CHRONIC BRONCHOPULMONARY
DISEASES
Department of pediatrics
BRONCHIECTASIS
Bronchiectasis is a chronic suppurative disease
characterized by destruction of the bronchial
and peribronchial tissues, dilatation of the
bronchi and accumulation of infected material
in the dependent bronchi.
Etiopathogenesis
• Most cases follow recurrent episods of respiratory infections such
as bronchitis, bronchiolitis, post measles or post pertussis
pulmonary infections, cystic fibrosis and pneumonitis in infancy and
early childhood. Infections damage the bronchial wall and cause
segmental areas of collapse, which exert a negative pressure on the
damaged bronchi, causing them to dilate. The bronchial dilatation is
widespread and patchy. The bronchi may show cylindrical, fusiform
or saccular dilatation.
•
Aspiration of foreign body, food, or mucus plug in the bronchus
may occlude the bronchial lumen and cause segmental areas of
collapse. The bronchi are dilated due to negative pressure by the
collapsed segment. If the occlusion is relieved before the stagnant
secretions are infected and the bronchial wall is damaged, the
bronchiectasis is reversible. The bronchial dilatations are generally
segmental or lobar. Extrinsic compression by the tuberculous lymph
nodes often causes collapse of right middle lobe.
Etiopathogenesis
• Congenital disorders of bronchi such as bronchomalacia,
communicating type of bronchial cyst or sequestrated lung
may be the cause of bronchiectasis in some cases.
•
Kartagener syndrome is characterized by bronchiectasis,
situs inversus and sinusitis and is attributed to disorder of
ciliary motility (immotile cilia syndrome)
•
Cystic fibrosis is rare cause of bronchiectasis.
•
Immunodeficiency syndrome may be responsible for
recurrent pulmonary infections and bronchiectasis.
•
Young syndrome has sinusitis, bronchiectasis and
azoospermia (detected later in life).
Clinical manifestations
• The onset is generally insidious. The respiratory infections tend to
persist longer and recur frequently with waxing and waning. Often
the illness can be traced back to an episode of measles or whooping
cough. A history of inhalation of foreign body is usually not
forthcoming as it is often forgotten.
•
The most prominent symptom is cough with copious
mucopurulent expectoration. Cough is more marked in some
postures because of irritation of the infected secretions draining
into fresh areas of lung. Likewise the cough is more marked when
the child wakes up in the morning due to a change of posture.
Younger children may not expectorate out the sputum which they
swallow. Infants and young children often have significant
wheezing. In the course of illness, the sputum may become blood
streaked or even frank hemoptysis may occur. In chronic cases
clubbing of fingers is seen.
•
The general health is poor, with recurrent infections. The patient
complains of loss of appetite, irritability and poor weight gain.
Investigations
X-ray film of the chest shows honeycombing of
the involved area indicating multiple small
abscess cavities. Bronchography remains the
mainstay for diagnosing bronchiectasis.
Bronchoscopy is undertaken where there is a
possibility of surgical intervention. Now-a-days CT
of the chest has replaced bronchoscopy in
following the evolution of disease and deciding
the need of surgical intervention. Sputum should
be sent for culture and sensitivity. Tuberculin
reaction is done to exclude tuberculosis.
Pilocarpine iontophoresis is done for estimating
sweat chlorides in cases suspected to be suffering
from cystic fibrosis.
Prevention
Most cases follow acute respiratory infections,
which are inadequately treated. All pulmonary
infections should be treated promptly and
adequately till the chest is clear of all signs,
long after the fever has subsided. Even in
ordinary pulmonary infections, airway should
be kept patent by encouraging postural
coughing. Measles and whooping cough
should be prevented by specific immunization.
Prompt medical help should be sought if there
is any suspicion of inhalation of a foreign
body.
Management
During acute exacerbation, bacterial infections should be controlled
and airway kept clear of secretions and exudates. This is facilitated
by effective coughing at regular intervals and postural drainage.
Assistance by a specially trained pulmonary physiotherapist may be
useful. Surgical resection of the involved area should be undertaken
only in children who have marked symptoms and in whom the
disease is localized. Extrinsic compression of bronchi by mediastinal
masses requires surgical intervention. Cases with significant
bronchographic changes but minimal symptoms need not be
operated upon. In young children with generalized disease
associated with recurrent pulmonary infections, ill advised surgery
may at times make the patient worse. If the child cannot cooperate
in post surgery postural coughing, segmental or lobar collapse may
occur in the postoperative period and new bronchiectatic lesions
may appear. Children with generalized disease may improve
significantly clinically with medical treatment alone during
adolescence.
PRIMARY CILIARY DYSKINESIA (IMMOTILE CILIA
SYNDROME, KARTAGENER SYNDROME)
The group of respiratory disorders making up
primary ciliary dyskinesia (PCD) have in
common the malfunction of airway cilia. The
ciliary abnormality is a result of various
inherited primary structural defects in the cilia
that lead to repeated and chronic lung
infections. However, the ciliary malfunction in
these diseases is not a result of acquired
repeated pulmonary infections.
Characteristic of cilia
Location and structure. Airway cilia are located on epithelial surfaces in
almost a ubiquitous fashion. They are present in the nose, sinuses, ears,
and airways. They are also present in places other than the respiratory
epithelium, such as in the fallopian tubes and in sperm. The density of cilia
varies, with the majority of cells (50-80%) in the large airways having cilia,
far fewer cells in the lower airways having cilia, and no cells in air sacks
and alveoli having cilia. The frequency of ciliary beating, or beatquency, is
obout 1 – 20 Hz, with the higher beatquency occurring in the larger
airways, correlating with the mucus velocity in various parts of the
tracheobronchial tree.
Cilia are finger-like structures that extend from the surface of cells into
the lumen of airways. They have a diameter of 0,25 μm and a length of
306 μm. Each cell usually has about 200 cilia on its surface. Each cilia has a
trunk, a basal body (where the cilia attaches to the cell), and a crown,
which is a specialized structure presumed to be important in cilia
attachment to mucus. The trunk is made of an outer cell membrane and
axonemes or cytoskeletal protein structures. The latter form a circular
array of nine microtubules in pairs with an additional central pair. Each
peripheral pair can attach to the other via bridges or dynein arms. Spokes
are also cytoskeletal proteins that join peripheral and central
microtubules.
Characteristic of cilia
Function. Cilia beat and move by a sliding motion of microtubules. At the
outset of the beating cycle, they bend at the base and move backward,
perpendicular to the surface. Subsequently, they extend (“slide”) as they
are rotating in a forward motion. These bending and rotating movements,
which are clockwise, three-dimensional rotations, are made possible by
adenosine triphosphate hydrolysis and the dynein arms, which are
adenosine triphosphates. When visualized under microscopy, airway cilia
are seen to coordinate their activity regionally, and waves of ciliary
movements (many cilia together) occur. How this is coordinated and how
effective and important such coordination is to ciliary function is not well
understood.
The main function of cilia is to transport, through its beating movements,
mucus toward the mouth. The effectiveness of this function depends on
the beatquency, the composition and thickness of the periciliary fluid and
mucus layer above it, and the coordination of ciliary movements. In
addition, there are a number of neurochemicals that modulate ciliary
beating by increased beatquency such as β-adrenergic compounds,
acetylcholine, bradykinins and serotonin. Alternatively, lowering airway
humidity significantly lowers the frequency of ciliary beating. In addition,
increasing bacterial loads decreases its beatquency.
Pathology
The structural abnormalities of these disorders can be
seen with electron microscopy. Defects in both inner
and outer dynein arms, radial spoke microtubular
assembly, and central core cytoskeletal proteins have
been described. It is estimated that there are more
than 200 polypeptides in the ciliary structure, and
primary ciliary dyskinesia is most likely based on the
absence of one or several ciliary cytoskeletal proteins.
All these structural defects result in ciliary malfunction
characterized by either abnormal beating or immotility
of cilia and defective mucociliary clearance of airway
secretions. The most likely pathogenic sequence is
airway mucus retention and failure to clear pathogenic
organisms, followed by chronic or frequently recurring
respiratory tract infections and, ultimately, injury to
airway walls.
Genetics
PCD occurs in about 1/20.000 whites and has
been reported in Japanese patients. It is probably
the 3rd most common form of inherited chronic
airway disease of white children, following cystic
fibrosis (CF) and genetic immunodeficiency
states. The inheritance pattern of PCD has not
been established. There is conflictind evidence
for autosomal recessive or autosomal dominant
inheritance with the mother having a new
mutation, mitochondrial inheritance, or an Xlinked mutation.
Clinical manifestations
•
•
About 50% of patients with PCD have Kartagener’s syndrome: situs inversus,
chronic sinusitis and otitis, and airway disease leading to bronchiectasis. However,
only about 25% of patients with situs inversus also have PCD. Situs inversus does
not establish or exclude the presence of PCD. Investigations have hypothesized
that normal rotation of viscera depends on the motion of ciliated gut cells early in
development. The absence of ciliary motility allows random rotation; a dynein
defect is at the basis of left-right asymmetry in the inversus viscerum mouse
model.
The course is variable. Individuals with PCD may have respiratory distress during
the newborn period or may survive to adulthood without overt chronic sinusitis
and airway disease symptoms. However, in one study of PCD, 100% of children had
productive cough, sinusitis, and otitis. A feature that is helpful in differentiating
PCD from CF is repeated bouts of acute otitis media or chronic serous otitis.
Children diagnosed after several years of life often have been treated with
tympanostomy tubes; conductive hearing loss is common. Nasal polyps or clubbing
is present in about 20% of patients. Many children with PCD experience frequent
wheezing and may have an initial diagnosis of asthma. The hallmark symptom is a
chronic, often loose of productive cough. Pneumonia may supervene and lower
respiratory tract disease can progress to weight loss, diminished exercise
tolerance, and bronchiectasis. Respiratory failure in childhood is uncommon, as
are lung complications such as pneumothorax and hemoptysis. Lobar atelectasis
occurs frequently. Males are frequently infertile and display absent or poor sperm
motility.
Diagnosis
•
•
PCD should be suspected in children with chronic or recurring upper and lower respiratory
tract symptoms, especially in the presence of substantial middle ear disease. Radiographic or
computed tomographic imaging shows involvement of the paranasal sinuses. X-ray chest may
demonstrate overinflation, bronchial wall thickening, and peribronchial infiltrates. Often,
atelectasis and consolidation are present. Bronchiectasis is best detected by computed
tomographic scanning. The presence of right-sided heart in a child with chronic respiratory
tract symptoms is virtually diagnostic, but this configuration occurs in only 50% of these
patients. Pulmonary function testing of older children yields a typical obstructive pattern.
Mucociliary clearance can be assessed in cooperative children by ascertaining the time to
taste perception of a saccharin particle placed on the inferior nasal turbinate. Scrapings or
brushings of nasal mucosa can be examined directly by light or, preferably, by phase-contrast
microscopy for evidence of motility. In most PCD tissue specimens, little or no ciliary motion
is seen. However, because substantial motility has been documented in scrapings of several
individuals with absent dynein arms, light microscopic examination of living tissue can be
used as a screening tool only. The gold standard is quantitative documentation of abnormal
structural elements, such as missing dynein arms or random orientation of cilia in nasal or
bronchial biopsies or scrapings on electron microscopic esamination. Concordance of
ultrastructural abnormalities in cilia and sperm is not complete. To avoid acquired ciliary
changes, mucosal specimens should not be obtained until 2 wk after an acute respiratory
tract infection. Ultrastructural evaluation should be reserved for highly suspicious cases.
However, some of the reported structural abnormalities are also observed after injury to
ciliated epithelial cells by viral infection or sulfur dioxide exposure. Therefore, definitive
evidence that any structural alteration represents a discrete form of PCD awaits the
identification of specific gene mutation.
Treatment
• Therapy is symptomatic. Cough should be encouraged. Chest
physiotherapy assists the clearance of mucus. Antibiotics should be
prescribed for evidence of infection of sinuses or lower airways. The
choise of antibiotics is best dictated by identification and sensitivity
testing of pathogenic organisms, often pneumococcus or untypable
Haemophylus influenzae. Oral antibiotic administration is usually
effective. Bronchodilators can be used for symptomatic wheezing or
documentation of reversible airway obstruction. Children should be
examined several times each year and followed by periodic chest
radiographs and serial pulmonary function testing. Sinus and middle
ear symptoms refractory to medical therapy deserve consultation
with an otolaryngologist. Surgical intervention may be helpful in
selected cases. Prevention of lung infection by measles, pertussis,
influenza, and possibly pneumococcal vaccines is highly desirable.
Additional preventive measures include avoidance of cigarette
smoke and other airway irritants.
Prognosis
• Progression of lung disease appears to be
much slower for patients with PCD than for
those with CF. With proper treatment,
disabling lung disease often can be avoided
for long periods. A normal life span is possible.
BRONCHOMALACIA AND TRACHEOMALACIA
• Chondromalacia of the trachea or of a main bronchus
is a common cause of persistent wheezing in infancy. In
these disorders, there is insufficient cartilage to
maintain the airway patency throughout the
respiratory cycle. Tracheomalacia and bronchomalacia
can be either primary or secondary. Although primary
tracheomalacia and bronchomalacia are seen
frequently in premature infants, most affected patients
are born at term. Secondary tracheomalacia and
bronchomalacia refers to the situation in which the
central airway is compressed by adjacent structure
(e.g., vascular ring) or deficient in cartilage due to
tracheoesophagal fistula. Laryngomalacia may
accompany primary bronchomalacia or
tracheomalacia. Involvement of the entire central
airway (laryngotracheobronchomalacia) is also seen.
Clinical manifestations
• Primary tracheo- and bronchomalacia are principally disorders of
infants, with a male:female ratio of 2:1. The dominant finding, low
pitched monophonic wheezing, is most prominent over the central
airways. Parents often describe persistent respiratory congestion
even in the absence of a viral respiratory infection. When the lesion
involves only one main bronchus (more commonly the left), the
wheezing is louder on that side. In case of tracheomalacia, the
wheeze is loudest over the trachea. Hyperinflation and/or subcostal
retractions do not occur unless the patient also has asthma or
another cause of small airways obstruction. In the absence of
asthma, patients with tracheomalacia and bronchomalacia are not
helped by administration of a bronchodilator. Acquired
tracheomalacia and bronchomalacia are seen in association with
vascular rings (and may persist after surgical correction),
tracheoesophageal fistula, and cardiomegaly, and after lung
transplantation.
Diagnosis
• The definitive diagnosis of tracheomalacia and
bronchomalacia is established by flexible or rigid
bronchoscopy. The lesion is difficult to detect on
plain radiographs, but fluoroscopy may
demonstrate dynamic collapse and can avoid the
need for invasive diagnostic techniques.
Pulmonary function testing may show a pattern
of decreased peak flow and flattening of the flowvolume loop. Other important diagnostic
modalities include MRI and CT scanning. MRI is
especially useful when there is a possibility of
vascular ring and should be performed when a
right aortic arch is seen on plain film radiography.
Treatment
• Postural drainage may help with clearance of
secretions. Β-Adrenergic agents should be avoided in
the absence of asthma. Nebulized ipratropium bromide
may be useful. Endobronchial stents have been used in
severely affected patients but have a high incidence of
complications, ranging from airway obstruction from
granulation tissue to erosion into adjacent vascular
structures. Constant positive airway pressure (CPAP)
via tracheostomy may be indicated for severe cases.
Surgical approach (aorticopexy and bronchopexy) is
rarely required and only for patients who have lifethreatening apnea, cyanosis, and bradycardia
(“cyanotic spells”) from airway obstruction.
Prognosis
• Primary bronchomalacia and tracheomalacia
have excellent prognosis, because airflow
improves as the airways grow. Wheezing at
rest is usually gone by age 3 yr. Prognosis in
secondary and acquired forms varies with
cause. Patients with concurrent asthma need
considerable supportive treatment.
INTERSTITIAL LUNG DISEASES
•
The interstitial lung diseases (ILD) in infants and children include a group
of uncommon, heterogeneous, familial, or sporadic diseases, that cause
disruption of alveolar gas exchange and symptoms of reactive lung
disease. Knowledge regarding pediatric ILD is limited because of its rare
occurrence, varied spectrum of disease, and lack of controlled clinical
trials investigating the disease process and treatment measures. The
pathophysiologicy is believed to be more complex than adult disease
because the injury occurs during the process of lung growth and
differentiation. In ILD, the initial injury causes damage to the alveolar
epithelium and capillary endothelium. Abnormal healing of injured tissue
may be more prominent than inflammation in the initial steps of
development of chronic ILD. Some familial cases, inherited as an
autosomal dominant trait, may be due to mutations in surfactant protein
genes, specifically surfactant protein C (SP-C). Some sporadic cases may
also have similar SP-C gene mutations.
Classification and pathology
• The classification of ILD in children is not standardized, but it is helpful to
separate diseases into those of known and unknown etiology. Respiratory
infections caused by adenoviruses, influenza viruses, Chlamydia and
Mycoplasma pneumoniae are usually self-limited illnesses but have been
associated with prolonged and progressive lung damage, often in the form
of bronchiolitis obliterans. Aspiration is a frequent cause of chronic lung
disease in childhood. Children with developmental delay or
neuromuscular weakness are at an increased risk for aspiration of food,
saliva, of foreign matter secondary to swallowing dysfunction and/or
gastroesophageal reflux. An undiagnosed tracheoesophageal fistula can
also result in pulmonary complications related to aspiration of gastric
contents and interstitial pneumonia. Children experiencing an exaggerated
immunologic response to organic dust, molds, or bird antigens may
develop hypersensitivity pneumonitis. Children with malignancies may
develop ILD related to the primary malignancy, an opportunistic infection,
or secondary to chemotherapy or radiation treatment. Unique forms of
ILD have been described in infants presenting with chronic tachypnea,
retractions, crackles, and hypoxemia. Defects in surfactant proteins may
be associated with forms of familial and sporadic chronic lung disease. The
prognosis in these diseases is variable.
Usual interstitial pneumonitis (UIP)
It is the most common form of ILD in affected adults
but is rare in children. The pulmonary lesion is
characterized by a mixed distribution of ongoing
inflammation and progressive end-stage fibrosis that is
patchy and heterogenous. The diagnosis is made by
biopsy; there is no definitive clinical or radiologic
feature. The diagnosis of desquamative interstitial
pneumonitis (DIP) depends on biopsy that
demonstrates a uniform, homogeneous process
characterized by hyperplasia of alveolar epithelial cells
with an accumulation of large macrophages within the
air spaces. Fibrosis is usually not seen. Some infants
with histology similar to DIP have been diagnosed with
surfactant B deficiency. A familial form has been
described in infants, which is unusually severe and
often fatal.
Lymphocytic interstitial pneumonitis (LIP)
It is the most common form of ILD in children,
is a form of pulmonary lymphoproliferative
disease. LIP usually develops in association
with conditions of impaired immunity, such as
an autoimmune disease or immunodeficiency
(HIV infection). The pulmonary interstitium is
invaded by a diffuse infiltrate of mature
lymphocytes. Fibrosis is rare. Infection with a
virus such as Epstein-Barr virus is often a
contributing factor in the development of
pediatric LIP.
Acute interstitial pneumonitis
It is also known as rapidly progressive
interstitial pneumonitis or Hamman-Rich
syndrome is a distinct, rapidly progressive
form of ILD. The alveolar damage progresses
from an acute exudative process to severe
fibrosis. An antecedent injury is often not
identified, the fatality rate is more than 50%.
Clinical manifestations
• A detailed history of needed to assess the severity of symptoms
and the possibility of an underlying systemic disease. Identification
of precipitating factors such as exposure to molds or birds or a
severe lower respiratory infection is important in establishing the
diagnosis and instituting avoidance measures. A positive family
history, especially in an affected infant, is suggestive of a genetic or
familial disease, such as a surfactant protein B or C deficiency.
Tachypnea, cough, dyspnea, and exercise intolerance are present in
more than 65% of patients. The majority have a reduced arterial
saturation. Hypercarbia is a late complication. Symptoms are
usually insidious and occur in a continuous, not episodic pattern.
Tachypnea and basilar crackles are present in >50% of the patients.
Retractions, failure to thrive, clubbing and wheezing are common
complaints. Cyanosis and a prominent 2nd heart sound are
suggestive of severe disease. Anemia or hemoptysis suggests a
pulmonary vascular disease or pulmonary hemosiderosis. Rashes or
joint complaints are consistent with an underlying connective tissue
disease.
Diagnosis
•
•
Noninvasive tests are initially used to determine the extent and severity of the
disease. Chest radiographic abnormalities can be classified as interstitial, reticular,
nodular, reticulo-nodular, or honeycombed. The chest film may also be normal,
with the extent of disease. High-resolution CT (HRCT) of the chest better defines
the extent and distribution of disease and can provide specific information for
selection of a biopsy site. Faster modalities such as helical, spiral, or ultra-fast CT
may provide precise resolution of disease patterns in tachypneic infants. Serial
HRCT images may be of benefit in monitoring disease progression and severity.
Pulmonary function tests are important in defining the degree of restrictive lung
disease and in following the response to treatment. In ILD, pulmonary function
abnormalities demonstrate a restrictive ventilator deficit with decreased lung
volumes. Functional residual capacity (FRC) is reduced but usually less than vital
capacity (VC) and total lung capacity (TLC). The residual volume (RV) is usually
maintained; therefore, ratios of FRC:TLC and RV:TLC are often increased. Diffusion
of carbon monoxide (DLCO) is usually normal when corrected for the decreased
alveolar volume. An impaired DLCO may suggest vascular disease. Bronchoalveolar
lavage (BAL) may provide helpful information regarding secondary infection,
bleeding, or aspiration but will not usually determine the exact diagnosis. BAL is
diagnostic for pulmonary alveolar proteinosis. Transthoracic lung biopsy for
histopathology is usually the final step and is necessary for a conclusive diagnosis.
Conventional thoracotomy or video-assisted thoracoscopy is used to obtain tissue
from children with suspected ILD. Evaluation for possible systemic disease may
also be necessary.
Treatment
• Supportive care is essential and includes supplemental oxygen for hypoxia
and adequate nutrition for growth failure. Antimicrobial treatment may be
necessary for intercurrent infections. Some patients may be responsive to
bronchodilators. Anti-inflammatory treatment with corticosteroids
remains the initial treatment of choice. Controlled trials in children are
lacking, and the clinical responses reported in case studies are variable.
The usual dose of prednisone is 1 – 2 mg/kg/24hr for 6 – 8 wk with
tapering dictated by clinical response. Alternative, but not adequately
evaluated, therapy includes hydroxychloroquine, azathioprine,
cyclophosphamide, cyclosporine, methotrexate, intravenous
immunoglobulin, and pulsed high-dose steroids. Hydroxychloroquine
treatment is successful in some children with classic ILD, particularly those
with histopathologic changes of DIP. Lung transplantation for progressive
or end-stage ILD is successful in some infants and children. Appropiate
treatment for underlying systemic disease is indicated. Preventive
measures include avoidance of all inhalation irritants such as tobacco
smoke and, when appropriate, molds and bird antigens. Supervised
pulmonary rehabilitation programs may be helpful.
Prognosis and genetic counseling
• Prognosis. The overall mortality of ILD is
dependent on specific diagnosis and is as high as
20% in infants and children. Prognosis is variable
and poor in children with pulmonary
hypertension, failure to thrive, and severe
fibrosis.
• Genetic counseling. A high incidence of
interstitial lung disease in some families suggests
a genetic predisposition to either development of
the disease or severity of the disorder. Genetic
counseling may be beneficial if a familial history is
obtained.
CYSTIC FIBROSIS
•
Cystic fibrosis (CF) is an inherited multisystem disorder of children
and adults, characterized by obstruction and infection of airways
and by maldigestion and its consequences. It is the most common
life-limiting recessive genetic trait in children. A dysfunction of
epithelialized surfaces is the predominant pathogenetic feature and
is responsible for a broad, variable, and sometimes confusing array
of presenting manifestations and complications.
•
CF is the major cause of severe chronic lung disease in children
and is responsible for most exocrine pancreatic insufficiency in early
life. It is also responsible for many cases of salt depletion, nasal
polyposis, pansinusitis, rectal prolapse, pancreatitis, cholelithiasis,
and insulin-dependent hyperglycemia. CF may present as failure to
thrive and, occasionally, as cirrhosis or other forms of hepatic
dysfunction. Therefore, this disorder enters into the differential
diagnosis of many pediatric conditions.
Etiology
• The most common severe inherited disease in the
Caucasian population (autosomal recessive in inheritance).
• Cystic fibrosis transmembrane regulator (CFTR): functions
as a cyclic AMP-activated chloride channel, which allows for
the transport of chloride out of the cell. It is accompanied
by the passive passage of water, which keeps secretions
well hydrated.
• In cystic fibrosis, an abnormality in CFTR blocks chloride
transport and inadequate hydration of the cell surface
results in thick secretions and organ damage.
• The CFTR gene is 250.000 base pairs long and located on
the long arm of chromosome 7. The most common deletion
is three base pairs, which results in the absence of
phenylalanine at codon 508.
Epidemiology
• Incidence of abnormalities in CFTR gene
1:25 individuals in Caucasian population;
• Incidence of cystic fibrosis
1:2500 in Caucasian population
1:17.000 in African-American population
(rarely seen in African blacks and Asians)
Symptoms
• Chronic cough, recurrent pneumonia,
bronchorrhea, nasal polyps, and chronic
pansinusitis.
• Pancreatic insufficiency: occurs in 85% of
patients. Fat malabsorption may lead to failure to
thrive or pancreatitis.
• Rectal prolapsed: occurs in 2% of of the patients.
• Meconium ileus: 15 – 20% of patients present
with this symptom.
• Distal obstruction: of the large intestine may be
seen in older children.
• Hypochloremic metabolic alkalosis.
Signs
• Cough (frequently productive of
mucopurulent sputum), rhonchi, rales,
hyperresonance to percussion, barrel-chest
deformity of thorax in severe cases, nasal
polyps, and cyanosis (in later stages).
• Digital clubbing, hepatosplenomegaly in
patients with cirrhosis, growth retardation,
hypertrophic osteoarthropathy, and delayed
puberty, amenorrhea, irregular menstrual
periods (in teenage patients).
Investigations
Sweat test: “gold standard” for the diagnosis of cystic fibrosis.
• Sweat chloride >60 mEq/L is considered abnormal. False positives are seen
in severe malnutrition, ectodermal dysplasia, adrenal insufficiency,
nephrogenic diabetes insipidus, hypothyroidism, hypoparathyroidism,
mucopolysaccharidoses. False negatives are seen in patients with edema
and hypoproteinemia.
• Genetic testing: over 600 identified genotypes, but only 20-70 of the most
common are tested: thus, the lack of a positive genotype reduces (but
does not eliminate) the possibility that a CF sample can be obtained from
blood or buccal cell scraping.
• Sputum cultures: frequent pathogens include Staphylococcus aureus,
Pseudomonas aeruginosa (mucoid and nonmucoid), Burkholderia cepaica.
• Pulmonary function tests: usually reveal obstructive lung disease.
• Pancreatic function tests: 72-hour fecal fat measurement, measurement
of serum para-aminobenzoic acid (PABA) levels, stool trypsin levels, serum
immunoreactive trypsin(IRT).
• Chest radiography: typical features include hyperinflation, peribronchial
thickening, atelectasis, cystic lesions filled with mucus, and bronchiectasis.
• Sinus radiography: typically shows pansinusitis.
Complications
• Respiratory: recurrent bronchitis and pneumonia,
chronic sinusitis, pneumothorax, hemoptysis.
• Gastrointestinal: include pancreatic insufficiency;
patients usually have steatorrhea; decreased
levels of vitamins A, D, E andK; poor growth and
failure th thrive; meconium ileus equivalent;
rectal prolapsed; and clinically significant
hepatobiliary disease (cirrhosis of the liver,
esophageal varices and splenomegaly).
• Reproductive: include sterility in 98% males and
75% females.
• Endocrine: abnormal glucose tolerance; diabetes
mellitus.
Differential diagnosis
• Pulmonary: recurrent pneumonia, chronic
bronchitis, immotile cilia syndrome, severe
asthma, aspiration pneumonia.
• Gastrointestinal: gastroesophageal reflux,
celiac sprue, protein-losing enteropathy.
• Other: failure to thrive (secondary to neglect,
poor caloric intake or feeding problems),
immune deficiency syndromes, nasal
polyposis, male infertility, hyponatremic
dehydration.
Treatment aims
• To maintain good nutritional status (good
nutrition is associated with better prognosis).
• To slow pulmonary deterioration as much as
possible.
• To maintain a normal lifestyle.
Diet and lifestyle
• High calorie diet with nutritional supplements (given
orally, via nasogastric tube feedings or through
gastrostomy tube feeding).
• Vitamin supplements: multivitamins and fat soluble
vitamin replacement (usually E and K).
• Pancreatic enzyme replacement therapy can be used in
patients who are pancreatic insufficient. Dosage is
adjusted for the frequency and character of the stools
and for growth pattern.
• Stool softeners treat constipation or meconium ileus
equivalent and include mineral oil, oral Nacetylcysteine, lactulose, enemas.
Pharmacologic treatment
•
•
•
•
•
•
•
Antibiotic therapy (based on sputum culture results).
Oral antibiotics: cephalexin, cefaclor, trimethoprimsulfamethoxazole, chloramphenicol, ciprofloxacin.
Intravenous antibiotics (given for 2-3 week course)
For Staphylococcus aureus: oxacillin, nafcillin;
For Pseudomonas aeruginosa or Burkholderia cepacica:
semisynthetic penicillin (ticarcillin, piperacillin) or a cephalosporin
(ceftazidime) plus an aminoglycoside (gentamycin, tobramycin, or
amikacin) to obtain synergic action.
For aid in clearing pulmonary secretions:
Aerosolized bronchodilator therapy (to open airways): albuterol;
Mucolytic agents (to help break up viscous pulmonary secretions):
N-acetylcysteine, recombinant DNase.
Chest physiotherapy with postural drainage.
Prognosis
• Long-term prognosis is poor.
• The course of the illness is variable; it is
impossible to predict the course of the disease in
a specific person.
• The current mean life span is 29 years.
• Due to new antibiotics, enzyme-replacement
therapy, and maintenance of good pulmonary
toilet with chest physiotherapy and
bronchodilators, the mean age of survival has
been increasing for the past three decades.
Follow-up and management
• Routine care should be at Cystic Fibrosis
Center.
• Frequency of visits is dependent on severity of
illness: usually every 2-4 m.
• Usually lifelong nutritional support is required.
• Duration of antibioticotherapy is controversial.
Chronic use is eventually required as the
patient’s pulmonary function deteriorates.
• All siblings should have a sweat test.