Advances in Pediatrics 55 (2008) 99–121

ADVANCES IN PEDIATRICS

Cystic Fibrosis: a Review of Pulmonary

and Nutritional Therapies
Reshma Amin, MD, Felix Ratjen, MD, PhD*
Division of Respiratory Medicine, Department of Pediatrics, The Hospital for Sick Children,
University of Toronto, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

C
ystic fibrosis (CF) is an autosomal recessive disease caused by a defect
in the cystic fibrosis transmembrane conductance regulator (CFTR)
gene. CFTR is expressed in the epithelium of several organs in the
body including the lungs, pancreas, gastrointestinal tract, reproductive tract,
and skin, as well as the nasal mucosa. The lack of functional CFTR protein re-
sults in disease manifestations in organs where CFTR has relevant physiologic
findings but respiratory disease is responsible for the shortened life span in
most patients. CF affects many organ systems and a thorough review of all as-
pects of CF is beyond the scope of this review. Therefore, given the significant
interplay between pulmonary disease and nutritional status, this review will
focus on the pulmonary and nutritional aspects of CF.

CYSTIC FIBROSIS GENETICS

The CF gene was identified in 1989 and to date more than 1500 mutations
have been described [1]. The CFTR mutations can be grouped into six classes
[2]. Class 1 mutations affect the transcription of CFTR by formation of prema-
ture stop codons into the messenger RNA. In most cases the introduction of
a premature stop codon results in a truncated protein that will undergo degra-
dation through nonsense-mediated decay, resulting in total absence of CFTR
protein. Class 2 mutations involve intracellular processing of the CFTR pro-
tein. CFTR protein is produced but is misfolded, making it unstable; this leads
to degradation by the intracellular quality control machinery. An example of
a Class 2 mutation is delta F508, the most prevalent CFTR mutation through-
out the world. Class 3 mutations alter the regulation of CFTR. CFTR protein
is successfully made and incorporated into the cell membrane surface. How-
ever, activation of the channel is perturbed, reducing its opening probability.
Class 4 mutations affect the chloride conductance of CFTR. The CFTR pro-
tein channel can be activated to open and secrete chloride but the conductance
is reduced. Class 5 mutations result in the production of CFTR protein with

*Corresponding author. E-mail address: felix.ratjen@sickkids.ca (F. Ratjen).

0065-3101/08/$ – see front matter

doi:10.1016/j.yapd.2008.07.015 ª 2008 Elsevier Inc. All rights reserved.
100 AMIN & RATJEN

normal chloride secretion but the number of CFTR channels is decreased.

Finally, Class 6 mutations are the result of accelerated CFTR turnover from
the cell surface.
The correlation between CFTR genotype and phenotype seems to corre-
spond best with the pancreatic disease manifestations of CF. Class 1 and 2 mu-
tations all result in the absence or severe reduction in functional CFTR and this
corresponds with pancreatic insufficiency (seen in 85% of CF patients). Patients
with Class 3, 4, 5, and 6 mutations often have some residual CFTR function
that corresponds to milder disease. These patients are usually pancreatic suffi-
cient (seen in 15% of CF patients). However, the same principal does not apply
to CF lung disease since the severity is highly variable even in patients carrying
the same CFTR mutation.

PATHOPHYSIOLOGY OF CYSTIC FIBROSIS

PULMONARY DISEASE
The pulmonary manifestations are the main cause of morbidity and mortality
in CF patients. CFTR is located on the apical surface of airway epithelial cells
and serosal cells of the submucosal glands. A lack of CFTR activity leads to
decreased chloride secretion as well as sodium hyperabsorption since one of
the physiologic functions of CFTR is to inhibit the epithelial sodium channel
[3]. This results in a decreased airway surface liquid volume, which leads to
collapse of respiratory cilia, impaired mucociliary clearance, and mucus reten-
tion on the lower airways. Inhaled microorganisms cannot be efficiently cleared
from the CF airway, which predisposes CF patients to chronic bacterial infec-
tion and recurrent pulmonary exacerbations.
CF airway infection is limited to a relatively small spectrum of bacteria. In
infants and younger children, Staphylococcus aureus and Haemophilus influenzae pre-
dominate, but a significant proportion already are infected with Pseudomonas
aeruginosa, the most common CF pathogen. The prevalence of P aeruginosa
increases with age and to date most adult patients will be chronically infected
with this organism. First infection occurs with a nonmucoid type of P aeruginosa.
If left untreated, P aeruginosa converts to a mucoid form that produces alginate,
making it less amenable to antibiotic therapy. Chronic P aeruginosa infection is
associated with a reduction in lung function and a poor prognosis [4]. Other
bacteria such as Burkholderia cepacia, Stenotrophomonas maltophilia, and Achromobacter
xylosoxidans have become more prevalent. Their role in CF lung disease is less
well established with the exception of B cepacia, which can cause a rapid decline
in lung function once a patient is infected [5].
Neutrophilic inflammation plays a key role in the pathogenesis and progres-
sion of CF lung disease [6]. Pulmonary infections attract neutrophils to the air-
way and trigger an inflammatory cascade that is excessive and persists over
time. The airways’ antiprotease defense system is overwhelmed resulting in
high levels of free elastase. Bronchoalveolar lavage (BAL) studies in CF infants
identified by newborn screening have demonstrated elevated levels of neutro-
phils and free elastase in CF airways as compared with controls [7]. Elastase
CYSTIC FIBROSIS 101

digests elastin and other structural proteins, increases mucus secretion, releases
interleukin-8 causing more neutrophilic recruitment, and cleaves opsonins,
which prevents bacterial killing by neutrophils [6]. This results in a vicious cy-
cle of airways infection and inflammation resulting in a decline in lung function
(Fig. 1).

TREATMENT OF CYSTIC FIBROSIS LUNG DISEASE

Treatment of CF lung disease can be broadly divided into two categories based
on their primary target within the cascade of CF pathophysiology (see Fig. 1)
into symptomatic treatment that addresses downstream effects of the CFTR
gene defect and those targeting the underlying abnormality. Symptomatic ther-
apy includes anti-infective and anti-inflammatory therapies as well as agents
that improve mucus clearance. Therapies that target the CFTR defect include
airway surface fluid hydration, ion transport modulators, and gene therapy, as
well as CFTR pharmacotherapy.

Symptomatic therapy
Anti-infective treatment
Pulmonary infections are the central component of CF lung disease and devel-
opments in strategies that target pulmonary infections are responsible for most
of the improvement in lifespan for CF patients in the past 2 decades. This re-
view focuses on therapies targeted against Staphylococcus aureus and Pseudomonas
aeruginosa, as these two bacteria are the most relevant for CF patients.

CF Pathophysiology
CFTR gene defect

Defective ion transport

Airway surface liquid depletion

Defective mucociliary clearance

Mucus obstruction

Infection Inflammation

Fig. 1. CF pathophysiology.
102 AMIN & RATJEN

CF patients are not infected right at birth but rather become infected with
increasing age. The best strategy to preserve an uninfected airway remains
unclear. As mentioned above, S aureus is usually the first bacterium causing
airway infection in CF patients. There is little argument that CF patients
with S aureus should be treated with antistaphylococcal antibiotics if they
develop a pulmonary exacerbation. However, what is unclear is whether
patients should be treated if they are newly infected with S aureus but remain
asymptomatic.
Continuous antistaphylococcal regimens for CF infants from the time of
diagnosis onwards have previously been studied in clinical trials. Treated
patients had a decreased number of respiratory cultures positive for S aureus,
less cough, and fewer admissions to hospital [8]. However, two clinical trials
demonstrated that antistaphylococcus treatment is associated with an increased
prevalence of P aeruginosa in the first 6 years of life [9,10]. However, most pa-
tients in these studies received cephalosporins and there is ongoing discussion
as to whether a narrow spectrum anti-staphylococcal antibiotic such as cloxacil-
lin would lead to the same increased risk of early pseudomonas. Currently,
continuous antistaphylococcal antibiotics are not standard of care.
P aeruginosa, the most prevalent CF pathogen, significantly contributes to CF
lung disease. The transformation from nonmucoid to mucoid P aeruginosa is as-
sociated with a decline in pulmonary function. Aggressive antibiotic therapy is
unable to eradicate mucoid Pseudomonas; this is partially because alginate pre-
vents antibiotic penetration into aerobic mucus plugs and provides a nidus
for the rapid development of resistant strains [1,11]. Given chronic infection
with Pseudomonas leads to a decline in lung function, many early aggressive anti-
pseudomonal strategies to prevent infection with pseudomonas have been stud-
ied and all studies demonstrate a significant microbiological effect [12–15].
Only one study has reported a beneficial effect on lung function [16]. However,
these results are questionable given the comparison with historical controls.
There are currently two large trials under way for CF patients with first P
aeruginosa infection. The outcomes for these two trials, The Early Pseudomonas
Infection Control (EPIC) trial and Early Intervention Tobi Eradication
(ELITE) trial, include pulmonary function and longitudinal monitoring of
the evolution of airway infection [17]. These studies will likely shed some light
on the both clinical effectiveness as well as the optimal strategy for early erad-
ication therapy in CF.
Once patients are chronically infected with P aeruginosa, inhaled antibiotics
have been tried as ongoing therapy for chronic bacterial suppression. Interest
in long-term inhaled antipseudomonal therapy first started 25 years ago be-
cause of the potential for high intrapulmonary concentrations with minimal
systemic toxicity [18]. The original formulations for tobramycin were off-label
intravenous preparations. The doses were chosen historically based on the vial
size of the antibiotic. The first study of low-dose tobramycin (80 mg twice
a day) was encouraging and demonstrated improved lung function [19]; how-
ever, this study had small numbers and was not controlled.
CYSTIC FIBROSIS 103

Ramsey and colleagues [20] conducted the largest randomized trial to date
using tobramycin (300 mg) a preservative-free tobramycin solution formu-
lated for inhalation. This was a placebo-controlled study of 300 mg of
inhaled tobramycin administered twice daily for 28 days alternating with
28 days off treatment. Treatment resulted in a significant increase in FEV1
(forced expiratory volume in 1 second) as well as in a 36% reduction in
the use of intravenous antibiotics for pulmonary exacerbations [20]. A recent
Cochrane review confirmed the benefits of inhaled antipseudomonal antibi-
otics on lung function and pulmonary exacerbations and their use is sup-
ported by the CF pulmonary guidelines [21,22]; however, the ideal dosing
regimen remains unclear. There has been only one study to date that com-
pared two inhaled tobramycin dosing strategies [23]. This was an open-label
crossover study for two, 3-month treatment periods that failed to show any
superiority in efficacy of tobramycin (300 mg) [23]. However, the study was
not blinded and a post-hoc analysis suggested that the study was not ade-
quately powered.
Colistin is another inhaled antibiotic that has been used to chronically sup-
press Pseudomonas. Nebulized colistin has been shown to reduce the decline in
lung function in CF patients compared with placebo [24,25]. Hodson and
colleagues [26] compared colistin (1 million units) twice daily to tobramycin
(300 mg) twice daily for 1 month; the within mean difference in FEV1 was
6.33% (95% CI 0.04 to 12.70) in favor of tobramycin. However, patients
were treated with colistin before the start of the study, which may have under-
estimated its treatment benefit. In clinical practice, the use of colistin is reserved
for patients deteriorating on alternating month tobramycin (300 mg) as an add-
on therapy during off months.
Recently, another inhaled antibiotic, aztreonam lysinate, has emerged as
a potential new treatment option for CF patients. A double-blind, placebo-
controlled, dose-escalation trial to assess tolerability and pharmacokinetics of
aztreonam lysinate has been completed in 24 CF patients [27]. Twenty-three
of the 24 patients tolerated the medication; 1 patient had an asymptomatic
FEV1 decrease of greater than 20% [27]. Aztreonam concentrations in sputum
were at or above the maximal inhibitory concentration at which 50% of the
isolates are inhibited (MIC50) for at least 4 hours post-dose; these data support
the continued development of aztreonam lysinate for treatment of pulmonary
infections in CF [27].
CF patients chronically infected with P aeruginosa, similar to patients infected
with other bacteria, go through periods of clinical stability interrupted by pul-
monary exacerbations. A pulmonary exacerbation can be loosely defined as
a constellation of clinical symptoms such as weight loss and increased cough,
new physical examination findings, radiographic changes, and a drop in pulmo-
nary function. Usually, patients are treated with oral antibiotics if they have
mild symptoms. Since limited options exist for effective oral therapy, patients
with more pronounced symptoms are often treated with intravenous antibiotics
for 2 to 4 weeks. Another approach to the treatment of pulmonary infections in
104 AMIN & RATJEN

CF patients is intravenous antibiotics every 3 months—irrespective of respira-

tory symptoms. Regular intravenous therapy is hypothesized to result in im-
proved clinical status and improved life expectancy; this has not been
supported by a randomized clinical trial [28]. However, clinical trials suffi-
ciently powered to compare on-demand versus regular intravenous antibiotic
strategies are lacking [29].

Mucolytic therapy
Mucus accumulation in the lower airways is a key feature of CF lung disease; the
major component of mucus in CF is not mucin derived from mucus-producing
cells but rather pus that includes viscous material such as polymerized DNA
derived from degraded neutrophils [30]. Currently, there are two nebulized med-
ications used as mucolytics for CF: N-acetyl-L-cysteine (NAC) and dornase alfa.
NAC disrupts the structure of the mucus polymer by substituting free sulf-
hydryl groups for the disulfide bonds connecting mucin proteins, lowering
both the viscosity and elasticity of the mucus [30]. Despite in vitro mucolytic
activity, there are no data to support the use of inhaled NAC in lung disease
[31]. One hypothesis for the lack of clinical efficacy may be that NAC selec-
tively depolymerizes the essential mucin polymer but leaves the pathologic
polymers of DNA and F-actin intact [30].
Oral acetylcysteine has been shown to improve pulmonary function in some
patients with chronic suppurative lung disease including chronic obstructive
pulmonary disease: exacerbation rates have been shown to decrease by 30%
[32,33]. The clinical benefit of oral NAC is likely secondary to the antioxidant
properties of acetylcysteine and its effect on inflammation rather than its
mucolytic properties. CF patients have a deficiency in the antioxidant, glutathi-
one, in neutrophils and oral acetylcysteine has been shown to replete glutathi-
one stores in a phase 1 trial [34]. Given the limited evidence to support the use
of both inhaled and oral N-acetylcystine, its use cannot be recommended at
present.
DNA released in large amounts from disintegrating neutrophils increases
mucus viscosity in respiratory secretions [30]. Dornase alfa is a recombinant
form of the human DNase 1 enzyme and digests extracellular DNA released
from necrosed neutrophils [30]. This results in decreased mucus viscosity
and improved mucus clearance. Inhalation of dornase alfa is indicated to re-
duce the frequency of respiratory infections requiring parenteral antibiotics
and to improve or preserve pulmonary function in CF patients [30]. The safety
and benefit of dornase alfa has been demonstrated across the entire spectrum of
CF lung disease severity: even in patients with forced vital capacity (FVC) less
than 40% predicted [35–38]. The inhalation of dornase alfa is also associated
with a decreased number of pulmonary exacerbations as well as a positive
effect on inflammation in the CF airways [39]. Efficacy during acute pulmonary
exacerbations has not yet been shown [40].
This medication is very well tolerated but some side effects that were found
to be significant in the Phase 3 study include voice changes, pharyngitis, and
CYSTIC FIBROSIS 105

laryngitis [35] Furthermore, this medication often induces coughing and should
not be given right before bed.
DNA and F-actin copolymerize in the sputum to form a rigid network in the
mucin gel [41,42]. Gelsolin, an actin-severing protein, has been shown to
reduce mucus viscosity but cannot be nebulized [43]. Interestingly, thymosin,
an agent that sequesters F-actin and decreases sputum polymerization, has
been shown to be more effective when combined with dornase alfa than either
substance alone [43,44]. At present, in vivo data are lacking to support the use
of either one of these agents.

Anti-inflammatory therapy
Neutrophilic inflammation plays a key role in the pathogenesis and progression
of CF lung disease [6]. Neutrophilic inflammation leads to the formation of
toxic oxygen free radicals and free elastase; their persistence leads to pulmo-
nary destruction [7]. The pathophysiological relevance of airway inflammation
for CF lung disease therefore supports the use of anti-inflammatory therapy.
Corticosteroids have been studied via oral, inhaled, and intravenous routes.
Long-term oral steroids were first shown to be effective more than a decade ago
[45]. However, the side effects (eg, growth retardation, diabetes, gastritis) in
both single and multicenter studies are too great to recommend long-term ste-
roid use [46,47]. A chest physicians’ survey administered to physicians in the
United Kingdom demonstrated that all survey responders admitted to using
short-term oral steroids to treat pulmonary exacerbations [48]. Interestingly,
despite the apparent widespread use of steroids to treat exacerbations by prac-
titioners, there have been only two trials to date to study the effect of oral ste-
roids during pulmonary exacerbations [49,50]. Tepper and colleagues [50]
studied 20 infants randomized to routine pulmonary exacerbation treatment
plus intravenous hydrocortisone or placebo for 10 days. They also found no
change in lung function at the end of admission but found improved lung func-
tion at the postadmission follow-up visit, suggesting a long-term benefit to lung
function [50]. Recently, a pilot study has been completed in older CF patients.
The addition of steroids to conventional treatment for a pulmonary exacerba-
tion did not significantly affect pulmonary function or sputum markers of
inflammation [49].
Lucidi and colleagues [51] have taken a novel approach to the delivery of
systemic corticosteroids: delivery of low-dose intravenous steroids through in-
fusion of autologous erythrocytes loaded with dexamethasone. A pilot study
compared nine patients receiving monthly intravenous infusions for 2 years
to patients receiving standard therapy. The FEV1 in the experimental group
was higher than in the placebo group and there were no steroid side effects re-
ported [51]. However, there is no evidence to date that this strategy will reduce
the negative side effects of corticosteroid therapy.
Despite the lack of evidence in the literature to support the use of inhaled
corticosteroids as a long-term anti-inflammatory therapy, many CF patients
are receiving this treatment [52]. There certainly is a role for inhaled steroids
106 AMIN & RATJEN

in CF patients who have a concomitant diagnosis of asthma with symptomatic

wheezing; however, a diagnosis of asthma is challenging in the CF population
given that the clinical phenotype varies over time.
Balfour-Lynn and colleagues [53] showed that withdrawal of inhaled cortico-
steroids in children and adults did not result in an increase in pulmonary exac-
erbations, adverse effect on lung function, or an increased use of antibiotics or
rescue bronchodilators. Although the Cochrane review concluded that there
were no adverse effects of inhaled steroids in CF patients, a recent study
showed a decrease in growth velocity in patients using fluticasone (1000 lg/
day) over 12 months; catch-up growth was not seen 1 to 2 years after medica-
tion discontinuation [52,54]. Therefore, inhaled corticosteroids do have a role
for CF patients with asthma but their use should be limited to this subgroup of
patients and high doses should be avoided.
High-dose ibuprofen has been studied as an alternative to corticosteroid ther-
apy. In high doses, ibuprofen inhibits the migration, adherence, and aggrega-
tion of neutrophils [55–64]. High-dose ibuprofen has been used instead of
conventional doses of ibuprofen because low doses of ibuprofen paradoxically
increase the influx of neutrophils [65]. In a blinded, randomized trial, CF
patients with mild lung disease were shown to have an improvement in their
FEV1% predicted decline [66]. However, the side-effect profile of this therapy
as well as the need for pharmacokinetic monitoring to achieve adequate serum
levels has prevented its widespread use [66,67]. A recent single-center study re-
ported that 45% of children had to discontinue high-dose ibuprofen because of
adverse effects [68].
A multicenter, Canadian trial of high-dose ibuprofen in CF patients with
mild lung disease (FEV1 > 60%) has recently been published [69] Patients in
the treatment group had fewer days in hospital in a post-hoc analysis and ex-
perienced no adverse effects; however, a significant change in FEV1 was not
seen [69]. Of note, the study recruitment fell far below the sample size calcu-
lated to power the study: 142 patients rather than 440 [69]. A 2007 Cochrane
review of oral anti-inflammatory therapies for CF identified six trials for review
[70]. All showed evidence of improved lung function or decreased intravenous
antibiotic use. No major adverse effects were reported, but the trials were
underpowered to detect clinically important differences in the incidence of
adverse effects. Konstan and colleagues [71] published an observational study
after the Cochrane review that compared the decline in FEV1 among CF pa-
tients aged 6 to 17 years on ibuprofen therapy with those who did not receive
ibuprofen. Treated patients had a slower rate of lung function decline, but were
also more likely to be hospitalized for a gastrointestinal bleed (relative risk 2.72,
P < .001). In summary, high-dose ibuprofen does seem to have a treatment
benefit but has not become standard of care for CF patients because of the
mixed results of trial data as well as the adverse event profile.
Antileukotriene therapy has been explored as a potential anti-inflammatory
treatment in CF. Leukotriene B4 plays a role in neutrophilic recruitment.
Konstan and colleagues [71] compared the eicosanoid content of epithelial
CYSTIC FIBROSIS 107

lining fluid (ELF) obtained by bronchoalveolar lavage (BAL) from 17 patients

with CF and 10 healthy subjects. LTB4 was the predominant eicosanoid in the
CF airway and the data suggested that the CF airways contain sufficient
amounts of LTB4 both to recruit additional neutrophils into the airways and
to stimulate neutrophils to release their injurious products [72]. In fact, the re-
duction of LTB4 is one of the proposed mechanisms of action of ibuprofen [73].
Therefore, therapies aimed at interfering with the production or action of
LTB4 may be beneficial for CF lung disease. A large phase 2 trial of a leukotri-
ene B4 antagonist (amelubant) in CF patients with mild to moderate disease
was stopped prematurely because of an excess number of significant adverse
events (admissions for pulmonary exacerbations), raising the question of
whether the anti-inflammatory effects were too potent thereby favoring bacterial
infection.
Cysteinyl leukotrienes have also been shown to be present in increased
amounts in the CF airways. In a randomized, double-blind, crossover, pla-
cebo-controlled study, 16 children with mild CF were treated with montelukast
or placebo for 21 days [74]. There was a significant reduction in serum eosin-
ophil cationic protein levels and eosinophils but no significant differences in
lung function tests or clinical symptom scores [74]. Therefore, some evidence
exists that montelukast reduces eosinophilic inflammation in CF patients but
effects on neutrophilic inflammation have not been demonstrated. Montelukast
is therefore likely to be useful only in the subgroup of atopic CF patients.
The success of macrolides for panbronchiolitis, a disease with many similar-
ities to CF, led to the study of macrolides in CF patients [75]. Macrolides have
been shown to improve lung function and/or decrease the number of pulmo-
nary exacerbations in more than 350 P aeruginosa–positive CF patients who
are 6 years of age and older [76–78]. Interestingly, a post-hoc analysis showed
that the reduction in exacerbations was not necessarily predicted by improved
pulmonary function for individual patients, suggesting a heterogeneous
response to treatment [79].
Although the clinical efficacy of macrolides has been demonstrated, the
mechanism of action of macrolides remains unclear [47]. A recent study aimed
to determine the mechanism of action of azithromycin explored three mecha-
nisms: a direct effect on CFTR and multidrug resistance (MDR) gene product
expression, improved epithelial ion transport, and impaired P aeruginosa adher-
ence and transport [80]. The authors felt that none of the three were likely and
speculated that the mechanism of action may be a result of the breakdown of
P aeruginosa biofilms, allowing penetration of the antibiotics [80].
More recently, azithromycin has been studied in younger CF patients who
are not necessarily P aeruginosa positive. In a multicenter trial conducted in
France, only 25% of the patients were chronically infected with Pseudomonas
[81]. There was a significant reduction in the number of pulmonary exacerba-
tions and equal effectiveness was shown in both those infected and not infected
with Pseudomonas [82]. This suggests that this treatment doesn’t need to be lim-
ited to those infected with Pseudomonas. A multicenter trial is currently under
108 AMIN & RATJEN

way to determine the efficacy of azithromycin in Pseudomonas-negative CF

patients [83].
Recently, there has been some concerning evidence regarding the emergence
of macrolide resistance. Phaff and colleagues [84] reviewed sputum cultures for
more than 150 CF patients over the 4 years after azithromycin was introduced.
S aureus resistance to erythromycin increased from 7% to 54% and Haemophilus
sp resistance to clarithromycin increased from 4% to 38%; actual azithromycin
resistance was not reported in the study [84]. One study that followed patients
for 3 years after the start of an oral macrolide interestingly showed that the
improvement in lung function that was seen after the first year was not sus-
tained for the next 2 years [85] The results of this study suggest that the
long-term effect of macrolides is an area that needs further clarification.
Three studies looked at the effect of a1-antitrypsin inhibitors in CF patients
[86–88]. The first study was a proof-of-concept study that showed that aerosol-
ized a1-antitrypsin inhibitors decreased free elastase in bronchoalveolar lavage
samples of CF patients [86]. The second study was a prospective, double-
blinded, randomized, placebo-controlled phase 2 trial to determine the safety
and efficacy of a1-antitrypsin inhibitors for CF patients. Thirty-nine patients
were randomized to receive nebulized a1-antitrypsin inhibitors for 4 weeks fol-
lowed by a 2- week washout period and then another 2 weeks of therapy [87].
This study did not demonstrate a significant reduction in sputum elastase
concentrations and no effect on airway inflammation or lung function could
be demonstrated. Recently, a prospective trial was done of 52 CF patients
whom received nebulized a1-antitrypsin inhibitor for 4 weeks [88]. Inflamma-
tory indices such as free elastase, neutrophils and pro-inflammatory cytokines
all significantly decreased but a change in FEV1 was not seen [88]. The differ-
ing results may be partially attributed to the delivery systems, as a highly effi-
cient nebulization system was used in the latter trial. The lack of effect on
pulmonary function may require longer studies, as anti-inflammatory treatment
is more likely to affect lung function decline rather than increasing lung func-
tion in treated patients [88]. Therefore, a large randomized trial is needed to
assess the efficacy of antiprotease inhibitors in this population.
A number of other potential anti-inflammatory agents have been evaluated
in pilot studies. These include oral cyclosporin, intravenous immunoglobulin,
simvastatin, pioglitazone, hydroxychloroquine, low-dose methotrexate, and
oral glutathione [47,89] Further details about each of these drugs and the ongo-
ing studies to evaluate them can be found on the Cystic Fibrosis Foundation
Web site [90].

Ion transport modifier therapy

Defective CFTR signaling results in impaired chloride secretion. Increased in-
tracellular Ca2þ has been shown to stimulate chloride secretion across the CF
airway through the alternative chloride channel [91]. As such, Ca2þ-dependent
agonists have been proposed as therapeutic agents for CF. Mason and col-
leagues [85] demonstrated that purine and pyrimidine nucleotide triphosphates
CYSTIC FIBROSIS 109

(ATP, UTP), acting at P2Y2 receptors, stimulate chloride secretion in CF tra-

cheal epithelium via an increase in intracellular Ca2þ. However, the natural
P2Y2 agonists, ATP and UDP, have very short half-lives, which is why deriv-
atives with enhanced stability such as denufusol have been developed [92]. De-
nufusol is a P2Y2-receptor agonist. Its main mechanism of action is to stimulate
chloride ion secretion and inhibit sodium ion reabsorption, thus hydrating the
airway lumen by fluid co-transport [93–96]. A safety and tolerability study of
denufusol in CF patients with mild to moderate CF lung disease has been com-
pleted [97]. Doses of up to 60 mg were inhaled, with good tolerance in most
patients [97]. The most common adverse effects in children were cough and
an acute, reversible drop in FEV1 [97]. Two phase 2 trials have been completed
and demonstrate improved lung function in the experimental group [98,99]. A
large multicenter phase 3 trial titled Transport of Ions to Generate Epithelial
Rehydration (TIGER) is currently under way to assess the efficacy of this
compound in patients with mild lung disease as an early intervention strategy
for CF [92].
Moli1901 (duramycin) is a peptide that interacts with phospholipids in the
plasma and cell membrane and also activates the alternative chloride channel
by elevating intracellular calcium [92]. A phase 2 trial of inhaled Moli1901 in
24 CF patients demonstrated that the medication was both safe and effective
[100]. A multicenter, European efficacy study has been started this year [92].

Treatments that target cystic fibrosis transmembrane

conductance regulator
Airway surface liquid hydration therapy
Effective mucociliary clearance depends on adequate volume of airway surface
liquid [101]. In CF lung disease, impaired epithelial chloride secretion and so-
dium hyperabsorption lead to depletion of airway surface fluid and subsequent
impaired mucus clearance [102]. This has led researchers to study osmotic sub-
stances such as inhaled mannitol and hypertonic saline that can increase airway
surface liquid volume.
Mannitol is a six-carbon monosaccharide that can be encapsulated to be a sta-
ble dry powder for inhalation [103]. Mannitol is able to create an osmotic gra-
dient that causes an influx of water into the CF airway and restores the volume
of the airway surface liquid [103]. The effect of mannitol on mucociliary clear-
ance has been shown in a radioaerosol study where mucociliary clearance was
significantly increased in the patients receiving mannitol (300 mg by inhalation)
as compared with controls [104]. Charlton and colleagues [105] demonstrated
the short-term efficacy of mannitol in a clinical trial. The investigators random-
ized 39 CF patients to inhaled mannitol (420 mg twice a day) or placebo for
2 weeks, followed by a 2-week washout, in a 6-week crossover trial. A 7% in-
crease in FEV1% predicted was seen in the group that received mannitol [105].
However, the long-term benefit of inhaled mannitol remains unknown and is
an area of further study.
110 AMIN & RATJEN

There is some concern that chronic mannitol inhalation can contribute to the
proliferation of bacteria. Mannitol is a carbon source that can be metabolized
by bacteria such as Pseudomonas [105,106]. This potential adverse effect needs
to be clarified by quantitative microbiologic cultures in future studies [104].
Dry powder mannitol is not currently approved for clinical use as a mucociliary
clearance agent in patients with CF.
Before 2006, smaller studies using hypertonic saline showed promising
short-term benefits including improved mucus transport, hydration of the air-
way surface, and improved mucociliary clearance and lung function in CF
patients [107–112]. Hypertonic saline has been shown to directly improve mu-
cociliary clearance [112]. The increase was concentration dependent, as muco-
ciliary clearance continued to increase up to a concentration of 7%. Higher
concentrations (12%) did not stimulate mucociliary clearance further and
were poorly tolerated; therefore, 7% is the concentration that was used in sub-
sequent clinical trials [112]. The sustained effect of hypertonic saline on airway
surface liquid (ASL) volume was elegantly shown in a study by Donaldson and
colleagues [102]. The ASL volume increased fourfold after inhaled hypertonic
saline (7%) in normal airways and returned to baseline within 10 minutes. In
contrast, the effect was much greater and lasted longer in the CF airway. In
a randomized controlled trial there was also evidence of improved mucociliary
clearance for up to 8 hours after one dose and lung function improved within
2 weeks [102].
In 2006, a large multicenter trial demonstrated for the first time the long-
term benefit of inhaled hypertonic saline [113]. After 48 weeks of inhaled
hypertonic saline (7%), patients had an improved FEV1 and fewer pulmonary
exacerbations as compared with controls [113]. There is not yet a study in the
literature assessing the effect of inhaled hypertonic saline on infants and young
children with CF. A single-center study recently showed that inhaled hyper-
tonic saline can be used safely in this age group [114]. A multicenter trial to
assess the effect of inhaled hypertonic saline in infants is planned for the start
of 2008.
Inhaled hypertonic saline (7%), 4 mL, as used in the phase 3 Australian
study would add on 30 minutes of therapy time for CF patients using contem-
porary nebulization systems. Nebulization systems with a more efficient nebu-
lizer system such as the eFlow Rapid Nebulizer (Pari, Germany) have been
shown to be both time saving and well tolerated [115]. These systems will
hopefully be available for clinical use shortly. Hypertonic saline is associated
with bronchospasm and patients should be pretreated with bronchodilators.
In addition, pre- and postnebulization spirometry should be done with the first
dose of the medication. Although, there are known side effects such as salty
taste, nausea, dyspnea, and chest pain, it has been well tolerated in the larger
studies [102,113]. Unlike many other CF therapies, it is a very inexpensive
medication. While its clinical effectiveness is clear in the short term, the
long-term effects of hypertonic saline on pulmonary infection and inflammation
remain unclear.
CYSTIC FIBROSIS 111

Gene therapy
The gene defect causing CF is known and as such CFTR gene therapy has
been explored by researchers as a curative treatment. Although several vectors
have been studied in human patients, adenoviruses, adeno-associated viruses
(AAV), and cationic lipids seem to be the most promising [116]. CFTR can
be successfully delivered to the airway epithelium but its effects are short-lived
which makes repeated dosing essential [92]. Unfortunately, this presents a ma-
jor challenge to the use of adenovirus vectors. Although they have a higher
transfection rate than lipid vectors, they are immunogenic, which limits the
ability for multiple dosing [92]. Furthermore, Tosi and colleagues [117] re-
ported an increase in antiadenovirus immune response in mice when hosts
have a preexisting infection with pseudomonas. Although similar studies
need to be repeated in humans, chronic infection may be a significant hurdle
for gene therapy.
Adeno-associated virus vectors have subsequently been developed with the
hope for decreased antiadenovirus immunogenicity. Moss and colleagues
[118] completed a phase 2 trial assessing the safety and efficacy of repeated
doses of gene therapy using AAV vectors. The investigators showed both a sig-
nificant improvement in FEV1 as well as a reduction in sputum interleukin-8
(IL-8) [118]. Based on these results, Targeted Genetics Corporation initiated
a study powered to detect changes in lung function; however, the trial did
not meet its outcome measure and the program has been discontinued [119].
The disappointing results may be attributed to one or a combination of (1)
the vector’s transfection inefficiency, (2) the promoter used to drive CFTR
expression, or (3) antiviral immunogenicity [119].
Recent attention has focused on the cationic lipid vector. The UK Cystic
Fibrosis Gene Therapy Consortium has a double-blind, placebo-controlled
gene therapy study planned for 2009 [120]. The intervention will be adminis-
tered over a 1-year time period. Although gene therapy is not an imminently
available therapy, it is a promising future intervention.

Cystic fibrosis transmembrane conductance regulator pharmacotherapy

Unlike the previously mentioned interventions, these therapies are CFTR mu-
tation class specific. As such, these interventions are tailored to a patient’s class
of genetic defect (see Fig. 1) [121]. Class 1 mutations, stop mutations, are the
result of the insertion of a premature stop codon (PTC). Aminoglycosides,
an example of a correcting agent, have been shown in proof-of-concept studies
to induce read-through of a PTC enabling the formation of a full-length and
functionally active CFTR protein [122–124]. Phase 2 trials are currently under
way to assess a second-generation agent known as PTC124 [17].
CFTR pharmacotherapeutic agents for other classes of CFTR mutations can
be classified as agents that correct the CFTR trafficking defect or agents that
potentiate CFTR function. VX-770, a compound developed by Vertex Phar-
maceuticals Inc (Cambridge, Massachusetts) is a promising CFTR potentiator.
VX-770 increases cyclic AMP–dependent chloride secretion in cell cultures
112 AMIN & RATJEN

expressing the dF508, R117H, or G551d- CFTR mutations [92]. VX-770 is cur-
rently being studied in CF patients with G551D mutations; if the results are
positive, this compound could then be used in CF patients with other muta-
tions [92]. Flavenoids are another known CFTR potentiator, and studies are
currently under way to assess their effectiveness for CF patients [125].

GROWTH AND NUTRITION

Malnutrition is a key feature of CF. Defective CFTR in the pancreatic epithe-
lium results in ductal obstruction by proteinaceous secretions and acinar
destruction. CF patients become pancreatic insufficient when more than 95%
of total pancreatic exocrine function is lost [126]. These patients develop fat,
protein, and carbohydrate malabsorption and are at risk for fat soluble vitamin
deficiencies (ie, vitamins A, D, E, and K) as well as other mineral deficiencies.
Nutrition and lung function are intertwined. Poor nutritional status and poor
somatic growth secondary to pancreatic insufficiency likely affects lung growth
as well as the ability to repair lung disease [127]. Similarly, pulmonary disease
affects linear growth through appetite suppression and increased energy expen-
ditures (see Fig. 2) [127]. Corey and colleagues [4] showed that a poor weight in
cystic fibrosis patients was associated with lung disease and suggested that mal-
nutrition may be part of the causal pathway leading to mortality. Although, this
relationship seems intuitive for CF patients with severe lung disease, it wasn’t
known until recently if this holds true for younger patients with milder disease.
Prospective data were used to determine if weight and height percentiles for
patients between 3 and 6 years of age predicted pulmonary function at age 6.
Pulmonary function was found to be highest in those whose weight for age
remained greater than the 10th percentile from ages 3 to 6 and lowest in those
who remained less than the 10th percentile [127]. These findings reinforce the
importance of good nutrition for CF patients starting from a young age.
Growth and nutritional management is a central component of CF therapy.
Pancreatic enzymes and fat-soluble vitamin supplements are standard of care

Caloric Caloric
Supply Expenditure
•Increased Caloric Needs
•CFTR Defect
•Decreased Caloric Intake •Persistent Infection and
•Anorexia Inflammation
•Repeated Pulmonary Exacerbations
•Enteral Loss due to pancreatic
insufficiency

•CFRD

Malnutrition in Cystic Fibrosis

Fig. 2. Factors contributing to malnutrition in a cystic fibrosis patient.

CYSTIC FIBROSIS 113

for pancreatic-insufficient patients. However, even with exogenous enzyme

supplementation, malabsorption is rarely completely resolved. In addition,
CF patients have an increased energy expenditure. Therefore, CF patients
are to consume between 20% and 50% more calories than non-CF patients.
Despite this increased caloric intake, some CF patients fail to thrive. When
CF patients show signs of growth retardation according to their percentiles,
patients will be started on oral nutritional supplements; if they fail to improve,
a gastrostomy tube will be inserted for nutritional supplementation.
Height is an independent risk factor for poor pulmonary function and is of
particular concern because even patients with good nutritional status do not
achieve full target height [127–129]. Chronically elevated inflammatory cyto-
kine levels have been shown to both affect the production and the secretion
of growth hormone (GH) and induce GH resistance at the tissue level
[130,131]. As such, GH therapy has been explored as a treatment option for
CF patients. Multiple small studies using recombinant human growth hormone
(rhGH) in CF children with height and weight less than the 10th percentile
have shown improvements in somatic growth [132–138]. A randomized, con-
trolled, crossover trial designed to determine both the efficacy of growth
hormone after 1 year of therapy and to assess the sustained effects after treat-
ment cessation has been completed. Patients who received rhGH had greater
gains in height and weight, increased lean mass, fewer exacerbations, and
the benefits were sustained for 1 year after the rhGH was stopped [139]. How-
ever, there was no difference in pulmonary function between the two groups
[139]. Schnabel and colleagues [140] conducted the only double-blind pla-
cebo-controlled study to assess the efficacy and safety of two dosages of GH
in CF. While a significant increase in growth was observed in treated patients,
increases in weight failed to be significant, since patients in the placebo group
also showed significant improvement. Interestingly, weight gain was limited to
patients with better lung function, raising the question of whether an earlier in-
tervention would be more efficacious. No effects on pulmonary function in
treated patients were observed, which was similar to the Hardin and colleagues
trial [137]. The maximal oxygen uptake during peak exercise increased signif-
icantly in treated patients. This suggests that GH may have a positive effect on
physical activity, which has been previously shown to be related to lung func-
tion decline [141]. However, rhGH is not a benign intervention. It is adminis-
tered by subcutaneous injection, weekly. In addition, there is a theoretic risk of
malignancy and diabetes. As such, there is currently insufficient evidence to
recommend the routine use of recombinant human growth hormone therapy
for patients with CF.

CYSTIC FIBROSIS–RELATED DIABETES

Cystic fibrosis–related diabetes (CFRD) can develop in CF patients as a conse-
quence of the pancreatic pathology. The prevalence increases with age; the
average age of onset is between 18 and 21 years [142]. It rarely develops in
114 AMIN & RATJEN

patients younger than age 10 [143]. Therefore, annual screening for CFRD
with an oral glucose tolerance test starts at age 10.
The onset of CFRD is often insidious and the diagnosis is usually preceded
by a decline in pulmonary function [144,145]. Therefore, delaying the diagno-
sis can result in a preventable decline in clinical status. CFRD can be chronic or
intermittent. In CF patients with intermittent CFRD, the hyperglycemia often
occurs during times of stress (ie, pulmonary exacerbations) or while on steroid
therapy. CF patients with CFRD may develop microvascular complications,
but macrovascular complications are rare. This may be a result of a shortened
lifespan in CF patients or a result of fat malabsorption [146].
The goal of treatment in CFRD is to achieve optimal nutrition and avoid
metabolic derangement by maintaining normoglycemia [146]. Insulin is the
treatment of choice. The decision to treat with insulin is a clinical decision
based on patient status as well as glucose levels measured at home or in the
hospital [146]. Intermittent CFRD can be treated with insulin during these
episodes of hyperglycemia as compared with patients with chronic CFRD
whom require daily insulin therapy. There is a broad range of different insulin
regimens and the treatment regimen chosen can be tailored to the individual
patient’s needs. In addition, studies are currently under way to determine if
oral antiglycemic agents are an effective intervention for patients with newly
diagnosed CFRD [147,148].

SUMMARY
In summary, there is a significant interplay between the pulmonary manifesta-
tions and nutritional status of CF patients. The advances in CF clinical care in
the past 2 decades are mainly attributed to anti-infective therapy as well as ag-
gressive nutritional management. Currently, there are multiple therapeutic
agents that are in clinical trial that target either the underlying CFTR defect
or the downstream effects of CFTR. The broad spectrum of therapeutic agents
being studied as well as the advances in therapies that target the underlying
CFTR defect are exciting, making it likely that at least one of the treatments
will make a major difference in how we will treat CF in the future.

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