have
entered the clinical pipeline. Read through drugs that overread pre- C O N FL I C T O F I N T E R E S T
mature stop codons are under development for subjects with a stop K De Boeck has received fees for consultancy and/or speakers fees
codon mutation. After the negative results for ataluren,51 which was from Ablynx, Boehringer, Chiesi, Eloxx, Galapagos/Abbvie, Gilead,
the first read through drug that was tested clinically in CF, there is Pharmaxis, PTC, Proteostasis ProQr, Vertex. She has been PI in stud-
now the novel compound ELX-02 that shows promise in preclinical ies from Ablynx, Boehringer Galapagos/Abbvie, Gilead, Pharmaxis,
assays.52 A CFTR amplifier is a CFTR modulator that is not mutation PTC, Proteostasis, ProQR Vertex.
or mutation class specific. By improving the docking of the messen-
ger ribonucleic acid to the translocon on the endoplasmic reticu- ORCID
lum, more efficient translation from the acid to the CFTR protein is Kris De Boeck https://orcid.org/0000-0002-2959-9964
achieved. More substrate is then available for correctors and poten-
tiators. The initial results of this combination of amplifier, namely REFERENCES
corrector plus potentiator, in subjects homozygous for F508del are 1. Mehta G, Macek M, Mehta A, European Registry Working Group.
encouraging. 53
CFTR stabilisers that aim to improve residence time Cystic fibrosis across Europe: EuroCareCF analysis of demographic
data from 35 countries. J Cyst Fibros. 2010;9:S5-21.
at the cell membrane are the last category.
2. De Boeck K, Vermeulen F, Dupont L. The diagnosis of cystic fibro-
Although CFTR modulators bring enormous promise for the im- sis. Presse Med. 2017;46:e97-108.
mediate future, taking a drug combination for life is not ideal, the cost 3. Goetz D, Ren CL. Review of cystic fibrosis. Pediatr Ann.
is huge and some patients may not tolerate the treatment. Therefore, 2019;48:e154-e161.
4. ECFS patient registry annual data report [Internet]. 2017.
other corrective strategies continue to be explored. There is renewed
Available: https​://www.ecfs.eu/sites/​defau​lt/files/​gener​al-conte​
interest in gene therapy by improving the efficacy of the vectors nt-image​s/worki​n g-group​s/ecfs-patie​nt-regis ​t ry/ECFSPR_Repor​
used.54 Gene editing is being trialled in vitro using the clustered inter- t2017_v1.3.pdf
spaced short palindromic repeat and associated genes technique.55 5. Kerem BS, Zielenski J, Markiewicz D, et al. Identification of mu-
tations in regions corresponding to the two putative nucleotide
The addition of normal messenger ribonucleic acid or influencing gene
(ATP)-binding folds of the cystic fibrosis gene. Proc Natl Acad Sci U S
expression and protein production by small interfering ribonucleic A. 1990;87:8447-8451.
acid are other strategies. A more extensive discussion of the current 6. Boucher RC. An overview of the pathogenesis of cystic fibrosis lung
preclinical pipeline we refer to has previously been published.56 All disease. Adv Drug Deliv Rev. 2002;54:1359-1371.
these corrective techniques face the challenge of delivering the prod- 7. Quinton PM. Cystic fibrosis: impaired bicarbonate secretion and
mucoviscidosis. Lancet. 2008;372:415-417.
uct to the nucleus or to the cytoplasm. In addition, the treatment will
8. Shah VS, Meyerholz DK, Tang XX, et al. Airway acidification ini-
have to be specific, so that only CFTR protein is increased and safe. tiates host defense abnormalities in cystic fibrosis mice. Science.
2016;351(6272):503-507.
9. Kunzelmann K, Schreiber R, Hadorn HB. Bicarbonate in cystic fibro-
sis. J Cyst Fibros. 2017;16:653-662.
7 | CO N C LU S I O N 10. Cystic fibrosis mutation database [Internet]. Available: http://www.
genet.sickk​ids.on.ca
Cystic fibrosis is now recognised as an important genetic disease 11. Kerem E, Viviani L, Zolin A, et al. Factors associated with FEV1
worldwide. In the western world, the diagnosis is mainly made via CF decline in cystic fibrosis: analysis of the ECFS patient registry. Eur
Respir J. 2014;43:125-133.
newborn screening. Being alert to CF remains important, because
12. Boyle MP, Sabadosa KA, Quinton HB, Marshall BC, Schechter MS.
screening will not detect all patients and milder disease may only Key findings of the US cystic fibrosis foundation's clinical practice
manifest itself in adulthood. The outcomes of patients have greatly benchmarking project. BMJ Qual Saf. 2014;23:i15-i22.
improved due to intensive treatment and follow-up in specific cen- 13. Lebecque P, Leonard A, De Boeck K, et al. Early referral to cystic
fibrosis specialist centre impacts on respiratory outcome. J Cyst
tres. Death during childhood has become very unusual, and many
Fibros. 2009;8:26-30.
young adults now live productive lives. Furthermore, treatment 14. Castellani C, Duff AJA, Bell SC, et al. ECFS best practice guidelines:
with CFTR modulators is rapidly changing the outlook for people the 2018 revision. J Cyst Fibros. 2018;17:153-178.
with CF. In the near future, this will lead to effective treatment for 15. Chotirmall SH, Smith SG, Gunaratnam C, et al. Effect of estrogen on
pseudomonas mucoidy and exacerbations in cystic fibrosis. N Engl J
at least 85%-90% of patients. In addition, starting these treatments
Med. 2012;366:1978-1986.
in the first year of life may allow to prevent or reverse complica- 16. Liou TG, Elkin EP, Pasta DJ, et al. Year-to-year changes in lung func-
tions like pancreatic insufficiency. There is hope that these drugs tion in individuals with cystic fibrosis. J Cyst Fibros. 2010;9:250-256.
will also prevent the development of bronchiectasis, diabetes and 17. Waters VJ, Stanojevic S, Sonneveld N, et al. Factors associated with
other complications. For patients with rare CFTR mutations, testing response to treatment of pulmonary exacerbations in cystic fibrosis
patients. J Cyst Fibros. 2015;14:755-762.
CFTR function and its rescue by CFTR modulators in vitro in patient
DE BOECK | 899

18. Mott LS, Park J, Murray CP, et al. Progression of early structural 41. Moss RB, Flume PA, Elborn JS, et al. Efficacy and safety of ivacaftor
lung disease in young children with cystic fibrosis assessed using in patients with cystic fibrosis who have an Arg117His-CFTR muta-
CT. Thorax. 2012;67:509-516. tion: a double-blind, randomised controlled trial. Lancet Respir Med.
19. Burgel PR, Bellis G, Elborn JS. Modelling future trends in cystic fi- 2015;3:524-533.
brosis demography using the French cystic fibrosis registry: update 42. Wainwright CE, Elborn JS, Ramsey BW. Lumacaftor-ivacaftor in pa-
and sensitivity analysis. Eur Respir J. 2017;50(2):1700763. tients with cystic fibrosis homozygous for Phe508del CFTR. N Engl
20. Simmonds NJ. Ageing in cystic fibrosis and long-term survival. J Med. 2015;373:1783-1784.
Paediatr Respir Rev. 2013;14:6-9. 43. Taylor-Cousar JL, Jain M, Barto TL, et al. Lumacaftor/ivacaftor in
21. Wagener JS, Millar SJ, Mayer-Hamblett N, et al. Lung function de- patients with cystic fibrosis and advanced lung disease homozy-
cline is delayed but not decreased in patients with cystic fibrosis gous for F508del-CFTR. J Cyst Fibros. 2018;17:228-235.
and the R117H gene mutation. J Cyst Fibros. 2018;17:503-510. 44. Keating D, Marigowda G, Burr L, et al. VX-445-tezacaftor-ivacaftor
22. Sims EJ, Clark A, McCormick J, et al. Cystic fibrosis diagnosed after in patients with cystic fibrosis and one or two Phe508del alleles. N
2 months of age leads to worse outcomes and requires more ther- Engl J Med. 2018;379:1612-1620.
apy. Pediatrics. 2007;119:19-28. 45. Davies JC, Moskowitz SM, Brown C, et al. VX-659-tezacaftor-
23. Dijk FN, McKay K, Barzi F, Gaskin KJ, Fitzgerald DA. Improved ivacaftor in patients with cystic fibrosis and one or two Phe508del
survival in cystic fibrosis patients diagnosed by newborn screen- alleles. N Engl J Med. 2018;379:1599-1611.
ing compared to a historical cohort from the same centre. Arch Dis 46. Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor-tezacaftor-
Child. 2011;96:1118-1123. ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J
24. Castellani C, Massie J, Sontag M, Southern KW. Newborn screening Med. 2019;381:1809-1819.
for cystic fibrosis. Lancet Respir Med. 2016;4:653-661. 47. Heijerman HGM, McKone EF, Downey DG, et al. Efficacy and
25. Barben J, Castellani C, Dankert-Roelse J, et al. The expansion and safety of the elexacaftor plus tezacaftor plus ivacaftor combination
performance of national newborn screening programmes for cystic regimen in people with cystic fibrosis homozygous for the F508del
fibrosis in Europe. J Cyst Fibros. 2017;16:207-213. mutation: a double-blind, randomised, phase 3 trial. Lancet.
26. Ren CL, Fink AK, Petren K, et al. Outcomes of infants with inde- 2019;394(10212):1940-1948.
terminate diagnosis detected by cystic fibrosis newborn screening. 48. Amaral M, De Boeck K. “ECFS strategic planning task force on
Pediatrics. 2015;135:e1386-e1392. speeding up access to new drugs for CF”. Theranostics by testing
27. Scotet V, Assael BM, Duguépéroux I, et al. Time trends in birth inci- CFTR modulators in patient-derived materials: The current status
dence of cystic fibrosis in two European areas: data from newborn and a proposal for subjects with rare CFTR mutations. J Cyst Fibros.
screening programs. J Pediatr. 2008;152:25-32. 2019;18:685-692.
28. CFTR2 mutation database [Internet]. Available: www.cftr2.org/ 49. Dekkers JF, Wiegerinck CL, de Jonge HR, et al. A functional CFTR
mutat​ions_history assay using primary cystic fibrosis intestinal organoids. Nat Med.
29. Bosch B, Bilton D, Sosnay P, et al. Ethnicity impacts the cystic fibro- 2013;19:939-945.
sis diagnosis: a note of caution. J Cyst Fibros. 2017;16:488-491. 50. CFF. Drug development pipeline [Internet]. Available: https​://www.
30. De Boeck K, Kerem E. Equitable CF care as a basic human right. J cff.org/trial​s/pipeline
Cyst Fibros. 2016;15:703-704. 51. Konstan MW, DiMango E, Kerem E, et al. WS13.3 Efficacy and safety
31. De Boeck K, Amaral MD. Progress in therapies for cystic fibrosis. of ataluren in patients with nonsense-mutation cystic fibrosis not
Lancet Respir Med. 2016;4:662-674. receiving chronic inhaled aminoglycosides: the international, ran-
32. Veit G, Avramescu RG, Chiang AN, et al. From CFTR biology toward domized, double-blind, placebo-controlled Ataluren Confirmatory
combinatorial pharmacotherapy: expanded classification of cystic Trial in Cystic Fibrosis (ACT CF. J Cyst Fibros. 2017;16:S23-S24.
fibrosis mutations. Mol Biol Cell. 2016;27:424-433. 52. Leubitz A, Frydman-Marom A, Sharpe N, van Duzer J, Campbell
33. McKone EF, Emerson SS, Edwards KL, Aitken ML. Effect of geno- KCM, Vanhoutte F. Safety, tolerability, and pharmacokinetics of
type on phenotype and mortality in cystic fibrosis: a retrospective single ascending doses of ELX-02, a potential treatment for genetic
cohort study. Lancet. 2003;361:1671-1676. disorders caused by nonsense mutations, in healthy volunteers. Clin
34. Dewulf J, Vermeulen F, Wanyama S, et al. Treatment burden in Pharmacol drug Dev. 2019;8(8):984-994.
patients with at least one class IV or V CFTR mutation. Pediatr 53. Flume P, Sawicki G, Pressler T, et al. WS01.2 Phase 2 initial results
Pulmonol. 2015;50:1230-1236. evaluating PTI-428, a novel CFTR amplifier, in patients with cystic
35. Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in fibrosis. J Cyst Fibros. 2018;17:S1-2.
patients with cystic fibrosis and the G551D mutation. N Engl J Med. 54. Alton EWFW, Beekman JM, Boyd AC, et al. Preparation for a
2011;365:1663-1672. first-in-man lentivirus trial in patients with cystic fibrosis. Thorax.
36. De Boeck K, Munck A, Walker S, et al. Efficacy and safety of iva- 2017;72:137-147.
caftor in patients with cystic fibrosis and a non-G551D gating mu- 55. Maule G, Casini A, Montagna C, et al. Allele specific repair of splic-
tation. J Cyst Fibros. 2014;13:674-680. ing mutations in cystic fibrosis through AsCas12a genome editing.
37. Bessonova L, Volkova N, Higgins M, et al. Data from the US and Nat Commun. 2019;10:3556.
UK cystic fibrosis registries support disease modification by CFTR 56. Cuyx S, De Boeck K. Treating the underlying CFTR defect in patients
modulation with ivacaftor. Thorax. 2018;73:731-740. with cystic fibrosis. Semin Respir Crit Care Med. 2019;40:762-774.
38. De Boeck K, Zolin A, Cuppens H, Olesen HV, Viviani L. The relative 57. Elborn JS. Personalised medicine for cystic fibrosis: treating the
frequency of CFTR mutation classes in European patients with cys- basic defect. Eur Respir Rev. 2013;22:3-5.
tic fibrosis. J Cyst Fibros. 2014;13:403-409.
39. Davies JC, Cunningham S, Harris WT, et al. Safety, pharmacokinet-
ics, and pharmacodynamics of ivacaftor in patients aged 2–5 years
How to cite this article: De Boeck K. Cystic fibrosis in the
with cystic fibrosis and a CFTR gating mutation (KIWI): an open-la-
year 2020: A disease with a new face. Acta Paediatr.
bel, single-arm study. Lancet Respir Med. 2016;4:107-115.
40. Rosenfeld M, Wainwright CE, Higgins M, et al. Ivacaftor treat- 2020;109:893–899. https​://doi.org/10.1111/apa.15155​
ment of cystic fibrosis in children aged 12 to. Lancet Respir Med.
2018;6:545-553.