Cell. Mol. Life Sci.

(2017) 74:129–140
DOI 10.1007/s00018-016-2393-9 Cellular and Molecular Life Sciences
MULTI-AUTHOR REVIEW

Cystic fibrosis: a clinical view

Carlo Castellani1 • Baroukh M. Assael2

Received: 27 September 2016 / Accepted: 28 September 2016 / Published online: 5 October 2016
Ó Springer International Publishing 2016

Abstract Cystic fibrosis (CF), a monogenic disease caused good clinical impact, others showing promising preliminary
by mutations in the CFTR gene on chromosome 7, is complex results that need to be confirmed in phase III clinical trials.
and greatly variable in clinical expression. Airways, pancreas,
male genital system, intestine, liver, bone, and kidney are Keywords Cystic fibrosis
CFTR
Genotype

involved. The lack of CFTR or its impaired function causes fat Phenotype
Precision medicine
malabsorption and chronic pulmonary infections leading to
bronchiectasis and progressive lung damage. Previously
considered lethal in infancy and childhood, CF has now Introduction
attained median survivals of 50 years of age, mainly thanks to
the early diagnosis through neonatal screening, recognition of The history of cystic fibrosis (CF), the severest autosomal
mild forms, and an aggressive therapeutic attitude. Classical recessive disease in caucasians, can be considered a para-
treatment includes pancreatic enzyme replacement, respira- digm of the successful outcomes achievable by collaborative
tory physiotherapy, mucolitics, and aggressive antibiotic international efforts in the basic and clinical research. Since
therapy. A significant proportion of patients with severe its recognition as a specific nosographic entity [1], at a time,
symptoms still requires lung or, less frequently, liver trans- when it was almost always considered lethal in the early
plantation. The great number of mutations and their diverse childhood, the clinical management of CF has slowly but
effects on the CFTR protein account only partially for CF constantly improved and patients median predicted survival
clinical variability, and modifier genes have a role in modu- has increased over the decades until reaching in some areas
lating the clinical expression of the disease. Despite the the age of 50 years [2, 3]. In several countries, the majority
increasing understanding of CFTR functioning, several of patients are represented by adults and this preponderance
aspects of CF need still to be clarified, e.g., the worse outcome is expected to amplify in the next years [4]. Concurrently, CF
in females, the risk of malignancies, the pathophysiology, and has been increasingly emerging as a disease more complex
best treatment of comorbidities, such as CF-related diabetes or than previously thought and the much pursued and wel-
CF-related bone disorder. Research is focusing on new drugs comed improvement in the disease control has implied
restoring CFTR function, some already available and with downsides of significant clinical relevance, such as the
increased prevalence of malignancies and renal and bone
metabolism complications [5].
& Carlo Castellani The protein, whose deficiency is responsible for the
[email protected] disease, named CF transmembrane regulator (CFTR), is
Baroukh M. Assael expressed in several organs, but its full tissue-specific role
[email protected] still needs clarification. In epithelial cell CFTR, an ABC
1
Verona Cystic Fibrosis Centre, Piazzale Stefani 1, 37126 protein [6] exhibits the properties of a chloride and
Verona, Italy anionic channel involved in a variety of physiological
2
Adult Cystic Fibrosis Center, Via Francesco Sforza, 20100 processes and is now seen as a hub modulating several
Milano, Italy functions [7].

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130 C. Castellani, B. M. Assael

In lower and upper airways, the intestine, pancreatic, and various structural defects in the protein elucidated. The
liver ducts, lack of functional CFTR is the major factor in steps forwarded in the comprehension of molecular
determining the degree of disease expression, and eventually mechanisms are leading to the development of com-
mortality. The protein plays a direct role in organs, such as the pounds aimed at modifying the clinical course of CF and
hypothalamus, kidney, and bone, where its malfunction may be thus impacting even more substantially on long-term
implied in linear growth retardation [8], delayed pubertal onset outcome. Moreover, we have learned that the forms of
[9], bone density modulation [10], and susceptibility to renal disease connected with CFTR are widely heterogeneous
calculi [11], all of which may be present in CF and for many in severity, rate of progression, and body district
years have been considered only secondary to pulmonary or involvement and that, among the organ specific mani-
intestinal disease. Besides, CFTR is involved in several physi- festations of CF, lung disease is possibly the most
ological mechanisms concerning natural immunity or immune variable in its expression. The large number of CFTR
response, which in turn play a role in the development of lung sequence variations, and, therefore, of genotypes, is the
disease. As patients reach older ages, relatively high malignancy major but by no means the only cause of such clinical
rates have led to hypothesize that impaired CFTR activity might heterogeneity.
also increase the risk of colonic cancer and leukemia [12, 13]. CFTR mutations are currently grouped into six cate-
Finally, the malfunction of CFTR is not only causative of CF but gories, based on their mechanisms of dysfunction and
seems also involved in very different disorders, such as secre- effects on the protein (Table 1) [19–21]. Despite a few
tory diarrhea and adult polycystic kidney disease, conditions, difficulties in fitting some mutations into this classification,
where the activity of the protein is higher than normal [14]. these classes have proved useful in functional studies and
After reviewing the various clinical aspects of CF, this to test new treatments supposed to act on specific protein
chapter will focus on the therapeutic approaches that may defects. Their utility is more limited in interpreting the
potentially impact or have shown effects on the clinical clinical liability of specific mutations [18, 22]. Large
course of the disease. cohorts of patients carrying mutations which allow some
residual protein activity have been shown to benefit from
milder disease, while patients with class 1–3 mutations on
From the gene to the disease both alleles tend to have a more rapid deterioration of
respiratory function and more severe lung disease. How-
The identification of the CFTR gene in 1989 has opened ever, there is considerable phenotypic overlap among
a new era in the understanding of CF [15–17]. Since classes and it is not possible to predict individual outcome
then, over 2000 mutations have been identified [18] and based on CFTR genotype (Fig. 1).

Table 1 Functional classification of CFTR mutations

Mutation Mechanism of dysfunction Representative Notes
class mutations

1 Premature termination codon in mRNA ? G542X Usually associated to more severe phenotypes
formation of a truncated, unstable protein that is R553X
rapidly degraded ? no functional protein in the
W1282X
apical cell membrane
2 Synthesis of a protein that is not properly processed F508del F508del is the most common mutation worldwide
to a mature glycosylated form ? only a small
quantity of partially functioning protein is
transported to the apical membrane
3 A normal amount of CFTR protein that is correctly G551D These so-called gating mutations have been the first
folded and trafficked to the apical membrane, but targeted by a specific drug, Ivacaftor, currently
the channel opening time is greatly reduced used in the treatment of patients
4 Reduced conductivity of the channel R117H Usually connected with pancreatic sufficiency and
R334W milder phenotypes
R347P
5 Partially aberrant splicing or inefficient trafficking 3849–10kbC[T Usually connected with pancreatic sufficiency and
? reduced synthesis of fully active CFTR A455E milder phenotypes
6 Instability of an otherwise fully processed and Q1412X Usually nonsense or frameshift mutations
functional protein 4326delTC 4279insA Generally associated with a severe clinical
presentation

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Cystic fibrosis: a clinical view 131

Fig. 1 Time-related
distribution of age groups of CF
patients in a large clinical
Centre. Data refer to the Verona
CF Centre, Italy. y-axis, percent
of patients; x-axis, year

Fig. 2 Correlation among 100% wild type no disease -ive normal

CFTR function, clinical
manifestations, sweat test, and
IRT at birth

50% carrier no disease ** -ive normal *****

CFTR-RD * mono organ *** -ive to +ive normal to elevated

PS CF mulorgan **** +ive elevated

0% PI CF mulorgan +ive elevated

CFTR funcon definion clinical manifestaons sweat test IRT at birth

*CFTR-RD = CFTR-related disorder
**Potenal modifier for other condions, e.g. pancreas
***CBAVD or pancreas or bronchiectasis
****With residual exocrine pancreac funcon
*****May be higher than wild type, sll in the normal range

The CF clinical spectrum At the other end, the spectrum is CFTR-related disorder.
These are conditions determined by mutations in the CFTR
The correlation between genotype and expression of dis- gene but not giving rise to the usual CF picture. They have
ease is influenced by various factors that make phenotype been defined ‘‘clinical entities associated with CFTR dys-
variability extend along a wide spectrum (Fig. 2). The function that do not fulfil diagnostic criteria for CF’’.
classical clinical picture of CF is mainly characterized by Clinical manifestations are limited to a single district and
fat maldigestion due to pancreatic insufficiency and include episodes of recurrent pancreatitis or isolated
chronic obstructive airway disease with bacterial colo- bilateral bronchiectasis. Males can manifest bilateral age-
nization predominantly by microorganisms, such as nesia of the vas deferens (CBAVD) with no digestive or
Pseudomonas aeruginosa and Staphylococcus aureus. This respiratory involvement [24].
was already known when Dorothy Andersen reported the The wide variability of clinical expression, particularly
first series of patients, whom she subdivided into three in lung disease, suggests that non-CFTR factors play an
groups: patients with congenital intestinal obstruction, i.e., important role in the development of individual clinical
meconium ileus; patients with onset respiratory symptoms histories [25–27]. This is not unexpected given the com-
in the first months of life; and patients who developed plexity of the mechanisms involved in the natural defense
chronic cough after 6 months of age [23]. of the airways, which include resident macrophages,

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132 C. Castellani, B. M. Assael

epithelial lining fluid pH, mucins and antibacterial proteins, the course of routine ultrasound examination, but hypere-
and a network of cytokines regulating the inflammatory chogenic bowel is neither sensitive nor specific, as it is
response to infectious agents. Studies have investigated the detected only in a minority of CF affected fetuses and it very
role of specific candidate proteins, and a number of mod- often have causes other than CF [45]. At birth meconium
ifier genes which can influence the course of the respiratory ileus, a neonatal emergency strongly suggests the diagnosis
disease have been identified [28, 29], such as mannose of CF. CF neonatal screening (NBS) programs are based on
binding lectin [30], interleukin-8 [31], and pentraxin [32]. blood trypsinogen (IRT) measurement in the first days of life
Conclusions have not always been consistent, probably followed in infants with raised IRT by various combinations
influenced by different methodological approaches and by of genetic analysis, measurement of the pancreatitis associ-
selection bias, such as the age of the population under ated protein, and IRT retesting by 1 month of age. CF NBS,
study and the number of patients examined. Genome-wide when properly designed and managed, has high sensitivity
association [33] and twin and siblings studies [34] are and specificity, and has been proved to be cost effective and
moving this research field forward, but further analyses are to ameliorate prognosis [46].
needed before reaching more definite conclusion.
Diagnosis in pediatric age
Inflammation and the immune system
Fully expressed CF can be easily suspected on clinical
The CF airway inflammatory response is characterized by grounds, since it is one of the few causes of pancreatic
neutrophilic infiltration, excessive pro-inflammatory cyto- insufficiency, bronchiectasis, and extra renal loss of sodium
kine production, and presence of free neutrophil elastase, in childhood. Evocative manifestations include chronic
and has been reported even in the absence of bacterial productive cough, typical CF pathogens in bronchial
infection, suggesting that it may be at least partially secretions, oily stools, wasting, stunting, and pseudo-
unrelated to bacterial infection [35, 36]. The increased Bartter syndrome. The involvement of the sweat gland has
inflammatory response, inefficient bacterial phagocytosis, been recognized in the 1950s when some affected children
and unbalanced oxidative stress in the CF respiratory tract developed an extrarenal salt loosing syndrome. NaCl loss
have been extensively studied, and different mechanisms through the sweat gland is a hallmark of cystic fibrosis and
have been suggested to explain the link between CFTR has led to the development of the sweat test that quantifies
malfunction and these events. Several studies have focused sweat chloride content under standardized conditions and is
on the possible role of CFTR in bacterial adhesion and the gold standard to diagnose CF [41, 47].
local inflammatory responses in bronchial epithelial cells.
The role of the innate immune response and of macro- Diagnosis in adolescence and adulthood
phages and neutrophils in the lung has also been considered
[37–39]. Increased inflammation is not only a major cause A diagnosis of CF can also be formulated in adolescents
of the progression of respiratory morbidity, but also a and adults, occasionally, because a classic clinical picture
significant determinant of CF intestinal disease [40]. had not been previously correctly interpreted, more fre-
quently, because of milder or incomplete phenotype. The
latter may lack signs of maldigestion and malnutrition,
Diagnosis prevented by residual exocrine pancreatic function. Sweat
chloride concentrations in the borderline range and muta-
Diagnoses of CF are usually straightforward, but occa- tions not unquestionably associated with CF are not
sionally, they may prove difficult to make. This has led to uncommon in these situations.
the implementation of guidelines for diagnosis [41, 42] and
to the development of assays, testing CFTR function
in vivo [43] and ex vivo [44]. Notwithstanding such The respiratory disease
diagnostic aids, a few diagnoses remain problematic and
controversial. Chronic pulmonary infection leading to respiratory failure
is the main cause of death and the main determinant of the
Prenatal and early diagnosis burden of the disease on quality of life.

Prenatal and preimplantation genetic diagnosis is possible The lung

whenever parents are known heterozygotes and their muta-
tions have been detected. During pregnancy, increased The detection of inflammatory markers from bron-
echogenicity of the fetal intestine is occasionally detected in choalveolar lavage [48, 49] and the evidence from High

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Cystic fibrosis: a clinical view 133

Resolution Chest Tomography of structural lung damage in Upper airways

asymptomatic infants [50, 51] attests that the lung is
affected very early. Structural damage is in turn probably Upper airways are almost invariably affected by CF, with
responsible for lung ventilation inhomogeneity found by patients exhibiting a variety of conditions, such as sinusitis,
washout techniques in CF infants [52]. nasal polyposis, and mucocele, and often requiring nose or
Different hypotheses have been suggested to illustrate sinusal surgery. The relationship between upper and lower
the pathogenesis of lung disease in CF. According to the airway colonizations by Pseudomona aeruginosa as not yet
most accredited theory, the lack of CFTR or its impaired been completely understood, and it has been suggested that
function results in lower water content in the periciliary upper airway disease sustains lower infection [59, 60].
fluid and thus in abnormally dense mucous. Besides, CFTR Aggressive treatment of nasal or paranasal infection/colo-
downregulates the sodium channel (ENac) on the apical nization by bacteria, such as Pseudomonas aeruginosa or
side of bronchial epithelial cells and the consequent Staphylococcus aureus, is offered by many CF clinics [61].
hyperreabsorption of sodium reduces the hydration and
increases the density of bronchial mucus. The hyperviscose
secretions sequent to this complex process end up hinder- The gastrointestinal disease
ing ciliary activity and their clearance mechanism [53].
HCO3 transmembrane traffic is probably involved too. CFTR is expressed along the GI tract and pancreatic and
CFTR is an HCO3 channel, and in the knockout, pig-defi- intestinal involvement due to loss of CFTR function begins
cient bicarbonate excretion has been connected to reduce as early as fetal life [62].
bacterial killing capacity [54].
Lack of CFTR function in the bronchial epithelia is also The pancreas
involved in increased inflammatory response and reduced
activity of natural defense mechanisms that ultimately CFTR is expressed in ductal epithelial cells. Lack of CFTR
result in facilitating the infection and chronic bacterial function results in reduced water content of the pancreatic
colonization of the lung [35]. Microorganisms typically secretions and decreased pH. Increased viscosity of the
involved in pulmonary chronic infection are Pseudomonas luminal content and the presence of pancreatic enzymes
aeruginosa, Staphylococcus aureus, Stenotrophomonas cause obstruction and progressive destruction of the acini,
maltophilia, and Burkholderia cepacia. More adequate inflammation, formation of cysts, and fibrosis. Hence, the
collections of sputum, samples from bronchoalveolar complete name of the disease: cystic fibrosis of the pancreas.
lavage, increased sensitivity of cultures, and the use of non Circulating trypsinogen is elevated in the CF neonate
cultural methods are showing that the microbiome of CF independently of the degree of pancreatic exocrine involve-
lung is far more complex and that other bacteria, including ment, which makes IRT measurement in dry blood spots the
anaerobes, might affect the progression of pulmonary dis- mainstay of neonatal screening. Pancreatic exocrine insuffi-
ease [55]. Furthermore, bacteria are not the only ciency severe enough to cause symptomatic fat malabsorption
microbiological agents that have to do with the develop- is detectable at birth in 60–80 % of affected infants and
ment of lung disease. Viral infection may trigger causes malnutrition and poor growth [63]. The measurement
pulmonary exacerbations and CF patients are more prone of fecal pancreatic enzymes is used for diagnosing exocrine
to fungal infections, particularly to Aspergillus fumigatus pancreatic insufficiency, usually measuring fecal elastase-1
and Scedosporium Apiospermium. An increased rate of [64]. Ductal plugging in patients with partially preserved
allergic reactions to Aspergillus (Allergic Bronchopul- pancreatic function can cause recurrent episodes of pancre-
monary Aspergillosis) is the characteristic of CF. atitis and, in the long term, the total loss of enzyme secretion.
Segregation of infected patients, frequent sputum sam- Endocrine pancreatic function is usually preserved in infancy,
pling, and aggressive protocols of eradication have but in older ages, parenchymal progressive destruction leads
succeeded in reducing or delaying chronic bacterial colo- to the so-called CF-related diabetes.
nization of the lower airways. Aggressive antibiotic
treatment of pulmonary exacerbations is the standard of The intestine
care in CF. Unfortunately, in spite of a very proactive
therapeutic conduct, a relatively large proportion of CFTR-mediated bicarbonate secretion is essential to buffer
patients still become chronically infected and suffer from gastric acidity and to allow expansion and hydration of the
frequent pulmonary exacerbations, which greatly con- intestine mucus. Meconium ileus affects approximately
tribute to the decay of lung function, poor quality of life 20 % of CF neonates and is more frequently associated
and may eventually end up in transplantation or end-stage with severe mutations. Its occurrence is influenced by
disease [56–58]. modifier genes [29, 65]. Older patients may exhibit

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134 C. Castellani, B. M. Assael

constipation or obstipation and may develop a subocclusive damaging the insulae. CF-related diabetes has distinctive
or fully occlusive manifestation called distal intestinal peculiarities that make it different from type 1 and type 2:
obstructive syndrome. Signs of inflammation have been it originates from reduced secretion of insulin, but is also
observed in intestinal biopsies [66] as well as altered partially due to insulin resistance, particularly during acute
microbiome composition [67] and are consistent with pulmonary exacerbations.
experimental findings in the knockout mouse [68]. Prevalence begins to rise after the age of 10 and reaches
40–50 % in older patients. Its insurgence is associated with
Bowel cancer worsening of the respiratory disease, and conversely, good
control of hyperglycemia reduces the number of respiratory
CFTR deficiency has been associated with raised onco- exacerbation and slows down pulmonary disease progression.
logical risks. A prospective 20 years study on more than CF-related diabetes is associated with increased mortality.
40,000 patients in the US Patient Registry resulted in a Conflicting data exist on the role of gender and on the sup-
diagnosis of bowel cancer in 31 cases, a significantly raised posedly worse severity and higher mortality in CF diabetic
frequency, either in the colon (26 observed vs 4.2 expec- female patients. Annual screening with oral glucose tolerance
ted) or small bowel (five observed vs 0.4 expected). The tests is recommended, since the age of 10 to identify diabetes
frequency was not age-related and higher in males and in or prediabetic conditions. Insulin treatment is recommended.
patients with mutations associated with pancreatic insuffi- Many patients with normal or borderline glycemic profiles
ciency. Increased cancer rates were also reported in the develop diabetes after lung transplantation [73].
biliary tract, in the esophagus, and in the stomach [12]. In a
single-center study, colonoscopic screening in CF patients Bone disease
(mean age 47 years) identified a high incidence of adeno-
matous polyps, again higher males. The authors concluded CF-related bone disease has been emerging in parallel with
that this evidence warrants earlier colon screening in the the progressive increase of survival. Between 10 and 15 %
CF adult population [13]. After transplantation, pharma- of patients, rising to 50 % in the late stage disease, show
cological immunosuppression increases cancer risk. low bone mineral density at dual-energy X-ray absorp-
tiometry (DEXA) and are at risk of osteopenia,
osteoporosis, and vertebral fractures [74]. The risk of bone
The liver disease is related to malnutrition, low BMI, severity of lung
disease, and a variety of other factors, such as poor
CFTR is expressed in epithelial cells of the biliary duct and mobility, reduced absorption of vitamin D, low levels of
regulates bile acid independent bile flow. Ispissated bile vitamin K, use of steroids, circulating inflammatory
may cause obstructive liver disease progressing to multi- cytokines, and increased bone turnover. CFTR is expressed
lobar biliary cirrhosis and portal hypertension. These in bone cells, and a direct role of the protein on bone
complications occur in a minority of patients, but are not metabolism cannot be excluded [75, 76].
rare. The actual frequency of liver disease manifestations is
difficult to determine, because designs and populations of Male infertility
studies included different definitions, such as neonatal
cholestasis, abnormal aminotransferases, fibrosis, steatosis, Congenital Bilateral Absence of Vas Deferens (CBAVD) is
focal biliary cirrhosis, and multilobular cirrhosis, with or detected in up to 90 % of CF males [77] and is also found
without portal hypertension. The prevalence of severe liver as an isolated clinical feature in CFTR-related disorders
disease peaks in adolescence and about 5 % of patients [24]. The most frequent genotype in mono organ conditions
may require liver transplantation [69]. Progression of liver is the in trans combination of a CF causing mutation and
disease is influenced by the genetic background [70–72], the IVS8-5T polymorphism [24, 78].
and a strong association has been found with the Z-allele of
the a1-antiprotease (SERPINA1) gene [72]. Growth

Pubertal spurt retardation reduced growth velocity and

Endocrine comorbidities diminished GH secretion after appropriate stimuli have
been reported in CF children [79]. Although short stature is
CF-related diabetes partly due to malnutrition and disease severity, low insulin-
like growth factor 1 (IGF1) levels in CF pigs and in
Diabetes is the most common endocrine complication of patients suggest a role of CFTR in the pituitary secretion of
CF and is due to progressive pancreatic fibrosis gradually growth hormone [80].

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Cystic fibrosis: a clinical view 135

Therapy Anti-inflammatory therapies

The treatment of CF is multidisciplinary and has to be Corticosteroids, ibuprofen, and macrolides have been
provided in specialized centers having access to all the shown to slow down the progression of lung disease.
necessary subdisciplines. This multiprofessional approach Whereas prolonged use of systemic steroids is limited by
has been quite successful and greatly contributed to their considerable side effects, ibuprofen and macrolides
increased life expectancy, better lung function, and are widely used [92–94].
reduction in the prevalence of chronic infections [81].
Gene therapy
Pulmonary therapy
Shortly, after the identification of the CFTR gene, gene
The backbone of lung disease treatment consists of removal therapy has been experimented by various research groups.
of ispissated secretions by means of airway clearance tech- Although in vitro studies had been successful in reaching
niques and of nebulizations that diminish mucus viscosity or high levels of gene expression, clinical results were
increase its water content. Prevention and treatment of air- impaired by low efficiency of the vectors and inflammatory
way infection represent the main therapeutic challenge in CF reactions [95, 96]. More recently, a 1 year study adminis-
[81]. Various strategies have been suggested to avoid tering monthly treatments of a nebulized gene/liposome
increased exposure to nosocomial strains and interpatients complex showed an increase in FEV1 % of 3.7 %, statis-
transmission of Pseudomonas aeruginosa, Meticillin Resis- tically significant but of modest clinical meaning [97].
tant Staphilococcus aureus, and Burkholderia cepacia. Therapies under study Pharmacological therapy has
Other microorganisms may produce lower airway damage, gained interest in the last decade. Compounds, such as
and guidelines are periodically updated to face old and new phenylbutyrate [98], glutathione [99], and amitryptiline
pathogens [57]. Nebulized antibiotics are widely used to [100–103], have been tested in clinical trials, but have not
eradicate and control chronic infection by Pseudomonas yet been definitely proved to produce clinically significant
aeruginosa. Notwithstanding aggressive preventive mea- benefits. Natural compounds, such as genistein, curcumin,
sures and treatment, the colonization of the lower airways and resveratrol, have also been considered as potential
remains a most significant clinical problem, leading to treatment for cystic fibrosis [104]. Denufosol, an inhibitor
progressive lung damage and chronic or frequent antibiotic of purinergic receptors, after initial promising results in a
treatment, both nebulized and systemic. phase 3 clinical trial failed to reach the primary endpoint in
a second large study [105]. Roskovitine is an inhibitor of
kinases currently in clinical trial phase II for the treatment
Gastrointestinal therapy
of a number of diseases. A phase II clinical trial is
undergoing, and, pending on its results, a phase III trial
Malabsorption and hypoproteinemia are usually managed
could be activated in the next years [106].
with the administration of pancreatic enzymes and the
addition of lipid soluble vitamins. Hypercaloric diets are
recommended and have been proved to improve survival
Personalized medicine for CF
[82]. Specific nutrients (i.e., essential fatty acids, polyun-
saturated fatty acids, and docosahesaenoic acid) have
Since its recognition CF has been treated symptomatically,
sometimes been used, based on CF specific abnormalities
and until recently, no therapy directed to the restoration of
in lipid metabolism [83–87].
CFTR function had been available. This is changing and
compounds targeting CFTR are becoming available or are
Surgery positioned in the therapeutic development pipeline.

A substantial subpopulation of patients develop respiratory The evaluation of the efficacy of drugs modifying
insufficiency and are listed for double lung transplantation. disease
This is rare nowadays in childhood but not in adults and the
median age of the procedure is in the third decade of life Evaluating the actual efficacy of treatments for CF is a
[88, 89]. A small proportion of patients (2–3 %) will major challenge. Survival, the more rational outcome
develop portal hypertension and undergo specific surgical measure in a life-shortening disease, such as CF, is inap-
procedures, including porto-systemic shunts and liver plicable due to the great increase in life expectancy. Other
transplantation [90]. ENT surgery is frequently needed for endpoints are needed and have been employed in clinical
nasal polyposis, mucocele, and chronic sinusitis [61, 91]. trials as surrogate outcomes The most widely used is the

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spirometric parameter forced expiratory volume in one achievements, such as better control of diabetes and
second (FEV1), often in association with time to first improvement of pancreatic function, infection, and nutri-
pulmonary exacerbation, number of exacerbations, and tion. Ivacaftor efficacy in these patients appears to be
measurements of quality of life. sustained in treatments prolonged up to 4 years [117, 118].
Inflammatory markers, particularly from bronchoalveo- Shortly, after this historical breakthrough, the use of Iva-
lar lavage, have been used as clinical endpoints in studies caftor has been extended to other gating mutations and to
on pathophysiology and in clinical trials of nebulized patients bearing R117H, a residual function mutation
antibiotics and recombinant human (rh)DNase. Nonethe- [119, 120].
less, the lack of adequate standard operating procedures The rescue of proteins originated by CFTR genes har-
limits their use to monitor disease progression or response boring other types of mutations is proving more complex
to treatment [107]. and laborious. Research efforts have concentrated on the
The sweat test, nasal potential difference (NPD) F508del mutation, the most widely represented worldwide.
[108–110], and intestinal current measurements (ICM) A combination of two molecules, a corrector and a
have been employed as biomarkers of the activity of drugs potentiator (ivacaftor ? lumacaftor), tested in a large
targeting CFTR [111]. phase III international clinical trial involving one thousand
A crucial point in individualized therapy in CF is the F508del homozygotes, showed significant clinical
screening of potentially useful drugs in patients carrying improvements, but to a lower extent than Ivacaftor alone in
rare mutations. To this end, organoids permit to study in patients carrying a gating mutation [121].
individual patients the effect of new compounds. They are New compounds are under current investigation, both
generated using intestinal adult stem cell cultures from preclinically and in human trials, and some of them explore
rectal biopsies and have been proven epigenetically new avenues to the pharmacological treatment of the basic
stable and useful to store and biobank cells [112–115]. defect in CF. The website of the US CF Foundation con-
tains an excellent illustration of the drug development
PTC 124 (AtalurenÒ) pipeline [122].

This compound is meant to overcome the gene translation Alternative approaches

stoppage caused by nonsense mutations. It is not specifi-
cally designed for CF and has already been approved for Acting on the cellular environment instead of directly
the treatment of Duchenne muscular dystrophy. A phase III targeting mutant CFTR represents an alternative way to
clinical trial has demonstrated some efficacy in patients permit F508del-CFTR to traffic to and reside at the
non-treated with nebulized tobramycin, which is a frequent plasma membrane level. Autophagic flux is defective in
therapeutic choice in CF for its elevated anti-pseudomonas CF epithelial cells because of overactivation of the
activity. It has been speculated that aminoglycosides, pleiotropic enzyme Tissue Transglutaminase (TG2). Fol-
which also show activity in preventing incomplete trans- lowing preclinical evidence in CF mice and in primary
lation, could antagonize AtalurenÒ [116]. nasal cells from CF patients, two phase 2 open-label
clinical trials tested the combination of the TG2 inhibitor
Modulators of CFTR activity cysteamine, a repurposed drug already used for the
treatment of cystinosis, together with the over-the-counter
CFTR modulators include correctors and potentiators. green tea flavonoid epigallocatechin-gallate (EGCG). The
Correctors are small molecules designed to increase the latter inhibits the master kinase CK2, the main responsi-
availability of full length and physiologically active CFTR ble for CFTR fragmentation, and decreased stability. The
protein at the apical membrane level of epithelial cells. combination decreased sweat chloride concentrations,
Potentiators are intended to improve the channel activity of increased chloride efflux in nasal cells, restored autop-
CFTR proteins which reach the apical membrane but have hagy, decreased inflammatory cytokines in patient’s
reduced function. Modulators are mutation specific, i.e., sputum, and increased FEV1 of 4 % points. These results
they have effect only on mutations producing a particular were observed in F508del homozygotes and in patients
protein defect. bearing F508del or other class II mutations in trans with a
The first clear evidence of success of a CFTR potentiator class I [123, 124].
was published in 2011 and concerned patients bearing the A considerable progress has been made in the under-
G551D ‘‘gating’’ mutation. The molecule, known as Iva- standing of CF pathophysiology and in conceiving
caftor and commercially available as KalydecoÒ, has traditional and new approaches to treatment. Much has still
produced unprecedented results in respiratory function gain to be done, but evidence is now available that targeted
and pulmonary exacerbations reductions, plus several other therapies for CF are within reach [125, 126].

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Cystic fibrosis: a clinical view 137

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1. Andersen DH (1938) Cystic fibrosis of the pancreas and its 20. Welsh MJ, Smith AE (1993) Molecular mechanisms of CFTR
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