Open Journal of Pediatrics, 2012, 2, 187-196 OJPed Published Online September 2012 (
Cystic fibrosis overview and update on infant care*
Raj Padman#, Vandna Passi
Division of Pulmonary Medicine, Nemours/Alfred I. duPont Hospital for Children, Wilmington, USA
Received 9 November 2011; revised 31 January 2012; accepted 16 July 2012
Cystic fibrosis is now the most common serious, auto-
somal-recessive disease. It has been described in
every population in all parts of the world. In the US,
newborn screening is available in all states. Current
studies demonstrate that newborn screening, early
diagnosis, early nutritional and environmental inter-
vention, and an understanding of the pathophysiology
of the disease may increase life expectancy and qual-
ity-of-life. Evidence-based guidelines encourage the
use of early nutritional intervention and initiation of
pulmonary therapies. The average lung function of
patients with cystic fibrosis corresponds with genetic
makeup, age of intervention, and environmental fac-
tors including the socioeconomic status of the pa-
tient’s family. We reviewed and updated current un-
derstanding of the pathophysiology of the disease,
diagnosis, and the benefits of early diagnosis via
newborn screening in evaluating the nutritional status
of our youngest cystic fibrosis patients; the direct
correlation of malnutrition to pulmonary- and cogni-
tive-function outcomes are reviewed and updated
from literature.
Keywords: Cystic Fibrosis; Newborn Screening;
Nutrition; Ai r way Infl am mation; Pseudomonas
Cystic fibrosis (CF) is an autosomal-recessive, generalized,
multi-organ-system disease caused by a single biochemi-
cal abnormality: the defective chloride channel caused by
the cystic fibrosis transmembrane conductance regulator
(CFTR) protein. The pathophysiology of the disease lies
in different gene mutations that encode abnormalities in
the structure of this protein. These abnormalities lead to
a physiologic defect in ion (chloride and sodium)
transport at the apical membrane of epithelial surfaces
[1]. This defect affects all the exocrine gland functions:
sweat glands, salivary glands, pancreas, hepatobiliary
system, lungs, intestines, and reproductive system. It is
characterized by the clinical phenotype of recurrent res-
piratory infections, pancreatic insufficiency, and an ele-
vated sweat chloride. The major morbidity and mortality
are related to the involvement of the lung s, which appear
free of infection at birth but within a few weeks exhibit
small airway mucus plugging and recurrent chronic
infection. Approximately three to seven percent of patients
may develop hepatobiliary involvement [2] with focal
biliary cirrhosis leading to portal hypertension and liver
failure needing liver tran splant. CF has been described in
every population, in every part of the world, and is
currently the most common serious, autosomal-recessive
inherited disease. The highest incidence of CF is in
people of northern European extraction, with an ap-
proximate incidence of one in every 3300 [3]. Curr ently,
there are an estimated 30,000 patients in the United
States [4] and an estimated 70,000 patients with CF
worldwide. More than 40% of these patients are adults.
Over 1720 mutations have been reported [5]. More than
12 million (one in 20) Americans carry the gene, and
many are unknowing, asymptomatic carriers [6]. Con-
tinuance of high gene-frequency has lead geneticists to
postulate a heterozygote advantage of 2% to 2.5%.
Carriers are resistant to tuberculosis and other infections,
such as chloride-secreting diarrhea and infantile gastro-
Cystic fibrosis is at the forefront of quickly evolving
medical discoveries. Currently, every state in the US
participates in some form of newborn screening for CF,
and it is estimated that over two million newborns are
screened annually for the disease. CF has become the
paradigm for biomedical research and the study of
genetic diseases and, indeed, for the medicine of the
future. It is possible to identify a gene whose structure
and function are unknown and use that information to
develop “designer” therapies. The accomplishments to
date have been absolutely outstanding and have provided
a foundation for this field that goes much beyond CF.
1.1. CF Gene/Pathophysiology
*No conflicts of interest or funding to report.
#Corresponding author. The CFTR gene, isolated in 1989 by Lap Chi Tsui and
R. Padman, V. Passi / Open Journal of Pediatrics 2 (2012) 187-196
Francis Collins, is located on chromosome 7q31.2. A
large sized gene, it contains 27 exons and 250,000 base
pairs. Through the effor ts of the Cystic Fib ro sis Mutation
Database, maintained by the Cystic Fibrosis Foundation,
a consortium comprised of approximately 80 laboratories
worldwide have identified 1720 mutations in the years
since the CF gene isolation. Seventy percent of the
mutations are a result of deletion of three base pairs of
nucleotides, leading to loss of a single amino acid,
phenylalanine (F), in position 508 [7]; this is referred to
as delta-F508 mutation. The gene codes for a cyclic
AMP-mediated chloride channel referred to as CFTR
protein. There are five major classes of CFTR mutation
causing CF [8,9]. Class I contains a defective protein
production. There is defective processing, regulation and
conduction in class II, III and IV, respectively, and there
is reduced synthesis in class V. The most common
delta-F508 mutation is a block in the processing; this is a
class II mutation where the protein is misfolded and the
internal quality-control system prevents it from coming
to the surface to function as a chloride channel. The
milder mutations—classes III, IV, and V—are all
potentially more amenable to therapy. Regarding the
genotype-phenotype relationship, patients homozygous
for delta-F508 have pancreatic insufficiency from birth,
higher sweat-chloride content, and a greater chance of
being diagnosed at an earlier age due to clinical presen-
tation of symptoms [10]. Regarding pulmonary-function
tests, however, there does not seem to be a close cor-
relation between genotype and phenotype; this may be
related to multiple factors, such as modifier genes and
environmental factors that may work in concordance
with socioeconomic status. Primary care providers will
be able to better counsel their patients with this back-
ground knowledge.
The gold standard for diagnosing CF is defined by two
positive sweat-tests obtained on two separate sites, per-
formed on different days, and performed in a laboratory
accredited by the Cystic Fibrosis Foundation with
continual levels of high quality-control. Sweat chloride
over 60 is considered diagnostic of CF, 40 to 60 is
considered the indeterminate range, and less than 40 is
normal [11]. The notable exception is infants under the
age of approximately six months; in this population, the
lower limit of abnormal sweat chloride is 30 [12,13]; this
is an important new information of which primary care
pediatricians need to be aware. The consensus statement
from Cystic Fibrosis Foundation [14] reports that the CF
diagnosis is suggested by the presence of one or more
characteristic clinical features, a history of CF in a
sibling, or a positive newborn screening test. This will
then be confirmed by laboratory evidence for CFTR
dysfunction, namely, two positive sweat tests or iden-
tification of two CF-causing mutations. For patients in
whom sweat chloride concentrations are normal or
borderline and in whom two CF mutations are not
identified, abnormal nasal PD measurements recorded on
two separate days can be used as evidence for CFTR
dysfunction [14]. Furthermore, infants screened with im-
munoreactive trypsin (IRT) who have an elevated IRT (>
95th percentile), a borderline sweat chloride, and only
one disease-causing mutation may have what is now
referred to as CF-related metabolic syndrome and need
to be followed closely for manifestations of classic CF
The sodium chloride at the bottom of the sweat duct
has the same concentration of salt in normal patients and
in CF patients. W ith the presence of the CFTR protein in
the normal lining membrane, as the sweat moves up the
duct, sodium and chloride are reabsorbed and a low-
salt-containing sweat is seen on the surface. In CF
patients, because of the lack of CFTR protein in the
sweat-duct lining, there is no reabsorption of sodiu m and
chloride; thus, high salt-levels are seen in the sweat.
1.2. Hypothesis for CF Airway Disease
Current theories provide two hypotheses for the genesis
of CF airway disease: the high-salt hypothesis and the
depleted- (or low-) volume theory [16]. Based on the
high-salt hypothesis, β-defensins on the epithelial sur-
faces of the lungs and trachea are salt-sensitive and do
not function properly in the relatively hypertonic airway-
surface liquid in CF airways. Alternately, the low-volume
hypothesis theorizes that ciliary clearance is affected by
dehydration of airway-surface liquid n the periciliary
liquid layer in CF individuals [17]. Normal airway-
surface liquid contains sol and gel layers. For the cilia to
stand straight up and beat fast forward with a slow,
backwards motion, the height of the sol layer is important
in mucociliary defense. In CF patients, secondary to the
abnormal chloride channel with excessive sodium re-
absorption, the periciliary liquid is dehydrated. The cilia
cannot function normally. The CFTR dysfunction leads
to decreased chloride secretion, increased amiloride-sen-
sitive sodium absorption, and a diagnostically signifi-
cant raised potential difference across the CF airway [17].
The defective transepithelial fluid transport in CF air-
ways points directly to the conclusion that a mutation in
CFTR causes CF disease.
1.3. CFTR
In the mid-1990s, CFTR was initially described as a
chloride channel with two membrane-spanning domains,
two nucleotide-binding domains, pyruvate kinase and
ATP-binding domains, leading to the chloride channel.
However, more research into CFTR uncovered that
intermolecular interactions between the C-terminus of
Copyright © 2012 SciRes. OPEN ACCESS
R. Padman, V. Passi / Open Journal of Pediatrics 2 (2012) 187-196 189
CFTR and regulatory networks are vital for CFTR
function. Through a number of mechanisms, CFTR
controls the epithelial sodium channel as well.1 In normal
individuals, 75% of the CFTR protein is degraded, and
25% functions as a chloride channel. In CF patients, 99%
of the CFTR protein is degraded, and only 1% functions
as a chloride channel. Current research postulates that if
at least 4% of the CFTR protein can be made to function
as a chloride channel, one can reverse the changes of CF.
However, increased sulfation of mucins may enhance
adherence of Pseudomonas aeruginosa [18]. Within the
Golgi apparatus, the CFTR protein derangement leads to
an abnormally high pH; such a change will affect the
activity of the most pH-sensitive enzymes, sialyl-trans-
ferases, which covalently modify newly synthesized
molecules. Less-impaired enzymes and less-pH-sensitive
sulfur transferases take over. As a result of this mo-
dulation of enzyme activity, abnormally sulphated mem-
brane constituents may be transported to the cell surface
and cause more avid adherence of P. aeruginosa to the
surface of the cell [19].
1.4. Role of CFTR Protein
The physiologic properties of CFTR are numerous: it
acts as a chloride channel, regulates the ep ithelial sod ium
channel and endosomal pH, is an interaction partner of
many cellular proteins, and may be responsible for pro-
moting P. aeruginosa adherence [20,21]. A mutant
CFTR affects ion and fluid transport across the epithelial
membrane, which may impair mucociliary clearance and
encourage bacterial colonization of the airways. Mutant
CFTR may act as a receptor for P. aeruginosa [21]. In
addition to mutant CFTR, environmental factors and
genetic modifiers also affect outcomes and phenotypic
presentation. This helps the pediatrician to understand
and explain a differing phenol-type despite having the
same CF gene mutation. Comprehending this basic
pathophysiology, clinicians will appreciate the manifes-
tations of the disease and understand the rationale for
prescribed treatment modalities, such as mucolytics, and
hydrating agents, such as hypertonic saline inhalations.
1.5. Mucus in CF/Structural Changes in Lung
Bronchoscopic findings reveal the very thick, viscous
and extremely elastic mucus adhering to the airways in
CF patients. The pulmonary abnormalities start as mu-
cous plugging and infection in the peripheral airways,
and as the disease progresses, more central airways be-
come involved, leading to bronchiolitis, bronchitis, and
bronchiectasis. The histopathological evidence of the
disease reveals airways filled with mucopurulent mate-
rial and inflammatory exudates, peribronchial inflamma-
tion, and some arterial changes of medial-wall hypertro-
In 1976, Bedrossian et al. [22] reported a qualitative
study of lower respiratory tracts in Human Pathology.
The 82 patients were divided into five groups based on
the age as follows: group one, 0 to 4 months, 16 patients;
group two, 4 to 24 months, eight patients; group three, 2
to 6 years, 28 patients; group four, 6 to 10 years, 14 pa-
tients; and group five, 2 to 24 years, 17 patients. Autop-
sies were reviewed with respect to pathologic changes in
the lung and their prevalence among different age groups.
Bronchitis, mucopurulent plugging, bronchopneumonia,
loss of cilia, and epithelial metaplasia with stratified
squamous epithelium were seen in more than 50% of
patients aged less than four months. Goblet-cell hyper-
plasia and hyperplastic bronchial glands were seen as a
result of chronic airway infection, along with increased
mucous; epithelial metaplasia, crippling of mucociliary
defense, and retention of mucopurulent exudates; bron-
chiectasis; and bronchopneumonia. They also noted in-
timal thickening of small muscular pulmonary arteries.
The complex vascular structure suggesting anastomosis
was seen in bronchial circulation—this is what fre-
quently causes hemoptysis. Increased pulmonary artery
pressure explains the right ventricular hypertrophy in CF
patients. Microscopic sections of subsegmental bronchi
revealed findings of squamous metaplasia of the epithet-
lium. A mucopurulent plug fills the bronchial lumen, an d
the wall is surrounded by extensive inflammation. The
occurrence of bronchiectasis in CF patients aged less
than four months was 20%, in patients four months to
two years was 75%, and in patients aged more than two
years was 100%. Bronchiectasis was seen early in the
disease in conjunction with P. aeruginosa infection. This
information helps pediatricians to understand the vital
need to advocate early intervention in their newly diag-
nosed infants. The disease clearly starts early in life,
even without any overt respiratory symptoms, with mu-
cus plugging and early asymptomatic infection/inflam-
1.6. CF Lung Infections
About 30% of CF patients may be colonized for P.
aeruginosa by one year of age; as such, a young infant
with CF seen in a primary care doctor’s office with an
incidental increase in cough will have to be evaluated for
early infections. Staphylococcus aureus and Haemophi-
lus influenzae colonization remain constant through the
age groups [4]. As CF patients continue to achieve
longer life spans, different kinds of infections are
emerging in this population, such as Stenotrophomonas
maltophilia, Burkolderia cepacia, xylosoxidans, asper-
1Welsh, M.J. “Bactericidal Activity of Airway Surface Fluid.” Pre-
sented at the Tenth Annual North American Cystic Fibrosis Confer-
ence; October 24-27, 1996, Or l a n do , FL.
Copyright © 2012 SciRes. OPEN ACCESS
R. Padman, V. Passi / Open Journal of Pediatrics 2 (2012) 187-196
gillus and other fungal infections, typical and atypical
mycobacterium, methicillin-resistant S. aureus, etc. The
primary-care physicians involved in the care of children
with CF need an increased index of suspicion for a wider
variety of pathogens. The neutrophils respond to infec-
tion in the lung, engulf the bacteria with pseudopodia,
and form phagosomes; they fuse with lysosome-con-
taining digestive enzymes and destroy the bacteria. As
the white cells degrade, they release elastase and oxi-
dants, which cause epithelial and cell-wall damage. As
there are adequate antielastase and antioxidants, the
epithelial damage can be repaired with the resolution of
pneumonia in non-CF patients. However, in CF patients,
because of the excessive number of white cells, the
naturally occurring antioxidants and antielastase sys-
tems are overwhelmed, and destruction of the lungs oc-
curs with resultant bronchiectasis. In CF patients, the
bronchoalveolar lavage, compared with that of normal
infants, reveals an increased number of white cells even
without an infection. Khan et al. [23] reported on bron-
choalveolar lavage fluid from 16 infants with CF, with a
mean age of six months, and 11 disease control infants
examined for neutrophil coun t, activity of free neutrophil
elastase and levels of interleukin (IL)-8, and the expres-
sion of IL-8 mRNA transcripts by airway macrophages.
The numbers of neutrophils and the expression of IL-8
were increased in infants with CF wh o had negative cul-
tures. Airway inflammation may be present in infants
with CF as young as four weeks. The source of IL-8 and
inflammation of the airways appears to be alveolar
macrophages. The airway inflammation in CF appears to
be neutrophil dominated. The neutrophils can secrete
oxygen radicals, and the cellular contents DNA and
F-actin make the mucous very thick and viscous. The
neutrophils also produce chemoattractants, eicosanoids,
leukotriene B4 (LTB4), IL-8, and proteases including
elastase. The neutrophil-mediated inflammation in CF
lung disease and elastase down-regulates the immune
system; cleaves the complements and the antibodies; and
causes elastin degradation and structural damage, bron-
chectasis, and an increase in macromolecular secretion
with plugging of the airways. Elastase has been shown to
cause opsonin and receptor mismatch. Elastase can cle ave
the IgG antibodies to P. aeruginosa [24]. It can cause
hypertrophy of mucus-secreting glands as seen in a mouse
model [25].
1.7. Airway Inflammation in CF
The CFTR mutations may promote and perpetuate air-
way inflammation by disrupting autocrine control of cy-
tokine secretion of epithelial cells. In the healthy co ntro ls,
IL-10 is in excess of IL-8, and inflammation is restricted.
However, in CF patients, there is neutrophil accumula-
tion and increased amounts of IL-8, and not enough IL-10
at the epithelial surfaces, promoting infection in immune
hyper-responsive CF airways. This environment promotes
bacteria to attach easily via flagella-adhesion molecules
being activated, and microcolonies form. The coloniza-
tion and infection noted with P. aeruginosa is an exam-
ple of such invasions that take place in the CF airways.
Furthermore, the biofilm community is seen with ex-
tracellular matrix surrounding them, turned on by quo-
rum-sensing genes that have been described [26]. The
lack of oxygen in thickened CF mucus simultaneously
promotes and perpetuates infection. At birth, there is no
noted infection; however, shortly thereafter, one can
have an S. aureus or H. influenzae positive culture and a
negative P. aeruginosa culture. Subsequent P. aeruginosa
culture with intermittent infection can lead to mucoid
transformation and chronic infection, promoting inflam-
mation and leading to bronchiectasis.
It is estimated that approximately 30% of CF patients
will be colonized with P. aeruginosa by one year of age.
As part of the ongoing Wisconsin newborn screening
project, Kosorok et al. [27] examined 56 patients diag-
nosed with CF on newborn screening. With a retrospec-
tive review of chest radiographs and lung function that
were compared pre and post P. aeruginosa colonization,
there is an expected worsening of both chest radiograph
scores and lung function. Both forced expiratory volume
in one second (FEV1) and forced vital capacity (FVC)
decline by 1.29% per year prior to acquisition of P.
aeruginosa, and they decline by 1.8% per year post ac-
quisition, with a P value of 0.001. Newborns have no
bacteria in the lungs; however, with a host-defense defect
related to CFTR mutation, there is promotion of inter-
mittent infection and then bacterial adaptation with biofilm
formation leading to permanent colonization with P.
Abdominal complications, especially involvement of
intestinal mucous glands, predispose patients with CF to
intestinal obstruction referred to as distal intestinal ob-
struction syndrome. The general pediatrician evaluating a
child with CF needs to be aware of the non-pulmonary
manifestations of CF. The bile is inspissated and causes
biliary cirrhosis. With repeated inflammation, the pan-
creas can form cystic changes and become fibrotic, lead-
ing to endocrine pancreatic dysfunction and necessitating
the use of insulin.
1.8. Sinus Disease in CF
Acute and chron ic sinusitis is a common complication o f
CF. The true incidence of sinusitis is not known, but a
great majority of patients with CF develop sinus symp-
toms, usually between the ages of 5 and 14 years [28].
The sinus disease associated with CF has unique features
that suggest the diagnosis, such as nasal polyps. Nasal
Copyright © 2012 SciRes. OPEN ACCESS
R. Padman, V. Passi / Open Journal of Pediatrics 2 (2012) 187-196 191
polyps in CF have fewer eosinophils (<4%), and mucus
glands contain acid rather than neutral mucins [29]. The
prevalence of nasal polyps on CT has been reported as
high as 48% and appears to be proportional to age [30].
Agenesis or lack of proper formation of frontal sinuses is
common in CF seen on plain radiographs because of ob-
struction of sinuses early in life. On CT and MRI, more
than 75% opacification on maxillary and ethmoid sinus
is considered a hallmark of CF. Bulging lateral nasal
wall near middle meatus and resorption of uncinate
process is considered distinctive of CF. Sinus disease can
cause significant symptoms and, in some cases, may
contribute to the worsening of lung disease [31].
The sinuses are lined by a layer of epithelium similar
to lower respiratory tract; the inflammatio n and infection
that causes harm leads to pansinusitis. Infection in CF
sinusitis is easy to pred ict and unlike non-CF sinusitis, as
it is a reflection of lung pathogens that are unique to CF,
namely P. aeruginosa, Staphylococcus, H. influenzae,
Burkholderia, Achromobacter, and Stenotrophomonas.
Treatments take on many forms: antibiotics, nasal
steroids, mechanical clearance with saline antihistamines,
decongestants, and surgery. Surgical treatment of sinus
disease is generally considered in patients with p ersistent
nasal symptoms, persistent headaches, and infection and
in those awaiting lung tran splants [32].
1.9. Potential Drug Therapies for CF
There are potential drug therapies for CF in development
every step of the way. The CF Foundation hopes the drug
development and approval process, which currently takes
17 years on average with a cost of $400 million , eventu-
ally will be limited to sev en years with a cost o f less than
$100 million in the safety dosage stage, with phase one,
two, and three trials shortened considerably as well. The
CF foundation’s website,, lists all the
medications in t heir re search pipeline for CF.
Lung transplant remains the only viable option for
treatment of end-stage lung-disease with diffuse bron-
chiectasis and moderate-to-severe lung-disease with re-
peated exacerbation and oxygen dependency. St. Louis
Children’s Hospital, the most active pediatric lung tran s-
plant center in the world, experiences a five-year survival
rate of 55% [33]. However, even with transplantation,
other systemic sequelae of CF are not cured.
Gene therapy is held as a possible cure for cystic fi-
brosis, and current research entails the use of adenovirus,
adeno-associated virus, and liposomes as vectors, which,
at the present time, do not work well for therapy. Re-
searchers hope for personalized CF care, genomics, and
proteomics for individualized treatment of patients with
CF. The motto of the CF Foundation is, “spanning the
globe and working together”.
1.10. Socioeconomic Factors and CF
In 2001, Schechter et al. studied the association of so-
cioeconomic status and the outcomes depending on each
status in CF patients in the United States [34]. In this
historical cohort study of CF registry data between the
years 1986 to 1994, with Medicaid status as a proxy for
lower socioeconomic status, they examined 20,390 CF
registry patients aged under 20 years. The median fol-
low-up was 8 years. Of the 20,3 90 patients in the eligible
group, 1894 (9.3%) received Medicaid during every year
they were listed in the registry. The adjusted risk of death
was 3.6 times higher in Medicaid patients than in those
not receiving Medicaid. Medicaid patients had 1.9%
lower FEV1, and were 2.1 times more likely to b e below
the fifth percentile for weight, 2.2 times more likely to be
below the fifth percentile for height, and 1.6 times more
likely to require treatment for pulmonary exacerbation.
There was no difference in the number of outpatient
clinic visits for Medicaid versus non-Medicaid patients.
Schechter et al. concluded that low socioeconomic status
may be associated with significantly lower outcomes.
This finding, however, was not due to access barriers to
specialty healthcare, as all patients had an equal number
of clinic visits. Therefore, one has to look further to de-
termine what adverse environmental factors might cause
worse outcomes in CF patients of low socioeconomic
status. Clinicians providing primary care to young in-
fants and children in this scenario need to be aware of the
lower outcomes and explore avenues to attempt to mod-
ify end-results.
Environmental factors that influence CF lung-disease
are cigarette smoke and other pollutants; allergens; viral
pathogens; respiratory syncytial virus (RSV) in infancy
(clinicians should be aware of the need for palivizumab
for the first winter); pathogen acquisition type and timing
(namely P. aeruginosa acquisition [20,21]); and, as pre-
viously mentioned, socioeconomic status. A study by
Collaco et al. [35] examined interactions between sec-
ondhand smoke and genes that affect CF lung disease.
Their research showed substantial disease variation in
conditions with single gene etiology, such as CF, by si-
multaneously studying the effects of genes and environ-
ment. The study looked at secondhand smoke exposure
and lung function in CF, and whether socioeconomic
status and secondhand smoke, along with genetic pre-
dispositions, combined to create negative outcomes in
lung function. This retrospective assessment of lung
function looked at 812 patients, stratified by environ-
mental and genetic factors, using data collected from the
United States CF Twin and Sibling Study and the CF
Registry. Secondhand smoking was found in 23.2% of
the subjects, and active maternal smoking during gesta-
tion was reported in 16.5%. Secondhand smoke exposure
led to a significantly lower cross-sectional lung function
Copyright © 2012 SciRes. OPEN ACCESS
R. Padman, V. Passi / Open Journal of Pediatrics 2 (2012) 187-196
and a 9.8% lower FEV1 with a P value of <0.001. The
longitudinal lung function in patients exposed to sec-
ondhand smoke was 6.1% lower (P = 0.007). Analysis
determined that socioeconomic status did not confound
the adverse effects of secondhand smoke on lung func-
tion: exposure to secondhand smoke will have detrimen-
tal effect on lung health regardless of socioeconomic
status. Additionally, the interaction between gene vari-
ants and secondhand smoke exposure resulted in a sig-
nificant percentile-point decrease in lung function.
Variation of the gene that causes CF (CFTR) and CF
modifier gene (TGF beta1) amplify the negative effects
of secondhand smoke exposure. Namely, CFTR non-
delta-F508 homozygotes had a 12.8% decrease in lung
function (P = 0.001) and the presence of transforming
growth factor gene as a modifier gene led to a 22.7 to
20.3 percentile-point decrease in lung function (P =
0.005). Simultaneous study of gene variations and envi-
ronment will explain the variation of disease expression
even with single gene etiology such as CF. General pe-
diatricians need to be aware of the interactions between
the gene pool, environment [smoking], and socioeco-
nomic factors to counsel parents and/or care takers ap-
1.11. Modifier Genes in CF
Research into mapping the CF-modified genes in the
mouse model and in humans is ongoing. Modifier genes
in CF, even in individuals with the same CF genotype,
will influence different clinical courses. Kno wn modifier
genes are tumor necrosis factor (TNF)-alpha, alpha-1
antitrypsin, and alpha-1 antichymotrypsin. The 2006 cross-
sectional study by McKone et al. [36] tested the associa-
tion between CF lung-disease and functional polymor-
phism in the glutamate-cysetine-ligase gene. Participants
included 440 subjects, recruited from CF clinics in Seat-
tle, WA, and centers in Canada, with a mean ag e of 26 ±
11 years and mild lung disease, with a mean FEV1 of
62%. The authors concluded that in patients with a
milder CFTR genotype, there is a strong association be-
tween functional polymorphisms of the glutamate-cys-
teine-ligase gene and severity of CF lung disease. Clearly,
other genes are affecting the phenotypic presentation;
this explains the difference in disease expression even
among related individuals with CF. Clinicians will be
better equipped to counsel their patients with this back-
ground information.
1.12. Survival
In 2009, the median age of survival was 35.9 years [4]
hoping to increase to 39 to 40 years. In previous years,
increases in median survival correlate with the discovery
of newer anti-Pseudomonas aeruginosa antibiotics. Cur-
rently, at specialized care centers, a team approach to
CF-patient care, improvement in nutrition, control of
infection, and improvement in early preventive care have
advanced survival. The specialist, working hand in hand
with the primary care pediatrician, enhances the care
given to these patients.
Because of the availability of newborn screening in all
50 states as of 2010 [37], and the recommendation from
the American College of Obstetricians and Gynecologists
for carrier screening, CF diagnosis is now occurring at an
earlier age than before [3]. There is strong evidence for
early onset of malnutrition [38], airway inflammation,
and structural changes in infants with CF. Although new
CF therapies have been introduced over the past 10 years,
none have been studied in infants, due in part to the
variability of this patient subgroup. Limited data are
available on the utility of available therapies in infants;
there are no controlled trials on newer CF therapies, and
no all-inclusive, age-specific guidelines specifically relat-
ing to the respiratory system. The nutritional benefits of
neonatal screening for CF have been evaluated by many
authors. Farrell et al. [39] compared nutritional status of
patients with CF identified by neonatal screening versus
those identified by clinical presentation after birth. The
early diagnosis group (12 weeks vs. 72 weeks) had sig-
nificantly greater height and weight percentiles and a
larger head circumference (52nd vs. 32nd percentile; P =
0.003). Higher antropometric indexes were found during
follow-up despite pancreatic insufficiency and delta-
F508 mutation. When there is a delayed diagnosis, se-
vere malnutrition exists th roughout infan cy, and catch-up
growth is more difficult to attain.
An example of a study that can attest to this is the fol-
lowing. Konstan et al. [38] reviewed growth and nutria-
tional indices in early life as predictors of pulmonary
function in CF. Using the Epid emiologic Study of Cystic
Fibrosis (ESCF) database, they compared 931 patients
for weight-for-age and height-for-age percentiles, ideal
body weight, and signs of lung disease at three years of
age; the patients were retested for lung function at six
years. Height-for-ag e and ideal body weight were poorly
associated with lung disease at three years, but strongly
associated with lung function at six years. If the weight-
for-age was below the fifth percentile at age three, then
lung function, or FEV1, at age six was 86 ± 20. If the
weight-for-age at age three was at the 75th percentile, the
FEV1 at age six was 102 ± 18. Patients with signs and
symptoms of lung disease at age three had lower lung
function at age six years. This work leads to the con-
clusion that aggressive intervention early in life aimed at
growth, nutrition, and lung disease will positively influ-
Copyright © 2012 SciRes. OPEN ACCESS
R. Padman, V. Passi / Open Journal of Pediatrics 2 (2012) 187-196 193
ence lung function.
In 2004, Kosick et al., also a part of the Wisconsin
newborn screening group, evaluated screened newborns
versus those given a clinical symptomatic diagnosis as to
cognitive function and the possible influence of both
early diagnosis through neonatal screening and the po-
tential effect of malnutrition [40]. Using a cognitive-
skills index and cognitive-factor scores (verbal, non-verbal,
and memory), outcomes of significantly lower cognitive
scores correlated with low plasma alpha-tocopherol level.
Prevention of prolonged malnutrition by early diagnosis
and traditional therapy minimizing the duration of vita-
min E deficiency is associated with better cognitive
function in children with CF. So clearly, early diagnosis
improves nutrition, even as long as 13 years later.
It has also been noted that children have evidence of
changes secondary to chronic inflammation in their lungs.
The 2004 study by Long et al. [41] reviewed full-infla-
tion, controlled -ventilation, high-resolution computed to-
mography (CT) scan images of the lungs in 34 CF in-
fants with a mean age of 2.4 years. In control infants, the
airway-wall thickness, airway-lumen diameter, and ves-
sel diameter were measured. The infants with CF had an
airway wall that was thicker, an airway-lumen diameter
that was larger, and a vessel diameter that was smaller.
The airway-lumen diameter to vessel diameter ratio in-
creased with age in patients with CF compared with
those in the control group. Further evidence of this
chronic inflammation leading to subsequent development
of bacterial infection has also been studied. In 2009, Sly
et al. (Australian Respiratory Early Surveillance Team
for Cystic Fibrosis [AREST-CF]) published a study [42]
in which 57 infants with median age of 3.6 months un-
derwent bronchoalveolar lavage and chest CT in Austra-
lia. Despite the absence of respiratory symptoms in 48
patients, a substantial proportion of lung disease with
bacterial infection was seen. Inflammation was increased
with infection; however, most were asymptomatic. There
was radiological evidence of abnormal CT scan in 80%,
bronchial dilation in 18.6%, bronchial-wall thickening in
45%, and air trapping in 66.7%. Most children with
structural lung-disease were asymptomatic and diag-
nosed by newborn screening at a median age of 30 days;
a CT and bronchoalveolar lavage were performed under
anesthesia at 4 kg weight. Prevalence of bronchiectasis
was 22% and increased with age. Factors associated with
bronchiectasis include absolute neutrophil count eleva-
tion, neutrophil elastase concentration, and P. aeruginosa
In 2007, Padman et al. [43] collected and reviewed
ESCF data to assess whether the patterns of care for in-
fants with CF at sites with superior average lung-func-
tions at six to 12 years of age showed any difference
from those at the lowest outcome sites. A total of 755
infants in 12 upper-quartile sites and 743 infants from 12
lower-quartile sites were reviewed. Upper-quartile sites
had more infants whose disease was diagnosed by family
history or newborn screening, fewer infants with symp-
toms at diagnosis, higher weight-for-age at enrollment,
more Caucasian patients, and more delta-F508 homozy-
gotes. Medical conditions and respiratory tract microbe-
ology differed between sites. Infants at upper-quartile
sites had more office and sick visits, more respiratory
tract cultures, and frequent use of antibiotics, oral ster-
oids, mast-cell stabilizers, and mucolytics. The authors
concluded that both enrollment characteristics and infant
care patterns are associated with lung function outcomes
in later childhood. Analysis also suggested that pulmo-
nary function of older children may be improved through
specific interventions during the first three years of life.
More antibiotics, specifically more oral antibiotics, in-
haled steroids, mucolytics, and cromolyn sodium, were
used in the top qu artile. There was an increase in aggres-
sive therapy for infants with CF and increasing detection
of S. aureus and other organisms. Specific practices, in-
cluding more frequent visits, more cultures, and more
therapies can lead to a better outcome in terms of lung
function as long as six to 12 years later.
All of the preceding studies collectively suggest early
intervention in nutrition and initiation of pulmonary
therapies as a means of prolonging lung remodeling and
addressing failure to thrive. In a retrospective cohort
study of CF registry data (1993-2004) from three CF
centers, Padman et al. [44] compared initial management
with respiratory, antimicrobial, and nutritional agents in
infants. They examined the association between dornase
alfa use prior to two years of age and body mass index
(BMI) percentile over time, controlling for possible fac-
tors including genes, gender, race, CF center, presenta-
tion, age at diagnosis, sweat value, delta-F508 status,
first P. aeruginosa infection, second-year weight percen-
tile, supplemental feeding use, and pancreatic enzyme
use. Patient characteristics and prescribed therapies were
similar at all sites for 165 patients. One CF center pre-
scribed dornase alfa more frequently, 82% vs. 10%, and
supplemental feeding significantly less frequently, 56%
vs. 78% (P = 0.04). Dornase alfa prior to two years of
age is associated with a 10% incr ease in BMI through six
years as compared with infants treated with dornase alfa.
Treating infants aged less than two years with dornase
alfa may improve nutritional outcomes up to six years of
This is also evident radiologically. Nasr et al. [45]
studied 12 patients, all under 5 years of age, at the Uni-
versity of Michigan CF center. Mean changes in high-
resolution CT-scan scores between dornase alfa and pla-
cebo groups were found to be significant at the 95%
percentile level. The difference in chest radiographic
Copyright © 2012 SciRes. OPEN ACCESS
R. Padman, V. Passi / Open Journal of Pediatrics 2 (2012) 187-196
scores was not significant between the two groups. Ad-
ministration of dornase alfa was associated with im-
provement in high-resolution CT scans in CF patients
aged less than five years.
Ratjen et al. [46] looked at the role of matrix metallo-
proteases in the remodeling and degradation of extracel-
lular matrix and their possible role in pulmonary tissue
destruction. They examined bronchoalveolar lavage on
two occasions within 18 months in 23 children with mild
CF, of whom 13 were treated with dornase alfa. For
comparison, they also studied 11 children without CF or
other pulmonary disease who were undergoing elective
surgery for nonpulmonary illnesses. Matrix metallopep-
tidase MMP-8, MMP-9, and the molar ratio were sig-
nificantly higher in children with CF than in the com-
parison group. A correlation was found between bron-
choalveolar lavage fluid concentrations of MMPs and
alpha (2)-macroglobulin, a marker of alveolocapillary
leakage. After 18 months, MMPs were increased in dor-
nase-alfa-untreated CF patients and were decreased in
patients with CF treated with dornase alfa. This indicates
that uninhibited MMPs contributed to pulmonary tissue
damage even in patients with CF who have mild lung
disease. Treatment with dornase alfa may have a benefi-
cial effect even in CF patients with mild lung disease.
In a 2009 retrospective cohort study, Van der Doef et
al. [47] looked at 218 patients with CF and examined
longitudinal lung function (FVC, FEV1, small airway
flow rates) and bacterial colonization rates, and com-
pared the patients that were and were not treated with
gastric acid inhibition for fat malabsorption or gasrtoe-
sophageal reflux. Patients with CF who were on gas-
tric-acid inhibition had similar yearly decline in lung
function when compared with control CF patients who
were not on gastric-acid inhibition. P. aeruginosa and S.
aureus colonization were not different between the two
groups. Gastroesophageal reflux disease (GERD) pa-
tients had an association with a reduced pulmonary func-
tion and an earlier acquisition of P. aeruginosa and S.
aureus, indicating GERD should be aggressively pursued
in patients with CF. Gastric-acid inhibition may have
beneficial effect on lung function with time as the de-
cline in flow rates were less pronounced with GERD and
gastric-acid inhibition in CF patients.
Guidelines for Management of Infants with CF
“The Cystic Fibrosis Foundation Evidence-Based Guide-
lines for Management of Infants with Cystic Fibrosis”
was published as a supplement to the 2009 Journal of
Pediatrics [2]. The guidelines promote an initial visit to
an accredited CF center within 24 to 72 hours of diagno-
sis and monthly visits to a CF center for the first six
months following diagnosis. In the realm of nutrition, the
CF Foundation lists the need for supplemental salt (1/8
of a teaspoon per day for the first six months, 1/4 tea-
spoon per day for the next six months), breast milk feed-
ing or standard infan t formula, initiation of caloric-dense
feeding for inadequate weight gain, maintenance of
weight-for-length greater than or equal to 50th p ercentile,
and prescription of pancreatic enzymes and fat soluble
vitamins with monitorin g of stooling pattern and vitamin
blood levels. Strong infection-control measures are to be
exercised, the environment must be smoke-free, airway
clearance must be started within the first few months,
chest physical therapy should not be performed in a
head-down position, and the use of albuterol is encour-
aged. The care plan should include influenza vaccination,
and palivizumab may be considered. Continued surveil-
lance for bacterial infection, discouraging the use of an-
tibiotics as prophylaxis, and treatment of the initial ac-
quisition and persistent infection are necessary. Chest
imaging and chronic therapies are recommended, but
mucolytics, including dornase alfa, and hypertonic saline
are not specified for the respiratory system, as there are
no large-scale, doub le-blind, randomized studies to prac-
tice evidence-based medicine at this po int in time.
The newborn screen has allowed the early detection of
a number of disease entities, CF being a recent addition
to the screen. For this screen to be effective in delaying
onset of the numerous detrimental aspects of this disease,
early, aggressive nutritional intervention and pulmonary
therapies are needed. Current pulmonary therapy does
not address the neutrophilic inflammation that starts
shortly after birth. Clinicians involved in the care of
many infants diagnosed by newborn screening need to be
aware of these recommendations. They must follow,
along with the specialist, both the typical and atypical
infants and children with this underlying diagnosis. They
must ensure that the routine immunizations are adminis-
tered, including annual influenza vaccine. Palivizumab is
a consideration for the first winter. They must monitor
growth parameters closely and maintain year-round sur-
veillance for lung infections. Through close work with
CF specialists, clinicians can improve and enhance the
lives of young patients with CF.
We gratefully acknowledge the generous help of Kristina Flathers,
MLIS, in the collection of data and preparation of th is manuscript.
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