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What is the genetics of CF?

CF is an autosomal recessive disorder caused by mutations
in the gene encoding the cystic fi brosis transmembrane
conductance regulator (CFTR) protein. The CFTR gene is located on the long arm of chromosome 7 at position 7q31.
Over 2,500 distinct CFTR mutations have been identifi ed, but
deletion of phenylalanine at position 508 (ΔF508) of the
CFTR protein is by far the most common. Between 65% and
75% of CF patients in the United States are homozygous or
compound heterozygous for a ΔF508 mutation.


What does the CFTR protein do? Where is it located? Where is its dysfunction most evident? What is it like?

The CFTR protein is expressed primarily on the apical
membrane of epithelial cells, where it functions as a regulated
chloride ion (Cl-) channel. However, CFTR has other important
regulatory roles in ion movement, notably infl uencing Na+
transport and water movement across many epithelial cells.
CFTR protein is expressed on epithelial cells of many organs,
as well as exocrine glands and blood cells, but its most important
pathophysiologic consequences involve the respiratory
epithelia; the cells lining the ducts of the pancreas; and serous
sweat glands. The mature CFTR protein is a 1480-amino acid
polypeptide of about 170 kDa (Fig. 38.1).

The CFTR protein is comprised of two hydrophobic
membrane spanning domains (MSD) and two cytoplasmic
nucleotide binding domains (NBD) that hydrolyze ATP.
CFTR also has a regulatory unit with several serine residues
that are phosphorylation targets of cyclic AMP-dependent
protein kinase. The ΔF508 mutation is located within the
NBD1, and the mechanism by which this type of CFTR dysfunction
leads to the clinical manifestations of CF is based
upon competing hypotheses.


Explain the low volume hypothesis.

Among those, the low volume
hypothesis is more generally accepted within the CF research
community. It postulates that impaired CFTR function causes excessive reabsorption of Na+ and water. Within the respiratory
mucosa, this CFTR defect dehydrates the aqueous or
“sol” periciliary layer (PCL) that lies beneath the secreted
mucus (Chap. 10), thereby slowing or preventing coordinated
ciliary movements (Fig. 38.2).

This defect inhibits normal ciliary movement and cough
clearance of mucus (Chap. 10), allowing hypoxic niches
to develop that promote infection with bacteria, notably
Pseudomonas aeruginosa. Due to this relative dehydration,
the mucus of CF patients is thickened and tenaciously sticky,
and therefore poorly cleared. This same low volume hypothesis
explains equally well the situation within airways and
pancreatic ducts, the latter being important for the GI manifestations
in many CF patients (see below).


Explain the high salt hypothesis.

The alternative high salt hypothesis proposes that the excessive [Na+] and [Cl−] in
the airway submucous liquid directly impair local innate host
defense (Chap. 10). It is argued that this salt-induced impairment
would allow proliferation of bacteria that are usually
cleared from non-CF airways. Still other hypotheses have suggested
that CFTR dysfunction directly compromises infl ammatory
responses of leukocytes that express CFTR, or reduces
poorly defi ned aspects of innate immunity in the lung.


What are a few signs and symptoms of CF?

Signs and symptoms that suggest a diagnosis of cystic fi brosis
include: recurrent symptoms such as cough, wheeze, and
respiratory distress; episodes of bronchitis or pneumonia
combined with complications linked to exocrine pancreatic
insuffi ciency including steatorrhea, failure to thrive, an
excessive or “voracious” appetite, malnutrition and fat soluble
vitamin defi ciencies. Up to 15% of patients with CF will
present as newborns with meconium ileus that causes symptoms
of small bowel obstruction, including vomiting, abdominal
distention, and an absence of bowel movements. However,
it bears emphasizing that 5%-10% of CF patients have pancreatic
suffi ciency that permits normal absorption and growth.
Table 38.1 summarizes the age-specifi c signs and symptoms
that would suggest or support a diagnosis of CF.


How is CF diagnosed?

The diagnosis of CF can be made in the presence of specifi
c phenotypic features combined with evidence of CFTR
dysfunction. The most useful and widely available measure
of CFTR dysfunction is the sweat chloride test performed by
the quantitative pilocarpine iontophoresis technique. Values
over 60 mM are considered diagnostic of CF; values between
40 and 59 mM are graded as intermediate and values <30 mM are normal, and values between
30 and 59 mM are considered intermediate.


Explain how newborn screening for CF is performed.

By the end of 2009, all 50 American states had programs in
place to perform newborn screening for cystic fi brosis. The goal
of newborn screening is to identify patients in a presymptomatic
stage before onset of signifi cant malnutrition or pulmonary
disease, and to direct early and aggressive interventions at the
respiratory and gastrointestinal manifestations of CF. All newborn
screening programs rely on elevations of immunoreactive
trypsinogen (IRT), a pancreatic enzyme found at increased
levels in virtually all CF patients, even those with pancreatic
suffi ciency. Patients with elevated IRT values in the fi rst
24 hours of life either have the IRT value repeated at 2 weeks of
age, or their newborn blood spot is amplifi ed by PCR for a discrete
group of CF mutations, depending on the state’s newborn screening program. Patients with persistently elevated IRT values
at birth and at 2 weeks (the IRT/IRT method) or patients
who have an elevated IRT at birth and have either one or two
identifi ed CF mutations (the IRT/DNA method) are referred to
an accredited CF center for diagnostic sweat testing. With the advent of universal newborn screening for CF, the anticipation
is that very few patients will be identifi ed through symptomatic
disease. Consequently, their early evaluation and treatment at a
CF Center is expected to have a substantial impact on pulmonary
function results, nutritional status, and survival.


What is the pathophys of CF in the lung?

The lungs of infants with CF are normal at birth, but excessive
airway infl ammation typically develops shortly thereafter
that includes an increase in airway neutrophils and release of
proinfl ammatory cytokines such as IL-8. In conjunction with
this process, infants often become infected with a variety of
pathogens, most notably H. infl uenza and S. aureus. Eventually,
most CF patients become infected with Pseudomonas
aeruginosa. Chronic airway infection ensues with mucus
plugging, vicious cycles of infl ammation and infection, and
airway injury due to the eventual development of bronchiectasis
(Chap. 20). Collectively, these events worsen lung function
and thereby lead to chronic hypoxemia and hypercarbia.
Thus, the period of indeterminate length when a newborn
CF patient is uninfected by bacterial pathogens is followed
by a “window of opportunity” during which bacterial infections
are transient and amenable to antibiotic eradication. For
example, non-mucoid P. aeruginosa may be cleared by the
host in conjunction with specifi c antibiotic therapy. Eventually,
most CF patients develop chronic infections with mucoid
P. aeruginosa that form biofi lms. Such biofi lms represent
colonies of bacteria that secrete a protective coating and
adhere to mucosal surfaces. Once present in the CF airway,
biofi lms containing mucoid P. aeruginosa become resistant to
the effects of parenteral, oral, and nebulized antibiotics, thereby
eluding both normal host defense and state-of-art antimicrobials.

As this microbial colonization evolves, airway infl ammation
and destruction progress with inexorable declines in lung
function values characteristic of severe obstructive patterns.
Recognition that early infection with non-mucoid P. aeruginosa
is amenable to eradication has led to recommendations
for improved surveillance of CF patients and aggressive treatment
with nebulized antibiotics when the bacteria are fi rst


What other microbes tend to infect CF patients and what are the results?

Other pathogens linked to CF lung disease include oxacillin-
resistant or methicillin-resistant S. aureus (MRSA),
Stenotrophomonas maltophilia, and Burkholderia cepacia
(consisting of nine distinct genomic variants or genomovars).
Evidence has increased that infection in CF patients with
MRSA leads to worse pulmonary function values and lower
survival rates. Up to 15% of CF patients have S. maltophilia
isolated from airway cultures, but the impact of this organism
on CF outcomes remains poorly defi ned. Of the members
of the B. cepacia complex, B. cenocepacia (genomovar III)
is associated with a particularly poor outcome. It is a leading
cause of the cepacia syndrome, a disease process that
is associated with accelerated decline in lung function, fever,
bacteremia, and high mortality rates.
Pulmonary infection with atypical Mycobacteria is an
increasingly important issue for CF patients. Routine surveillance
of CF patients is in part responsible for greater recognition
of this organism’s role in serious CF exacerbations.
Among the mycobacterial species, Mycobacterium avium
complex (MAC) and M. abscessus are most commonly found
in CF. The implications of obtaining a defi nitive diagnosis
when mycobacterial disease is suspected are signifi cant, in
that the use of triple antibiotic treatment regimens directed
against MAC are recommended for up to a year. Infection
with M. abscessus, even with a variety of treatment regimens,
is generally not considered eradicable except when it presents
as focal disease.
In addition, CF patients can develop allergic bronchopulmonary
aspergillosis (ABPA), a severe response to
Aspergillus fumigatus characterized by increased circulating
[IgE], generally >1,000 IU/mL. Patients with ABPA usually
show increased levels of IgG-precipitating and IgE-precipitating
antibodies to A. fumigatus, as well as cutaneous reactivity to
Aspergillus extracts. Such patients may have worsening respiratory
symptoms that are unresponsive to standard CF therapy,
notably severe wheezing, declining PFT results, increased
radiographic infi ltrates, and central bronchiectasis. Treatment
of ABPA entails a combination of itraconazole and a prolonged
course of systemic corticosteroids.


What are the GI disease features of CF? How are these treated?

As described above, up to 15% of infants with classic CF present
with meconium ileus. Roughly 85%-90% of all CF patients
have evidence of exocrine pancreatic insuffi ciency that
develops variably in the fi rst or second year of life. Symptoms
associated with CF pancreatic dysfunction include: large, oily, foul-smelling stools; abdominal distention, discomfort, and
fl atulence; and increased food and fl uid intake. Collectively
these symptoms of CF disease in the GI tract lead to poor
growth, malnutrition, failure to thrive, and defi ciencies of the
fat soluble vitamins A, D, E, and K. Regular replacement
therapy with pancreatic enzymes and provision of supplemental
vitamins are essential components of proper nutritional
management in CF. The critical link between improved nutritional
status and better lung function has been recognized
clinically for years. Indeed it underscores the importance of
a multidisciplinary approach to nutritional management that
includes the dietician and gastroenterologist.

Patients with CF are at signifi cant risk for hepatic dysfunction
arising from bile duct obstruction, again secondary
to serous gland secretion defects and the resulting increase in
secretion viscosity. In newborns and infants, this may be noted
as transient elevations of liver transaminases or in rare cases,
as persistent elevations in conjugated hyperbilirubinemia. In
older CF patients, liver disease may present as focal biliary
cirrhosis with attendant risks of developing portal hypertension,
splenomegaly, esophageal varices, multifocal gastrointestinal
hemorrhage, and thrombocytopenia. In CF patients
who have relatively well-preserved lung function, liver transplantation
is an option for treating severe liver disease. Distal
intestinal obstruction syndrome (DIOS) is another potential
complication in CF patients, particularly among those who have
received inadequate pancreatic enzyme replacement or who
have adhered poorly to their treatment programs. Symptoms
of DIOS resemble those of the CF infant born with meconium
ileus, namely vomiting, abdominal pain, abdominal distention,
and absent stools. Treatment approaches include therapeutic
barium enemas and regular use of oral products that improve
GI transit, such as polyethylene glycol-electrolyte solutions.


What are the endocrine abnormalities in CF? How are they treated?

The obstruction of pancreatic ducts with abnormal CF mucus
leads to the characteristic exocrine pancreatic defi ciency
mentioned above, but also results in autodigestion of the
pancreas and eventual replacement of pancreatic tissue with
fat. As pancreatic islet function declines in the midst of this
process, insulin defi ciency and possibly insulin resistance
ensue so that a presentation of diabetes develops. About 10% of
CF patients develop cystic fi brosis-related diabetes mellitus
(CFRDM) in their second decade of life, with prevalence rates
as high as 30%-40% reported among young adults. Although
ketosis is not a typical feature of CFRDM per se, the elevated
blood sugars in affected CF patients lead to glucosuria and
impaired growth. Importantly, CFRDM tends to develop in
patients who have more severe disease. It may fi rst come to
the physician’s attention when problematic hyperglycemia is
observed during the early stages of treating a CF patient for
a severe pulmonary exacerbation. Oral hypoglycemic agents
are generally not helpful in patients with CFRDM, such that
insulin injections are required to achieve euglycemia in them.


What are the reproductive abnormalities in CF?

In male infants with CF, obstruction of the vas deferens is
the fi rst pathological abnormality observed, pre-dating any
abnormalities within the lungs. Hence, all males with classic
CF have obstructive azoospermia, absence of the vas deferens,
and infertility (Table 38.1). While females with CF are
reported to have abnormal cervical mucus, they are generally
fertile and can successfully deliver a normal infant if they
receive appropriate perinatal nutrition and have adequate lung
function at parturition.


What treatments help improve airway function? How?

Nebulized hypertonic saline (a 7% w/v solution of sterile
NaCl) has been demonstrated to improve lung function and
reduce the frequency of pulmonary exacerbations. Its effi cacy
supports the low volume hypothesis of CF pathogenesis
(Fig. 38.2), in that a hypertonic solution delivered into the airways
will draw water to itself by osmosis from the underlying
epithelium. This water adds to the aqueous subphase of airway
secretions, irrespective of the type of CFTR protein dysfunction.

The increased hydration of the periciliary layer (PCL) then
allows at least a partial restoration of normal ciliary motion and
thus improved clearance of bacteria-laden secretions. Presuming
that this is the mechanism of hypertonic saline’s actions, it
would seem prudent to begin such therapy early in life and perhaps
even prior to the onset of pulmonary disease. Hypertonic
saline may also relieve bronchial obstruction by improving sputum
consolidation and cough clearance.

The sources of airway obstruction in CF are many and
include retained mucus, infl ammatory debris, microbes and their
by-products, and host infl ammatory cells recruited to foci of infection.
These infl ammatory cells include neutrophils that undergo
apoptosis, releasing their intracellular constituents including
DNA and fragments of DNA. Such DNA appears to contribute
to the viscosity of abnormal airway secretions. Nebulized solutions
of recombinant human DNase (Pulmozyme®) hydrolyze
this DNA, reducing mucus viscosity, improving airway clearance,
and decreasing the frequency of pulmonary exacerbations.
Although more than one-half of CF patients in the
United States receive such therapy, there is no consensus as
to the severity of PFT fi ndings or the appropriate age that would
dictate the start of this treatment.

Airway clearance techniques that improve mucus removal
and relieve bronchial obstruction have been a mainstay of CF
treatment for decades. Traditionally, airway clearance took the
form of manual chest therapy and postural drainage delivered
by a trained caregiver. Newer techniques provide more
independence to the patient, including high-frequency chest
wall oscillation vests (Fig. 38.5), positive expiratory pressure
devices, airway pressure oscillating devices (“fl utter valves”),
and autogenic drainage. Although the CF community endorses
many of these techniques to enhance airway clearance, few
randomized controlled studies have documented their effi cacy.
General recommendations espoused by the Cystic Fibrosis
Foundation are that some form of airway clearance should
be part of every CF patient’s daily regimen. A regular exercise
program is another important aspect of CF care, improving
quality of life and maintaining lung function (Chap. 12). However,
there is little evidence that exercise represents an adequate
replacement for more standard airway clearance techniques.


What are some antimicrobial options for CF? How do physicians know which ones to use?

Antimicrobial agents, whether parenteral, oral, or aerosolized,
remain an integral part of CF care, particularly during
an exacerbation of pulmonary symptoms. Statistics from
the CF Foundation Patient Registry show that CF patients
treated more aggressively with antibiotics have improved
clinical outcomes versus patients receiving fewer antibiotics.
Antibiotic choices are guided by routine surveillance cultures,
ideally obtained every 3 months. The need to aggressively
treat a fi rst isolation of P. aeruginosa in an effort to eradicate
this organism was addressed above. For patients with
persistent P. aeruginosa infection, 28-day on/off cycles with
aerosolized tobramycin have successfully improved lung
function, reduced the log order of P. aeruginosa organisms
isolated, and decreased the frequency of recurrent infections.
The newest anti-Pseudomonas agent, aztreonam lysate for
inhalation via a new nebulizer device shortens administration
time to 6 years of age who are infected with P. aeruginosa was moderate,
showing improvement in FEV1 and fewer respiratory exacerbations.
When azithromycin was studied in patients who were not
infected with P. aeruginosa, their minor clinical improvements
were insuffi cient to recommend its routine use in these patients.


What are some options to treat the inflammation in the lungs in CF?

The intense neutrophilic infl ammatory response in the
lungs of CF patients has led to considerable interest in antiinfl
ammatory therapies. While oral steroids improve pulmonary
function measures, they can cause unacceptable adverse
events including cataract formation, hyperglycemia, and
persistent growth retardation (noted even 2 years after completing
a therapeutic course). Inhaled corticosteroids would
seem an attractive alternative but their effi cacy has been diffi
cult to document, due in part to obstacles of drug delivery to
intermediate and distal airways, and penetration of the thick
airway mucus layer. High doses of oral ibuprofen have a variety
of immunomodulatory effects on neutrophils, including
their recruitment, adherence, and release of proinfl ammatory
cytokines. Such high ibuprofen doses also reduced the rate of
decline in FEV1 among treated patients over a 4-year period
versus controls, while improving their nutritional status when
measured by weight gain. Despite such potential benefi ts,
widespread concern regarding ibuprofen’s potential side
effects has slowed its adoption within the CF community.


When is lung transplantation an option? What are the criteria? What is a contraindication? How common is one year survival? Long term survival? Why?

For CF patients with end-stage pulmonary disease, lung transplantation
is the only therapeutic option. Specifi c criteria for
referring a patient for lung transplantation are inexact, but an FEV1 that is consistently <30% of predicted is generally used
as the threshold for referral to a transplant center. In the United
States about 150-200 CF patients undergo lung transplantation
annually, with many more such patients dying before donor lungs
are available. Although selection criteria for potential recipients
vary among transplant centers, preexisting infection with certain
B. cepacia genomovars (particularly B. cenocepacia) is an
absolute contraindication at most centers. One-year survival
after lung transplantation is 85%-90%, but longer term survival
is often limited by the development of bronchiolitis obliterans,
a manifestation of chronic allograft rejection (Chap. 26).