++
Cystic fibrosis (CF) is the most common profoundly life-shortening
inherited disease in North America. In 1938, Dr. Dorothy Andersen
first described the complex of respiratory and digestive signs and
symptoms that make up this syndrome,1 but references
to a childhood disorder characterized by salty sweat and early death
date back to at least the Middle Ages. The cellular and molecular
bases for the disorder have recently been elucidated.2,3
++
Cystic fibrosis (CF) is inherited as an autosomal recessive disorder.
It is most common in those of northern European descent, with an
incidence of approximately 1 in every 3200 live births. It is seen
in about 1 in every 17,000 births in African Americans and is much
less common in Asian populations. It has been found in virtually
every ethnic and racial group. Approximately 4% of whites
are heterozygous for CF (ie, carry one CF allele); heterozygotes
have no evidence of clinical disease.
+++
Pathophysiology
and Genetics
++
CF affects virtually every organ system with epithelial surfaces—most
importantly, the lungs, pancreas, intestinal mucus glands, liver,
the reproductive tracts, and sweat glands. A common pathogenetic
mechanism in major target systems is abnormal ion transport across
epithelial surfaces. Impermeable chloride channels and overactive
sodium pumps of these epithelial cells lead to biochemical and bioelectric
abnormalities within organ lumina, leading in turn to viscid intralumenal
secretions in the affected organs. These abnormally viscous secretions
cause the blockage of ducts and air passages.
++
The most common mutation in the CF gene is a three-base-pair
deletion that leads to the loss of a single phenylalanine at position
508 of the protein product (“ΔF508”).4 The ΔF508
mutation accounts for 70% to 80% of CF chromosomes;
about 50% of CF patients in North America are homozygous
for this mutation. More than 1500 other mutations at the CF locus
have been discovered, but these account for only a small percentage
of CF cases. In a few ethnic groups, a small number of mutations
account for a large proportion of CF cases (Table
514-1). Prenatal testing and carrier testing can be accomplished
in virtually every family desiring this information.
++
++
The gene for CF is on the long arm of chromosome 7 and spans
250 kb. Its product is a 1480–amino acid protein that regulates
transmembrane ion transport.4 It serves as the
most important apical membrane chloride channel and influences sodium
and water transport across epithelial cells of many organs and glands.2,3 Because
of this functional role, both the protein product and the gene itself
are called cystic fibrosis transmembrane conductance regulator (CFTR).
The gene is transcribed into mRNA, which is translated into protein
in the endoplasmic reticulum (Fig. 514-1).
Then, the CFTR protein is glycosylated in the Golgi apparatus and
folded into a configuration that allows it to travel through the
cytoplasm to the apical surface of epithelial cells. Once it resides
in the apical membrane, it must have appropriate regulation, in
that it must be able to respond to regulatory molecules. Finally,
normal conductance of chloride and other ions depends on the channel
remaining open for the appropriate time. CFTR mutations can be classified
according to which step in this sequence of events is defective
(Fig. 514-1). As in vitro studies have shown
restored chloride conductance with various interventions in each
of these classes, there is hope that clinically useful class-specific
treatment might someday be possible.
++
++
The ion transport abnormalities result in diminished amounts
of airway surface liquid and therefore interfere with clearance
of airway mucus, resulting in the airway problems common to patients
with CF.3 It is not yet clear how the ion transport
abnormality leads to the characteristic clinical abnormalities in
the pancreas or other involved organs of CF patients, but it is
likely through similar mechanisms. Regardless of the mechanism by
which the abnormal gene and protein lead to the luminal abnormalities,
virtually all organs with epithelial lining cells are affected.
In addition, it is not yet clear how the different mutations affect
clinical disease. There does seem to be a genotype-phenotype correlation
for pancreatic status, with most CF genotypes, notably homozygosity
for the ΔF508 mutation, associated with pancreatic
insufficiency and a few alleles apparently conferring pancreatic
sufficiency. Very few CF alleles appear to be associated with a
delayed onset and slower progression of pulmonary disease, but by
and large, genotype-phenotype relations for CF lung disease and survival
have eluded discovery.2 Characteristics of some
of the most common CFTR mutations are listed in Table
514-1. Because there is substantial phenotypic variation within
the population of ΔF508 homozygotes, it is thought
that there are genes other than CFTR that can modify the phenotypic
expression of CF. Evidence for the existence of these modifier
genes includes the observations that monozygotic twins
have closer concordance of their clinical disease than do dizygotic
twins. Variant alleles for both transforming growth factor β (TGF-β)
and mannose binding lectin (MBL) have been associated with more
rapid decline in lung function.5
+++
Gastrointestinal
Tract
++
The typical cystic fibrosis (CF) patient has exocrine pancreatic
insufficiency, with maldigestion of fats and protein and consequent malabsorption,
steatorrhea, and failure to thrive.6 Pancreatic
insufficiency is present at birth in 50% of CF patients
and develops by age 9 years in another 35% to 40%.6 This
is important to keep in mind, since the diagnosis of CF is often
delayed or missed in patients without typical gastrointestinal involvement.
Pancreatic status is determined in large part by genetic factors, as
certain genotypes (eg, ΔF508) are nearly always
associated with pancreatic insufficiency, while others confer pancreatic
sufficiency (Table 514-1).
++
Bowel obstruction, a result of thickened intestinal mucus and
pancreatic insufficiency, is present at birth (meconium ileus) in
10% to 20% of patients, especially those who are ΔF508
homozygotes. Later in life, distal intestinal obstruction syndrome
(DIOS) occurs in 20% to 25% of affected individuals.
Rectal prolapse, caused by bowel obstruction and by malnutrition
with loss of anal sling musculature, is seen in 20% of
CF patients in the first years of life. Intussusception is much
less common, but CF patients account for a substantial portion of
all patients with intussusception after 1 year of age. Gastroesophageal
reflux, which may complicate the pulmonary disease, interfere with
nutrition, or both, occurs with increased frequency in infants (and
older children) with CF. Reflux may be worsened, especially in infants,
by head-down positioning for chest physical therapy. Acid peptic
disease can result from gastric acid hypersecretion and deficient
pancreatic bicarbonate secretion. Cholelithiasis is more common
in CF than healthy control populations. Liver pathology, including
nonspecific steatosis; cholestasis; and the specific lesion, focal
biliary cirrhosis, occurs in up to 10% of infants and children with
CF. However, the clinical manifestation of cirrhosis with hepatic
failure or portal hypertension with hypersplenism, bleeding esophageal
varices, or both, is much less common. These hepatic complications present
most commonly in the first decade and a half and seem not to be
increasing in incidence as life span has increased. Children or
adults, particularly those with normal exocrine pancreatic function,
may develop recurrent episodes of acute pancreatitis. Endocrine
pancreas dysfunction also can occur, leading to carbohydrate intolerance
and diabetes mellitus that is unassociated with ketoacidosis.
++
The epithelial ion transport defect is expressed in the sweat
glands, leading to the high salt content of CF sweat, long recognized
as a hallmark of this disorder. In patients without CF, sweat precursor
fluid is isotonic to plasma, and as the fluid moves through the
sweat apparatus toward the skin, chloride is reabsorbed, with sodium
following to maintain electrical neutrality. This results in sweat
on the skin surface that is hypotonic to plasma and usually has
sodium and chloride concentrations below 40 meq/L. In CF,
the absent or poorly functioning cystic fibrosis transmembrane conductance
regulator (CFTR) chloride channel makes chloride reabsorption substantially
below normal.2,7 The resultant fluid that emerges
as sweat has sodium and chloride concentrations greater than 60
meq/L. This ion transport defect in the sweat apparatus
provides the basis for the sweat test (discussed under “Diagnosis”). CF patients lose more
salt during exercise in the heat and during febrile illnesses than
do persons without CF, and they may experience dehydration or heat
prostration. Infants may develop hyponatremia and hypochloremia.
For unknown reasons, African American infants with CF seem to be
at greater risk for this complication than Caucasian infants.6
++
The upper respiratory tract is involved in virtually all cystic
fibrosis (CF) patients, with radiographic evidence of pansinusitis.
This is much more evident radiographically than symptomatically.6 It
occasionally is helpful diagnostically (particularly in childhood),
because persistent pansinusitis is uncommon except in CF, and CF
is extremely uncommon without pansinusitis. Nasal polyps may be
found in as many as 25% of CF patients and may be recurrent.
Indeed, the finding of large nasal polyps in children less than
12 years of age should prompt the clinician to consider CF.
++
The lower respiratory tract involvement in CF accounts for over
90% of the morbidity and mortality. Although the lungs
are histologically and radiographically normal at birth, the respiratory epithelium
is abnormal electrophysiologically, leading to obstruction of small
airways by viscid mucus, by airway inflammation, and by recurrent
endobronchial infection, which typifies the disease.2,3 Invading
organisms and inflammatory cells release inflammatory mediators
and leave behind large amounts of DNA when the cells lyse, adding
further to viscosity of lung mucus. Because of these factors, obstructive
pulmonary disease, beginning in the small airways, eventually is
present in almost all patients with CF. Recurrent cough, wheeze,
or both, which may be diagnosed initially as recurrent bronchiolitis, asthma,
or pneumonia, are often the first indications of pulmonary involvement.
As the disease progresses, hyperinflation and crackles become apparent,
and diffuse bronchiectasis eventually develops.
++
Pulmonary function tests reveal a pattern of obstructive airway
disease: decreased forced expiratory volume in 1 second, decreased
peak expiratory flow, and increased residual volume, indicative
of air trapping. These obstructive changes show varying responses
to bronchodilator inhalation: some patients improve, whereas many
do not change, and a few actually worsen, because bronchiectatic
airways may require bronchoconstrictor tone to remain stable. The
response to bronchodilators is not consistent over time. Exercise
testing6 typically shows reduced exercise tolerance
and fitness, with relatively high minute ventilation for the oxygen
consumed, presumably because of greater-than-normal dead-space ventilation.
Often, a higher-than-normal proportion of the ventilatory capacity
is required at peak workloads. Male patients have greater exercise
tolerance and cardiopulmonary fitness than female subjects. The
pulmonary function and exercise tests are relatively sensitive tools
for following progression of disease in the older, cooperative child
(see Chapter 503).
++
Chronic pulmonary infection and inflammation, with episodes of
acute exacerbation, are typical of CF patients.6,8 The
chronic and acute conditions are most accurately thought of as purulent
bronchiolitis and bronchitis. Exacerbations are characterized by
increased cough, often producing purulent sputum, particularly in the
morning on arising and with exertion; decreased exercise tolerance;
lethargy; malaise; and weight loss. Fever is often absent. In the
early stages of the disease, the bacterial organisms most commonly colonizing
the lower respiratory tract of patients with CF include Staphylococcus
aureus, Hemophilus influenzae, and a variety of gram-negative
organisms. Eventually, most patients permanently acquire Pseudomonas
aeruginosa and related gram-negative organisms, many of
which become resistant to conventional antibiotic therapy. Increasing
numbers of patients have Pseudomonas species at
diagnosis; whether this represents a true increase in prevalence
or represents better microbiology laboratory performance is uncertain.
There seems to be a unique relationship between CF patients and Pseudomonas; at
least half of all CF patients are colonized with a peculiar mucoid
strain of this organism that is seldom seen in other human disease
states. Some studies have suggested that early colonization of the
respiratory tract with Pseudomonas is an independent
risk factor for progressive pulmonary disease. Recently, other organisms,
such as Aspergillus fumigatus, Burkholderiacepacia, Alcaligenes (Achromobacter) xylosoxidans,
and Stenotrophomonas maltophilia, have become increasingly
important as pulmonary pathogens.
++
Despite the universal finding of chronic pulmonary colonization
and infection, extrapulmonary infection is unusual, indicating that
any defect in innate immunity is limited to the lungs. Pulmonary
defenses are almost certainly inhibited by viscid mucus, and mucociliary
transport rates are dramatically reduced. It is not yet clear whether
the ion transport abnormalities affect microbial adherence. It seems
likely that airway surface liquid is normal in tonicity yet deficient
in volume, rendering cilia ineffective in clearing secretions and
microbes.3 In addition, there appear to be circulating
or locally secreted toxins, some from neutrophils and some from Pseudomonas organisms,
that inhibit the phagocytosis and killing of Pseudomonas by
pulmonary alveolar macrophages and neutrophils. Whatever the bacterial
burden, there is also an overabundance of neutrophil-derived inflammatory
mediators that add to airway inflammation and obstruction. Current
research is focused on a better understanding of the mechanisms
of lung inflammation in CF.
+++
Progression
of CF Lung Disease2,3,6,8
++
The rate of lung disease progression varies widely among individuals,
influenced in part by environmental factors; secondhand cigarette
smoke, lower socioeconomic status,9 and recurrent
viral infection are three proven factors associated with worse pulmonary
prognosis.
++
The initial histological lesion is bronchiolitis, reflected physiologically
as small airways obstruction and radiographically as overinflation and
prominent bronchial markings (eFig. 514.1).
Further worsening of the lung disease includes extension from bronchiolitis
to bronchitis, with thickened bronchial walls demonstrable on radiographs
as circular lesions if the bronchi are projected in cross section
or as characteristic parallel linear opacities (“tram tracks”)
if the bronchi are projected longitudinally. With further progression
and the development of bronchiectasis and small cysts, rounded densities become
evident on radiographs. The right upper lobe is commonly affected
earlier and more severely than other lobes (eFig.
514.2). With more advanced disease, small abnormal areas coalesce
to form larger cysts (which may be dense when filled with mucopurulent
secretions or may be lucent when relatively empty) and regions of fibrosis.
Enlarged tortuous bronchial arteries may contribute to the opacities
visible on chest radiographs and may also lead to hemoptysis. Large
apical blebs may form and rupture, leading to pneumothorax (eFig. 514.3).
++
++
++
++
Pulmonary complications include chest pain, pneumothorax, hemoptysis,
segmental and lobar atelectasis, pulmonary hypertension leading
to cor pulmonale, and respiratory failure (see the “Treatment
of Pulmonary Complications” section). Digital clubbing
is a nearly universal finding in patients with even mildly abnormal
lung function.
++
The reproductive tract is involved in most male patients, with
atresia of the vas deferens and consequent obstructive azoospermia
and sterility. However, male CF patients can produce children through
in vitro methods. In female patients, thick cervical mucus often
results in decreased fertility. Delayed puberty may be seen in either
sex as a consequence of chronic illness and poor nutrition.
+++
Impaired Glucose
Tolerance and Diabetes
++
Some teens and adults with CF show an impaired insulin response,
characterized initially by an impaired first-phase insulin response,
then by a delayed and reduced peak insulin response. Decreased insulin sensitivity
(insulin resistance) may also be present in patients with CF. Insulin
is the only currently recommended therapy for all types of CF-related
diabetes, and many clinicians find that basal/bolus regimens are
optimal. Adolescents and adults display a unique pattern of hyperglycemia.
Abnormal glucose tolerance tests are frequent, but diabetic ketoacidosis
is rare, and microvascular complications of diabetes are less frequent.
With improved survival, microvascular diabetic complications are
likely to be seen more frequently.
++
Patients with CF, especially those who are older, have a higher
incidence of bone fracture caused by decreased bone density. This may
be secondary to malabsorption of vitamin D and calcium, hypogonadism,
inactivity, or cytokines from chronic infection. Contemporary management
with appropriate vitamin and nutritional supplementation likely
limits this complication. Exercise during childhood may be helpful.
Occasional patients, particularly those with severe lung disease,
have hypertrophic pulmonary osteoarthropathy involving the long
bones and adjacent joints. This complication is characterized clinically
by joint (especially knee) pain and radiographically by periostial
thickening. A systemic vasculitis syndrome with arthritis and a
vasculitic skin rash has also been described in CF patients.
++
The key to diagnosing cystic fibrosis (CF) is a high index of
suspicion in the presence of any of the manifestations. Increasingly,
the diagnosis of CF is made by newborn screening, but diagnosis
still requires confirmatory evaluation and testing in a specialized
CF center. CF is rarely diagnosed without a confirmatory positive
sweat test. The accepted criteria for diagnosis of CF are shown
in Table 514-2.10
++
++
Most newborns with CF have an elevation of blood immunoreactive
trypsinogen (IRT). The assay for IRT can be carried out from the dried
blood spots obtained from newborns for routine screening for other
genetic and metabolic diseases. The IRT test is used in more than
30 states and in many countries, and its use is likely to continue
spreading. There appear to be very few false negatives with this
screen, but the false-positive rate is as high as 90%.
Some screening programs move directly to genetic analysis for the
most common cystic fibrosis transmembrane conductance regulator
(CFTR) mutations in blood spots with elevated IRT, while others repeat
the analysis for IRT after one elevated level. If the second test
still shows elevated IRT, or if one or two CFTR mutations are identified
on DNA analysis, prompt referral to a CF center is indicated for
definitive genetic or sweat testing and initiation of comprehensive
treatment for those confirmed to have CF.
++
Sweat testing remains the gold standard for diagnosis of CF. Table 514-3 lists the indications for performing
a sweat test. Most physicians are sufficiently aware of the disease,
so few children with the triad of growth failure, steatorrhea, and
chronic pulmonary disease escape diagnosis. However, atypical patients,
especially those who have no clinically apparent pancreatic involvement
(as many as 15% of all CF patients and as many as 50% of
young infants with CF) or who have normal growth may escape diagnosis
for years.
++
++
Theoretically, the sweat test is simple, but false positives
and false negatives are extremely common in tests performed outside established
CF centers.7 Contrary to widespread belief, sweat
tests can be accomplished in young infants, although some young
infants might not produce a large enough volume of sweat for analysis.
Concentrations of sodium and chloride in sweat are below 40 meq/L
in normals, but nearly all patients with CF have values greater
than 60 meq/L. Very few patients fall in the intermediate
or borderline range (40–60 meq/L); in these individuals,
genotype analysis or measuring nasal potential difference may be
required for definitive diagnosis. Patients with intact exocrine
pancreatic function have somewhat lower sweat chloride concentrations
than those with pancreatic insufficiency, but their values are still
well outside the normal range. Table 514-4 lists
conditions giving false-positive and false-negative sweat test results.
++
+++
Nasal Potential
Difference
++
The function of the CFTR protein in respiratory epithelium can
also be assessed directly in vivo by measuring the bioelectric voltage
difference across nasal epithelium (the “nasal potential difference,” or
nasal PD); this is available in a few specialized CF centers.10 Three
abnormalities characterize the CF nasal PD (eFig.
514.4): (1) more negative than normal PD (reflecting abnormally
high Na+ transport across a Cl– impermeable
barrier); (2) greater-than-normal inhibition of PD with perfusion
with amiloride, a Na+ channel blocker (reflecting
inhibition of greater-than-normal Na+ transport);
and (3) little or no change in PD with perfusion with isoproterenol
and a Cl– free solution (reflecting the absence
of Cl– secretion).
++
++
Although the sweat test remains the gold standard for confirming
the diagnosis of CF, DNA analysis is increasingly used for CF diagnosis.
Demonstration of two of the known CFTR mutations in DNA in the appropriate clinical
setting is considered definitive for the diagnosis. Until more CF
gene mutations can be detected inexpensively, there will be some
patients with CF who have one or both unidentified alleles. Therefore,
DNA analysis cannot yet definitively rule out CF, nor can it positively
identify all CF patients. DNA analysis should be performed in those patients
for whom sweat testing is logistically difficult (live far from
a CF center) or has yielded equivocal results. DNA analysis for CF
is relatively easy for the referring physician: blood, buccal brushings,
or chorionic villus samples can be sent by overnight courier to
any of several commercial laboratories, with results often available
within a week. Most commercial laboratories examine DNA for 25 to
100 of the most common mutations, which together account for more than
95% of all CF patients. Therefore, results must be interpreted
with caution. For example, an individual may be found to have one
abnormal cystic fibrosis allele and one unknown allele. This second
allele may be normal, and the person is a CF carrier, or it may
be one of the mutations that are not included in the laboratory’s
panel, and the person has the disease. In the event of such a result
(one CF allele and one “negative”), the physician
should seek the advice of an individual who is experienced in the
genetics of cystic fibrosis. Some labs can now sequence the entire
CFTR gene and therefore minimize the likelihood of missing a mutation.
+++
General Approach
to Treatment
++
Cystic fibrosis (CF) is a complex disease, and patients require
a comprehensive evidence-based approach. Recent studies demonstrate unequivocally
that the early diagnosis of CF and the institution of an aggressive
treatment program can improve the quality and length of life. This
is usually best carried out in, or at least coordinated by, a center
that specializes in diagnosing and treating CF and that has different specialists
focusing on cystic fibrosis. Survival is greater for patients followed
in CF centers than for those followed outside centers. Patients who
are treated aggressively in CF centers that see their patients more
frequently, do more intensive monitoring, and use more antibiotics have
better outcomes than those followed in centers with a less aggressive
approach.
++
Therapy has three primary components: pulmonary; gastrointestinal;
and, importantly, social and psychological support for the patient
and family.
+++
Strategies for Preventing Progression
++
The goal of pulmonary therapy is to prevent or delay progression
of the pulmonary involvement. This is accomplished by relieving
airway obstruction and inflammation and by controlling infection.
+++
Therapy to Improve
Mucociliary Clearance
++
Airway clearance therapy (ACT) is the mainstay
of all treatment programs in CF patients who have evidence of pulmonary
disease. Most patients undergo ACT one to four times daily, with
increased frequency at the time of clinical pulmonary exacerbations.
Chest physical therapy (CPT) with percussion and postural drainage
is the traditional method of ACT and remains the only method appropriate
for infants. Beyond infancy, newer methods of airway clearance are
available, including the “flutter valve,” Acapella
forced expiratory technique (FET), use of forced expiratory efforts
into a mask with positive expiratory pressure (PEP masks), or the
use of a vibrating vest. Each method has its own proponents. No
definitive studies indicate the ideal time for instituting ACT or
the benefits of various techniques. Patient acceptance—and
therefore adherence to the prescribed treatment—varies
from method to method and patient to patient. Bronchoscopy and airway
lavage have demonstrated mucus plugs, inflammation, and infection
in the airways of even asymptomatic infants, implying that airway-clearance
procedures should be instituted very early in life. Head-down positions
should probably be avoided during chest physical therapy in infants,
as they increase gastroesophageal reflux.
++
Aerobic exercise (jogging and swimming) are
beneficial for CF patients in terms of increased cardiopulmonary
fitness (oxygen consumption, VO2) and work capacity. Further,
high aerobic fitness is correlated with prolonged survival.11 There
is some suggestion that various kinds of exercise may be as effective
as traditional CPT in relieving pulmonary obstruction, but studies
examining this question have had conflicting results. Therefore, until
a definitive study is available, most experts advise the use of
both exercise and CPT.
+++
Inhalation-Based
Therapy
++
Various kinds of aerosols have been employed for patients with
CF in order to dilate bronchi, reduce mucus viscosity, reduce mucosal
edema and inflammation, suppress microbial growth, and perhaps even
to correct the epithelial ion transport abnormality. Bronchodilators
increase airflow acutely in some patients, make no difference in
many, and actually reduce airflow in a few patients with severe
disease where smooth muscle relaxation causes airway instability
during exhalation. There have been few studies of the effects of
long-term bronchodilator aerosol use. Mucolytic agents (eg, N-acetylcysteine)
are effective in vitro, but they may cause irritation, bronchoconstriction,
and bronchorrhea in vivo. Recombinant human DNase, which can degrade neutrophil-derived
DNA and decrease the viscosity of airway secretions, reduces the
rate of pulmonary function decline.12 Hypertonic
(7%) saline also improves pulmonary function and increases
the time between episodes of worsened airway infection, although
it is not clear if its benefit is from replacing airway surface
liquid that is depleted via the basic ion and water transport defect
or simply by stimulating cough. Antibiotics, especially aminoglycosides13 and
semisynthetic penicillin derivatives, can be delivered by aerosols,
with favorable results.
++
Several experimental aerosol therapies have been introduced and
await definitive study to assess their safety and efficacy. Some
agents in clinical trials are thought to increase delivery of CFTR
protein to the airway epithelial cell surface or improve its function,
while other new drugs may improve epithelial ion transport by opening
auxiliary chloride channels or blocking sodium absorption. Airway
delivery of healthy genes via various viral and nonviral vectors
is also being studied. Alpha 1-antitrypsin14 and
other inhibitors of neutrophil and bacterial-derived proteases may
diminish the damaging effects of chronic airway infection and inflammation.
Several other anti-inflammatory agents are undergoing clinical trials.
+++
Anti-Inflammatory
Therapy
++
Several approaches have been proposed to reduce airway inflammation
in cystic fibrosis. Clinical trials of alternate-day corticosteroid
therapy suggest some benefits (improved pulmonary function over
a 4-year period) and some drawbacks (decreased growth velocity and
possible glucose intolerance).15 Cromolyn sodium
has been shown in a small study to be ineffective. Inhaled topical
steroids have shown small benefits in a few small studies but may
be useful in patients who have clear-cut evidence of asthma. Ibuprofen
therapy seems to benefit some patients and decrease the rate of
pulmonary decline,16 but the therapeutic index
is narrow, and the logistical bother of needing to monitor blood
levels, along with fear of side effects, has limited its use.
+++
Treatment of
Infection
++
More aggressive treatment of pulmonary infection is the single
most important factor leading to the markedly improved prognosis
in CF. Staphylococcus and Hemophilus may
occasionally be eliminated from the bronchial tree in CF, and recent
evidence suggests that even Pseudomonas might be
eradicated if it is treated aggressively (eg, with an oral quinolone
and aerosol aminoglycoside) soon after the initial positive throat
or sputum culture.17
++
A variety of antibiotic treatment strategies are employed at
CF centers around the world. Some CF centers advocate continuous
inhaled or oral prophylactic antibiotic treatment, with additional
treatment with intravenous antibiotics for acute exacerbations.
There is some concern that this approach might lead to the early emergence
of drug-resistant pathogens in the airways. Another approach is
to restrict the use of antibiotics to times of exacerbation of pulmonary
disease, as evidenced by increased symptoms or signs (such as cough
or sputum production) or worsening objective data, such as chest
radiograph or pulmonary function test results. Some patients, especially
those with advanced disease, suffer exacerbations whenever they
are not being treated with antibiotics; in such patients, virtually
continuous treatment is indicated. A third approach is to treat
with an aggressive course of antibiotics (oral, aerosol, or IV),
based on culture results, for 2 to 3 weeks every 1 or 2 months in
patients with any evidence of pulmonary disease (morning cough, abnormal
x-ray, etc). For example, in some European countries, CF patients
whose cultures grow Pseudomonas aeruginosa are
hospitalized for 2 weeks of intravenous antibiotics and aggressive
chest physiotherapy every 3 months, regardless of their clinical
condition. Survival has increased dramatically since the institution
of this approach.17 A 6-month trial of alternate-day
azithromycin has been shown to increase pulmonary function and lengthen
time between infectious exacerbations, but a European study suggested
decreased benefit after a year.
++
An algorithm for the approach to CF lung infection used in one
U.S. center is shown in Figure 514-2. Because
of the extremely large variation in CF from patient to patient,
most centers employ an individualized approach to this issue, which
includes a thorough discussion of the risks and benefits of any proposed
therapeutic approach.
++
++
A cornerstone of most successful treatment programs is frequent
comprehensive clinical evaluation of patients, including microbiological
examination of respiratory tract flora by a laboratory that is experienced
in detecting potential cystic fibrosis pathogens. Oral antibiotics
(amoxicillin/clavulanate, cephalexin, trimethoprim-sulfamethoxazole,
erythromycin, clarithromycin, or azithromycin) at the first sign
of worsening respiratory symptoms may successfully treat a pulmonary
exacerbation. Some of these drugs (eg, the macrolides, including
azithromycin) have anti-inflammatory effects unrelated to their
bactericidal effects. The quinolones (eg, ciprofloxacin, ofloxacin,
levofloxacin) are a class of oral antibiotics with impressive in
vitro activity against Pseudomonas and good penetration
into the lung. The quinolones have been useful and apparently safe
in children as young as 4 years, although the possibility of quinolone-associated
arthropathy must be considered. Linezolid is a relatively
new orally administered antibiotic, effective in vitro and
clinically against methicillin-resistant Staphylococcus
aureus, which has become more common in patients with CF
and in the rest of the population. Simultaneous treatment with rifampin
may prevent the rapid emergence of resistant organisms, which is
otherwise common during treatment with quinolones.
++
Aerosolized antibiotics, especially tobramycin, may be effective
in many patients colonized with Pseudomonas. High
endobronchial concentrations of tobramycin can be achieved via the
inhaled route that would be impossible to achieve with intravenous
dosage. Twice-daily nebulized tobramycin for a month at a time, alternating
with a month off treatment, has been shown to improve pulmonary
function and lengthen time between infectious exacerbations, without
increasing tobramycin-resistant strains of Pseudomonas.13 Patients
who cannot tolerate certain drugs (eg, colistin) intravenously may
do well with the same drugs delivered by aerosol. In patients with
severe airways obstruction, aerosol penetration into the lung may be
limited and render this form of treatment less valuable. The sequential
use of inhaled bronchodilators or DNase may increase antibiotic
deposition.
++
Intravenous antibiotics are indicated when the patient does not
respond to outpatient oral or aerosol antibiotic therapy. When deciding
whether to begin parenteral therapy, an important consideration
is whether the child is sicker than his or her own baseline and
not whether the child seems dreadfully ill. It is clear that a significant
amount of lung can be lost irreversibly while a child still looks
reasonably well. Because Pseudomonas aeruginosa is
usually the offending organism, intravenous therapy is commonly
carried out with an aminoglycoside and a semisynthetic anti-Pseudomonas penicillin
or a third-generation cephalosporin. It is commonly believed that
using two or more antibiotics from different classes improves effectiveness
and decreases the emergence of antibiotic-resistant organisms, but
strong supporting data for this belief are lacking. Intravenous
antibiotics are usually administered during hospitalization, but
in carefully selected cases, they may successfully be administered at
home, either initially or for 1 or 2 weeks following hospitalization.
Response to treatment is often slower or absent at home, and the
burden on a family of administering two or three different antibiotics
on different schedules around the clock should not be underestimated.
The most commonly used intravenous antibiotics, dosing schedules,
and toxicities are listed in eTable 514.1.
Intravenous antibiotic treatment should be continued until the patient’s
pulmonary status has reached a plateau, as assessed by patient/parent
report, physical examination, oximetry, and spirometry. The time to
reach this plateau is usually 2 to 3 weeks but can be longer in
sicker patients. Occasionally, the new plateau may be better than
the previous level of functioning. At other times, because cystic
fibrosis remains a progressive disease, the patient may not regain
his or her previous level of functioning. Most patients will be
able to maintain levels they achieve during hospitalization for
at least a few weeks after discharge, but most will not continue
to improve after intravenous antibiotics have been discontinued.
++
++
Intravenous antibiotics are usually administered during hospitalization.
Studies have shown that the benefits of hospitalization cannot be
explained completely by the use of intravenous antibiotics alone.
Some patients improve in the hospital even if intravenous antibiotics
are not given. Possible benefits of hospitalization include effective
and frequent chest physical therapy and aerosol treatments, improved
nutritional support, relatively clean air, absence of inhalant hazards
and aeroallergens, enforcement of a strict therapeutic regimen,
and opportunities for continuing patient education.
+++
Treatment of Pulmonary Complications
++
Chest pain is relatively common in cystic fibrosis (CF), particularly
in patients with advanced lung disease. If the onset of the pain
is abrupt, unilateral, pleuritic, and associated with shortness
of breath, the most likely and the most ominous cause is pneumothorax
(see below). Other causes of chest pain include pleural inflammation
and musculoskeletal strains, especially from prolonged paroxysmal
coughing episodes. The musculoskeletal strains usually respond to
rest, anti-inflammatory treatment, or both. Pleural inflammation
is usually secondary to underlying parenchymal infection and is
treated with antibiotics. The occasional patient reports chest pain that
is relieved when a hard coughing spell produces a large mucus plug.
Esophageal pain can be due to “pill esophagitis,” which
is prevented by assuring adequate fluids for swallowing the large
number of pills and capsules required for CF treatment. It may also
be due to esophagitis. Gastroesophageal reflux disease (GERD) is more
common in patients with CF, as is Barrett esophagus and adenocarcinoma
of the esophagus. Treatment is with proton pump inhibitors. In patients
receiving inhaled or systemic steroids, Candida esophagitis
may occur.
++
This condition occurs in up to 10% of CF patients when
apical blebs, associated with advanced pulmonary disease, rupture.
Many pneumothoraces eventually resolve with oxygen therapy or with
simple chest tube drainage, but recurrence rates of 50% to
100% are likely. Therefore, therapy to prevent recurrence
is advisable. The instillation of chemical sclerosing agents has
been used with some success but is painful and may not reduce the
risk of recurrences. However, in some centers, surgical or chemical
ablation of the pleural space is considered a contraindication to
lung transplantation. A stepwise approach to the first episode of
pneumothorax has been advocated, whereby simple chest tube drainage
is undertaken first. If the air leak does not resolve within the next few days, or if an
episode recurs, an attempt should be made to identify and seal apical
blebs via a small thoracotomy. The most successful treatment for
early resolution of the pneumothorax, prevention of subsequent episodes,
with the least morbidity has been open thoracotomy through a small
subaxillary incision, identification and excision of any apical
blebs, stripping of the apical pleura, and manual abrasion of the
remainder of the accessible pleura.18 Thoracoscopic
surgery is an alternative to small thoracotomy. If these steps fail,
physical or chemical pleurabrasion, via thoracoscopy or open thoracotomy,
should be performed.
++
Hemoptysis with minor blood-streaking of sputum is a common complication
of CF, but massive hemoptysis, defined as more than 300 mL in 24
hours, is much less common. It occurs in 5% to 10% of
patients. Although terrifying to patient and family, it rarely is
severe enough to interfere with gas exchange or to require transfusion.
Deaths have been reported but are exceedingly rare. Massive hemoptysis
is thought to be the result of local infection that erodes one of
the tortuous bronchial vessels adjacent to bronchiectatic airways.
The appropriate treatment for all but the most overwhelmingly brisk bleeding
is to reassure the patient and family and to initiate or continue
aggressive treatment of pulmonary infection, including intravenous antibiotics.
Because infection plays a causative role and blood reduces ciliary
function and is a fertile bacterial medium, aggressive chest physical
therapy should be continued. In some patients, hemoptysis may be
associated with an iatrogenic platelet-aggregation defect (eg, seen with
aspirin, carbenicillin, or ticarcillin therapy). Because CF patients
malabsorb fat-soluble vitamins, treatment of hemoptysis includes
supplementing with vitamin K. With brisk bleeding, intravenous vasopressin
can be effective. In the rare recalcitrant case of hemoptysis, embolization
of the offending bronchial artery under radiological guidance may
be required. Lobectomy is seldom necessary.
++
Lobar or segmental atelectasis, particularly of the upper lobes,
occurs even early in the course of the disease (eFig.
514.1). Segmental or lobar atelectasis is best treated with
antibiotics, bronchodilators, and vigorous chest physical therapy.
It may take weeks or months for atelectasis to resolve. Bronchoscopy
is unlikely to speed the resolution but should be considered when
the atelectasis is associated with an otherwise unexplained deterioration;
in these cases, culture of bronchoscopically obtained specimens
may yield an unexpected organism that can be used to guide antimicrobial
therapy.
++
Cor pulmonale, characterized by pulmonary hypertension
with enlargement of the right ventricle, is common in end-stage
CF. Overt heart failure with enlarged liver and peripheral edema
is much less common but more ominous. One study has suggested that
survival is less than 8 months after the onset of heart failure,
although more recent results have been better. Diuretics are usually
helpful, but digitalis is not used unless there is also left ventricular
dysfunction. Salt intake should be restricted. Treating the underlying
suppurative lung disease and administering supplemental oxygen are
the approaches most likely to be of benefit. In CF patients with
advanced pulmonary disease and cor pulmonale, simultaneous heart
and lung transplantation may be employed, although cardiac function
most often recovers rapidly with replacement of lungs alone.
++
Respiratory failure in CF is almost always the end result of
a long, devastating course. Occasionally, it can be seen acutely
in a previously stable patient who had been doing well and abruptly
worsens due to a severe viral infection, trauma, or surgery for
nonpulmonary problems. For acute respiratory failure in a previously
relatively healthy patient, treatment should be aggressive with
oxygen, antibiotics, aerosols, and airway clearance. Mechanical
ventilation may be indicated for those individuals with good lung function
before an acute deterioration. The prognosis for regaining the previous
status is good. With chronic respiratory failure, the prognosis
is much different; therefore, the approach to the patient is different.
Oxygen therapy is indicated to keep oxygen saturation above 90%.
If the patient has carbon-dioxide retention (a very late finding in
CF), oxygen should be administered with caution in order to avoid
suppressing the hypoxic drive to breathe. This is much more a theoretical problem
than a real one, however, because the majority of patients with
cystic fibrosis will either not change or will actually improve
their ventilation with supplemental oxygen. In these patients, supplemental
oxygen may improve gas exchange by reducing anxiety and improving respiratory
muscle function. Emphasis should be on patient comfort. Terminally
ill CF patients may have CO2 narcosis and be comfortable,
whereas in others, air hunger from hypoxemia may dominate the clinical
picture. Morphine may be helpful in these latter patients by decreasing
anxiety and promoting comfort. Morphine must be used carefully in
this setting, as some terminal CF patients appear to be exquisitely
sensitive to the drug, perhaps because of acidosis. Some centers
use a starting dose as low as 0.1 mg (not 0.1 mg/kg) and
double the dose until the desired result is achieved.
++
A number of options are available to support ventilation in CF
patients with respiratory failure. These include conventional invasive
approaches using endotracheal intubation or tracheotomy and mechanical
ventilation, and less invasive devices such as mask BiPAP or intermittent
positive-pressure breathing. The choice of techniques may be different
in those patients who are lung transplant candidates and those who
are not. Without transplantation, once patients begin these therapies,
they have little chance of being able to stop them. Long-term mechanical
ventilation is unlikely to enhance the quality of life of CF patients
with respiratory failure and is not recommended. At some centers,
some patients accepted for lung transplantation have been supported
for weeks or months with mask BiPAP or conventional mechanical ventilation
as a “bridge” to transplantation. Some patients
have died on ventilators awaiting the availability of suitable donor
lungs. Some centers view mechanical ventilation as a contraindication
to transplantation and feel that initiating such treatment unconscionably complicates
the letting-go, dying, and grieving process. These issues are best
addressed with patients and families on multiple occasions when the
patient is not in impending respiratory failure.
+++
Lung Transplantation
for CF
++
Heart-lung or double-lung transplantation has been successful
in a limited number of CF patients with end-stage disease. One-year
survival ranges from 50% to 85%.19 Donor-organ
availability is a limiting factor for most North American lung transplant
programs, and pretransplant mortality is high among those on transplant
waiting lists. After transplantation, medical care is even more
complex than that for cystic fibrosis before transplantation. Postoperative
problems with immunosuppression, infection, acute and chronic organ
rejection, finances, and psychological adjustment require constant
attention. Nonetheless, some patients have had excellent results,
with return to full-time work or school. Because waiting lists for
donor lungs are as long as 2 years, most centers begin discussing
transplantation with patients before they have respiratory failure,
perhaps when pulmonary status begins to decline rapidly and oxygen
therapy is required. Some recent studies have questioned the benefit
of lung transplantation in CF, indicating that it seldom increases
longevity, particularly in children.20
+++
Treatment of Gastrointestinal
and Nutritional Complications
++
Longitudinal surveys of growth patterns in cystic fibrosis (CF)
patients indicate that maintaining a normal weight-to-height ratio
is associated with a slower pace of lung function deterioration.21 For
this reason, the main goal of gastrointestinal therapy is to provide
good nutrition and to teach and reinforce age-appropriate nutritional
habits. A diet specific for the CF patient is not necessary, but
usually a high-fat diet is useful to ensure adequate total caloric
intake. Energy intakes of 110% to 200% greater
than the standard for the general population are often required
for appropriate weight gain and growth in children and for weight
maintenance in adults with CF. Oral nutritional supplements are
often useful, but even these supplements may prove inadequate in
a subset of CF patients who simply cannot consume adequate calories.
These patients may have anorexia related to chronic illness or may
have greater-than-normal caloric expenditure because of chronic
infection or increased ventilatory muscle energy expenditure. Many
of these patients do well with nocturnal enteral feeds provided
through a gastrostomy or jejunostomy tube. Formula can be provided
continuously overnight to provide much of the patient’s
caloric needs, including “catch-up” needs. Elemental
formulas can be used and may reduce the need for pancreatic enzyme
supplements, but many patients have thrived on much more standard,
less expensive formulas with enzyme replacement at bedtime and in
the morning. The Cystic Fibrosis Foundation consensus panel recommends
that behavioral therapy; oral nutritional supplements; and, if required,
enteral nutritional supplements can improve the weight gain goals
of maintaining a weight/length at or above the 50th percentile
in children under 2 years and a BMI above the 50th percentile in
children and adolescents ages 2 to 20 years. These recommendations
are based upon retrospective findings showing a favorable effect
on prognosis.
++
Supplemental vitamins, especially the fat-soluble vitamins A
and E, require supplementation. The recommended daily supplements
that usually achieve normal plasma levels in infancy are vitamin
A, 4000 IU (120 mcg); vitamin D, 400 IU (10 mcg); and vitamin E,
37 to 75 IU (25 to 50 mg). The recommended doses for children over
1 year of age are vitamin A, 8000 IU; vitamin D, 800 IU; and vitamin
E, 100 to 200 mg. These doses are considerably higher than the usual
dietary intake, and plasma levels should be monitored intermittently.
+++
Pancreatic Enzyme Supplementation
++
Treatment of pancreatic insufficiency uses pancreatic enzyme
supplements that are available in a variety of formulations. Enteric-coated
varieties are generally more effective. Correct dose of enzyme is
determined by trial and error, titrating against the symptoms and
signs of maldigestion and malabsorption (steatorrhea, abdominal
discomfort, excessive hunger, and poor weight gain). Generally,
doses of 500 to 2500 units lipase per kilogram body weight per meal,
or less than 10,000 units lipase per kilogram body weight per day,
or less than 4000 units lipase per gram dietary fat per day are
adequate. Enzyme doses greater than 2500 units/kg per meal
of the lipase component are rarely necessary and are associated
with complications of fibrosing cholangiopathy and hyperuricemia.
Some patients who seem to require very large numbers of enzyme capsules
may do better if they are treated with H2 blockers or proton
pump inhibitors, which enhance the bioavailability of ingested enzymes.
In these patients, it is likely that gastric acid hypersecretion,
along with the usual absence of pancreatic bicarbonate, has rendered
their duodenum and jejunum sufficiently acidic to prevent the complete
dissolution of the enteric coating of the enzyme supplements.
+++
Pain Due to
Gastrointestinal Disorders
++
This is relatively common in patients with CF and can be caused
by a large number of problems, not all of which are CF-related (Table 514-5).
++
+++
Constipation,
Meconium Ileus, and Distal Intestinal Obstruction Syndrome
++
Clinical presentations of these disorders are described above.
Treatment of distal intestinal obstruction syndrome (DIOS) can be
initiated with careful administration of hyperosmolar enemas, such
as meglumine diatrizoate (Gastrografin) or, if in its early stages,
with (ie, abdominal distension and constipation without complete
obstruction) polyethylene glycol (MiraLAX or large volumes of oral
or nasogastric GoLYTELY22), eliminating the need
for enemas. Chronic constipation can often be prevented from leading
to DIOS by adjusting pancreatic enzyme dosing or by the use of lactulose
or MiraLAX.
+++
Fibrosing Cholangiopathy
++
This serious complication of very high doses of pancreatic enzymes
emerged in the 1990s. Patients may have abdominal pain, bloody diarrhea,
or signs of obstruction. Surgery is usually required. The problem has
not been seen in patients taking less than 5000 units of lipase
per kilogram of body weight per meal and has become uncommon with
the reformulation of many enzyme preparations.
++
As in any patient, appendicitis, cholecystitis, Clostridium
difficile colitis, hepatitis, trauma, and other causes
must be considered in the differential diagnosis of acute abdominal
pain.
++
Rectal prolapse is treated by gentle manual pressure on the protruding
rectum and is prevented by adjusting the diet and enzymes to reduce
bulky stools.
++
Gastroesophageal reflux in infants should be treated conservatively
by using the prone position and avoiding the seated position, which
provokes reflux. The head-down chest physical therapy position should be
avoided in infants. Reflux that manifests in infants as regurgitation
with loss of calories is treated by thickening formula feedings
with one tablespoon of rice cereal per ounce of formula. Reflux
that manifests at any age as esophagitis with heartburn or feeding
refusal is treated with H2 blockers or proton pump inhibitors.
Reflux that manifests as reflex bronchospasm is also treated with
acid suppression and bronchodilators. In any of these manifestations
of reflux, the administration of a prokinetic agent may increase
lower esophageal sphincter tone and promote gastric emptying.
++
In patients with reflux symptoms who do not respond to medical
management, the possibility of gastric outlet obstruction should
be excluded with gastric-emptying studies.
++
Liver disease associated with cystic fibrosis is discussed in Chapter 423.
++
Carbohydrate intolerance, with or without overt diabetes, occurs
in a small but important group of cystic fibrosis (CF) patients.
In some patients, dietary manipulations, including use of high-calorie,
low-carbohydrate supplements, may help. In others, oral hypoglycemic
agents have eliminated or delayed the need for insulin injections.
However, reluctance to begin insulin therapy may be misguided, as
institution of insulin therapy can improve growth and pulmonary
function.
++
Salt loss may be excessive, especially during febrile illnesses
or exertion in warm weather, but it can be prevented if patients
are well hydrated. Older children and adults will generally regulate
their salt intake quite adequately if given free access to salt
and water. CF patients underestimate their fluid needs during exercise
in the heat and need to be encouraged to drink more than they think
they need at such times. Salt tablets are not necessary and may
be harmful.
+++
Social and Psychological
Support
++
The emotional burdens of a genetic, incurable, progressive, life-shortening,
financially draining, and activity-limiting disease on patient and
family are substantial. It is remarkable how well the large majority of
patients and families adjust, with a very low incidence of depression.
Issues that patients must face include education and vocation, marriage,
reproduction, medical expenses, independent living, and anticipation
of disability and death. Establishing and maintaining a positive,
optimistic, yet realistic attitude are extremely important. These
goals are attainable, especially if the primary physician shares
this attitude and maintains a close, supportive relationship with
the patient and family. Knowledge of the tremendously improved prognosis
over the past decades facilitates such an attitude. High-quality
CF centers provide appropriate social work and psychological support
resources such that access to these resources is ensured when needed.
++
Institution of specialized CF centers and comprehensive aggressive
treatment programs beginning in the 1950s has improved the prognosis tremendously.
Projected national median survival was 10.6 years in 1966, 20 years
in 1981, and 37 years in 2006. It is important to note that these
advances in survival have not resulted entirely from major conceptual
breakthroughs or new classes of antibiotics but mostly from the adoption
of aggressive treatment programs that emphasize daily attention
to the complex details of CF care. There are currently many CF patients
in their 30s and 40s with excellent lung function, and in 2008,
43% of CF patients in the United States were 18 years old
or older. Survival probably depends on several factors, including
inherent severity of the disease, determined in part by genotype;
aggressiveness of the treatment program as prescribed by the physician
and carried out by the patient and family; and some degree of chance,
especially concerning contact with various bacterial and viral pathogens.
Exposure to cigarette smoke speeds pulmonary decline. In general,
the survival of male patients is better than that of females. Recently,
survival has been shown to be closely correlated with physical fitness,
as measured during an exercise test, with fitness being a stronger
correlate of survival than even pulmonary function. Perhaps most
importantly, long-term prognosis may depend on the timing of diagnosis
and the institution of treatment. Several studies indicate that
those CF patients who are diagnosed early and who begin an aggressive
treatment program before the onset of significant pulmonary damage
have significantly better pulmonary function and survival than those
discovered and treated only after considerable pulmonary tissue
has been lost.