DR. DAKSH JHIM
FIRST YEAR JUNIOR
• Cystic fibrosis (CF) is a monogenic disorder that presents
as a multisystem disease.
• was first described as a unique disease entity in 1938.
• Most common lethal genetic disease in Causasians.
• lethal autosomal recessive disease.
• incidence: 1 in 2000-3000; predominantly Caucausian
populations (carrier frequency 1 in 22-28).
• “Woe to the child which when kissed on the forehead
tastes salty. He is bewitched and soon will die” - old
• Patients typically presented with intestinal
obstruction or malnutrition and died from
overwhelming pneumonia within the first year of life.
• Over the last 40 years, the median survival with CF
has increased dramatically from 6 years in 1955 to
36 years in 2005.
• The improvement in CF outcomes has paralleled
advances in antibiotic therapies, nutritional
approaches, and the collection of clinical expertise
into specialized treatment centers.
CF AND GENETICS
• Caused by mutation in the cystic fibrosis transmembrane
conductance regulator (CFTR) gene.
• Anion channel
• ATP Binding Cassette family
• Regulates other ion channels
• Plays crucial roles in
absorption and secretion
• Found mainly in wet epithelia
• CFTR functions as a cAMP-activated ATP-gated anion
• increasing the conductance for certain anions (e.g.
Cl–) to flow down their electrochemical gradient.
• ATP-driven conformational changes in CFTR open and
close a gate to allow transmembrane flow of anions
down their electrochemical gradient.
• found in the epithelial cells of many organs including
the lung, liver, pancreas, digestive tract, reproductive
tract, and skin.
• Mainly found in exocrine glands.
• Normally, the protein moves chloride and thiocyanate
ions along the concentration gradient.
1. Sweat glands
3. Digestive fluids
SWEAT GLAND PATHOPHYSIOLOGY
SWEAT GLAND PATHOPHSIOLOGY
CFTR important for Cl- absorption
Na+ and Cl- generally reabsorbed
Cl- buildup = negative charge on luminal side
Decreased Na+ reabsorption
NaCl formation and secretion in sweat
Used as diagnostic factor
• The CFTR gene located on chromosome 7, on the
long arm at position q31.2..
• The mutations in the CFTR gene fall into five major
• Classes I–III mutations are considered "severe," as
indexed by pancreatic insufficiency and high sweat
• Class IV and V mutations can be "mild," i.e.,
associated with pancreatic sufficiency and
intermediate/normal sweat NaCl values.
• Over 1900 mutations in the CFTR gene that can cause
• Most common is ΔF508.
• CFTR plays a central role in the regulation of ion
transport across airway epithelia.
• In CF, dysregulation of airway surface liquid (ASL)
volume occurs as a consequence of ion transport
• impairing mucociliary clearance and, therefore, lung
• Airway surfaces are coatedwith a thin layer of liquid,
the ASL, which is composed of a
1. periciliary layer (PCL)
2. more viscous mucus layer.
• The mucus layer, which normally floats on top of the PCL,
efficiently traps inhaled pathogens and particulates.
• The mucus layer, which normally floats on top of the PCL,
efficiently traps inhaled pathogens and particulates.
• The underlying PCL layer, in turn, provides a low viscosity
environment in which cilia can beat freely and thereby
propel the mucus layer toward the mouth.
• The PCL also acts as a lubricant layer that prevents
adhesion of the mucus layer to cell surfaces.
• proper regulation of ASL volume and the hydration of its
component layers are critical to the maintenance of mucus
• An adequate PCL height is necessary to allow ciliary
• Adequate hydration of the mucus layer is a key
determinant of its viscoelastic properties and
• CFTR important for Cl- secretion
• CFTR also mediate ENaC activity
• Net decrease in Cl- secretion and increase in Na+
• Osmotically surface mucous dehydrated
• Buildup compresses cilia resulting no mucous
Sweat Glands :hypersecretion of salt
Lungs :mucous buildup + infection
Pancreas :fibrous cysts + blockage
GI Tract :blockage from thick feces
Liver : obstruction, possible cirrhosis
Male Reproduction : sterile
LUNG :SECONDARY PATHOGENESIS
• ASL dehydration produces progressive mucostasis.
• Initiates a cascade of events that leads to clinically
apparent CF lung disease.
• Firstly, thickened mucus secretions eventually become
adherent to airway surfaces with the loss of PCL
volume, and begin to obstruct small airway lumens.
• Mucus plugs and plaques not only provide a
protected environment in which bacteria can escape
mechanical and immune-mediated clearance, but
also create a unique environment that drastically
alters bacterial gene expression.
LUNG :SECONDARY PATHOGENESIS
• Paradoxically, the center of a mucus plug is in fact
anaerobic (pO2 less than 2 Torr) due to a combination
of an increased diffusion distance for O2 as well as
increased oxygen consumption by CF epithelia (owing
to heightened Na+ transport).
• Within this environment, P. aeruginosa converts to an
anaerobic mode of metabolism, increases alginate
production, and ultimately establishes a biofilm
• Organisms growing within the biofilm possess
increased resistance to secondary host defense
mechanisms (e.g., neutrophils and soluble
• Failure of neutrophils to clear this infection,
accompanied by the release of proteases and other
harmful substances destroying lung tissue, ultimately
leads to bronchiectasis.
ASL dehydration and mucus plugging, also develops chronic
airway inflammation without readily identifiable bacterial
• Current hypothesis to explain these findings include:
1. a low burden of typical bacteria avoids eradication in the
dehydrated mucus environment of the CF lung and drives
the inflammatory process in very early disease.
2. the presence of atypical, perhaps anaerobic, organisms
are poorly identified with usual culture systems but
dominate early disease and cause inflammation.
3. intermittent events, including viral infections and/or gastric
aspiration drive the inflammatory process early in life.
• Regardless, these observations point to the very early onset
of lung disease, even in asymptomatic infants, and the need
to develop and institute effective interventions in this
• Over a relatively short period of time, the CF lung becomes
chronically infected with typical pathogens.
• In childhood, Haemophilus influenzae and Staphylococcus
aureus are often identified first organisms to invade typically
followed by the establishment of chronic Pseudomonas
• Pseudomonas may take many morphologic forms, but
mucoid phenotype signifies chronicity and the inability to
eradicate this organism, even with aggressive antibiotic
• Other important pathogens that are encountered in CF
include a variety of gram-negative bacteria, especially
Stenotrophomonas maltophilia, Achromobacter
xylosoxidans, and the Burkholderia cepacia complex (Bcc).
• Mycobacterial pathogens are also encountered in CF,
including M. avium complex and M. abscessus.
• MAC is the most prevalent mycobacterial pathogen in
CF, but often does not cause discernible clinical
disease, as opposed to the much more problematic
infection with M. abscessus.
• Viral infections, although probably not more frequent
than in other populations, do appear to cause more
morbidity and may be an important trigger of lung
• Fungi, particularly aspergillus species, are common
colonizers but may cause allergic bronchopulmonary
• The primary cause of morbidity and mortality in CF
patients is bronchiectasis and obstructive lung disease.
• Pulmonary disease is present in 98% of patients with CF
by the time they reach adulthood.
• A recurrent cough that becomes persistent is often the
• Airway hyperreactivity and wheezing are common in
• Pansinusitis with opacification of the paranasal sinuses
is a universal finding in nearly 30% patients with CF.
• Exacerbations of CF lung disease are extremely
important events in the life of a CF patient.
• These periodic illnesses often remove the patient from
their usual work or school activities, are associated with
significant reductions in quality of life, exact a large
financial toll in terms of health care costs, and are
associated with reduced survival.
• Exacerbations are typically acute to subacute events
that are superimposed upon a previously stable clinical
• Patients usually report increased cough, sputum, fatigue,
and weight loss during these episodes.
• Fever, leukocytosis, chest pain, and new infiltrates on
chest radiographs are less consistent findings with
• The inciting events that trigger an exacerbation have
not been clearly defined, although acute respiratory
viral infection may be one important cause in addition
to inadequate use of preventative therapies.
1. Bronchiectasis: occurs as a result of destruction of lung
tissue and erosion of the bronchial cartilage.
2. Atelectasis: Lobar and segmental atelectasis occurs in
about 5% of patients. This complication is most
prevalent in the first 5 years of life and thereafter has a
diminishing frequency. The right lung is the site of
atelectasis in the majority of patients.
3. Pneumothorax : is a more frequent complication .The
overall incidence is about 1%/yr, and increases with
age and disease severity, so that about 20% of CF
adults will experience at least one pneumothorax.
4. Hemoptysis: is a common event in older CF patients.
Minor to massive hemoptysis may occur .Massive
hemoptysis is increasingly common in older patients, with
an average annual incidence of 0.87 percent.
5. Allergic bronchopulmonary aspergillosis (ABPA):
develops in 1% to 10% of patients at some time in their
6. Pleural effusions and empyema: are uncommon in
patients with CF, but pleuritic symptoms and signs may
accompany exacerbations of lung disease.
• Staphylococcal and pseudomonal empyemas have
been described, but respiratory tract infections usually
spare the pleural space.
7. Respiratory failure: leads to death in greater than 90%
of CF patients.
• The earliest radiographic change is usually
hyperinflation of the lungs, reflecting obstruction of
• The degree of hyperinflation generally increases with
• As bronchitis progresses, peribronchial cuffing
becomes increasingly prominent.
• Mucous impaction in airways may be seen as
branching finger-like shadows.
• Evidence of bronchiectasis, such as enlarged ring
shadows and cysts, is common by 5 to 10 years of age.
• peripheral rounded densities are noted during acute
exacerbations and may disappear with treatment,
leaving residual cysts.
• Subpleural blebs often become evident during the second
decade of life and are most prominent along the
• For reasons that remain unexplained, the right upper lobe
usually displays the earliest and most severe changes.
• With advancing disease, the pulmonary artery segments
become more prominent.
• A relatively small and vertical cardiac shadow is typical,
but the heart enlarges with onset of cor pulmonale.
• Hilar adenopathy is rarely prominent.
• Lobar or segmental atelectasis is uncommon but is most
often seen in infants or small children.
PULMONARY FUNCTION TESTS
• Newborns with CF are thought to have normal lung
• However, within weeks to months, many infants with
CF show evidence of increased airway resistance, gas
trapping, and diminished flow rates.
• In general, patients progress from initial reductions in
maximum midexpiratory flow rates to reductions in
forced expiratory volume in 1 second/forced vital
capacity (FEV1/FVC) and then to diminished vital
capacity and total lung volumes.
• The progression occurs from peripheral airway
obstruction to more generalized obstruction and then
to acquisition of a restrictive component.
1. New born screening
• Since October 2007, newborn screening for CF has
been in place throughout the whole of the UK.
• NHS of U.K. has made it mandatory for screening of
newborns for cystic fibrosis.
• Immunoreactive trypsinogen (IRT) is measured on a
dried blood spot obtained on the Guthrie card at day 6
• Samples with abnormally raised IRT levels will undergo
CFTR mutation screening as per the flow chart
• An increased IRT must be followed by direct diagnostic
testing (typically with the sweat chloride test).
2. Sweat testing(pilocarpine iontophoresis)
• remains the “gold standard” diagnostic test because
genetic screening only identifies a small number of the
most common mutations.
• The results of this test are abnormal in the large majority
of patients with CF.(about in 98% of patients).
• However, the test must be repeated at least twice, and
an adequate sample containing at least 75 mg of
sweat must be collected over a 30-min period.
• Approximately 1% of patients with CF have normal
sweat chloride test results.
FALSE POSITIVE SWEAT TEST RESULTS
Adrenal insuffi ciency
Glucose-6-phosphate dehydrogenase defi ciency
Glycogen storage disease, type I
Mucopolysaccharidosis, type I
Nephrogenic diabetes insipidus
Prostaglandin E1 infusion, long-term
3. Molecular diagnosis: according to GUIDELINES, reasons for
full genotyping include the following:
• Any child diagnosed with CF:
1. facilitates screening for other family members.
2. allows prenatal diagnosis of future pregnancies.
• Since the advent of the first mutation-specific therapy
ivacaftor, and on-going clinical trials of other small molecule
CFTR-modulators, all CF patients MUST be genotyped. Full
gene sequencing should be carried out when there is
diagnostic doubt (especially in ethnic minorities).
• In newborn siblings of affected children, cord blood should
be taken at the time of birth (arrange with mother in clinic,
give form and blood bottle).
• Generally older siblings will have a sweat test for
diagnosis rather than genetic analysis. The latter would
detect carriers, which is something that should be
postponed until the sibling is old enough to decide
whether they wish to know their carrier status (usually
mid teens and older).
• To aid confirmation of diagnosis in case of borderline
However, genotype analysis should not be used to
guide prognosis in an individual child, except rarely (and
very cautiously) in the case of mutations usually
associated with pancreatic sufficiency (e.g. R117H).
LIMITATIONS OF MUTATION ANALYSIS
• Due to the large number of identified mutations, and
the extreme rarity of many of these, it is only practical
to screen for a few on a routine basis.
• Clearly therefore failure to detect mutations does not
exclude the diagnosis. The above is of particular
importance in a child of non-Caucasian origin.
• There is now a specific panel of mutations, which are
common in the Asian community.
• It is therefore CRITICALLY IMPORTANT that in every
case the child’s ethnic origin is included on the
request form so that the most likely mutations can be
4. Potential Diff. across the respiratory epithelium
• This is a research tool to aid in the diagnosis of CF.
• Difficult in small children as requires cooperation, but
may be useful in older indeterminate cases (over 8-10
• The abnormal transport of chloride leads to a very
negative PD across the nasal epithelium.
• Nasal perfusion with amiloride hydrochloride and with
chloride-free solutions leads to characteristic changes
in the PD.
5. Stool elastase:
• may be supportive of the diagnosis.
• low in CF with pancreatic insufficiency (usually <15
1. Normal : > 200 mcg/g stool
2. Mild/moderate pancreatic insufficiency :100-200
3. Severe pancreatic insufficiency :< 100 mcg/g stool
DIAGNOSTIC CRITERIA ACCORDING TO
• Elevated sweat chloride level ≥ 60 mmol/L on two occasions
• Identification of mutations known to cause CF in both CFTR genes
• In vivo demonstration of characteristic abnormalities in ion
transport across the nasal epithelium
• One or more phenotypical features of CF
1. Sinopulmonary disease
2. Characteristic GI or nutritional disorders
3. Obstructive azoospermia
4. Salt loss syndrome
• Sibling with CF
• Positive NBS result
• The primary objectives of CF treatment are to control
infection, promote mucus clearance, and improve
• Experience has repeatedly demonstrated that
attention to preventive aspects of lung care and
psychosocial factors is important.
PHYSICAL MEASURES TO PROMOTE
• The use of postural drainage with chest percussion to
clear mucus is based on the concept that cough clears
mucus from large airways but chest vibrations are
necessary to move secretions from the small airways
where expiratory flow rates are low.
• When patients were receiving chest physical therapy on
a regular basis, the only immediate effect documented
was an increase in peak expiratory flow rate 30 minutes
• However, after 3 weeks without chest physical therapy,
both FVC and flow rates were significantly reduced.
• Theoretically, chest physical therapy might prevent or
delay inspissation of mucus in small airways.
INHALED HYPERTONIC SALINE FOR
• Inhaled hypertonic saline (HS) osmotically draws water
onto airway surfaces.
• Indeed, because of the limitation with respect to Clpermeability of CF airway epithelia, inhaled salt may
remain on CF airway surfaces longer, and hence be
osmotically more active, than on normal airway
• Recent data suggest that the rehydrating effect of
inhaled HS (7%, four times daily) produces short term
(2-wk) effects that restore mucus clearance and
improve lung function and quality of life.
• The lysis of viscous DNA with the recombinant enzyme
DNase offers benefit to some patients with purulent
• When taken once daily, aerosolized DNase reduced
relative risk of respiratory exacerbations by 28% and
improved FEV1 approximately 6% above baseline over
• Not all patients had objective improvement in lung
function, but symptomatic benefit occurred in many of
treated patients without improved lung function.
• Daily inhalation slows the usual decline in lung function
and decreases the frequency of exacerbations.
NOVEL AIRWAY SURFACE
• A number of novel agents are being developed to
treat CF airways dehydration. For example, as an
alternative osmotic agent, inhaled mannitol
(“Bronchitol”) is being developed as a dry powder
inhalation and is currently in phase III clinical testing.
• There are also novel small molecules in development
designed to redirect CF ion transport from absorptive to
• An extracellular ATPase resistant analogue of UTP,
INS37217, is currently completing phase III testing.
NOVEL AIRWAY SURFACE
• Like endogenous ATP, INS37217 slows Na+ absorption
and activates Ca2+-activated Cl- channel-mediated
Cl- secretion in CF airways to rehydrate surfaces.
• long-acting, potent, and safer amiloride derivatives
(e.g., GS9411) are being developed for inhalation in an
HS vehicle to greatly amplify the hydrating effect of HS.
• Lung infection is the major source of morbidity and
mortality in CF.
• Antibiotics are the mainstay of therapy designed to control
progression of disease.
• In general, antibiotic therapy should be predicated on the
presence of symptoms and guided by the identification of
organisms from the lower respiratory tract.
• There is evidence that early and vigorous use of antibiotics
produces better results than delaying the administration of
antibiotics until symptoms are well developed or
• Another principle of antimicrobial therapy in CF is that
dosages need to be higher than for non–CF-related chest
• Both total body clearance and volume of distribution
are considerably greater for CF than for other patients.
• Large doses are needed to achieve therapeutic levels
in the infected and mucus- or pus-filled endobronchial
• The choice of antibiotics optimally should be based on
the results of sputum culture and sensitivity testing.
• For patients with nonproductive cough, specimens are
best obtained by throat swab placed just above the
glottis during repetitive coughing.
• ß- Agonists can be nebulized, administered by
metered-dose inhalers, or given orally.
• Caution should be exercised concerning long-term
therapy with these agents because animal studies
show that administration of large amounts of ßadrenoceptor agonists cause submucosal gland
hypertrophy and presumably a hypersecretory state.
• CF patients seem to be less tolerant of theophylline
because of frequent gastrointestinal irritation.
• An initial double-blind controlled study of alternateday oral corticosteroid administration demonstrated
better maintenance of pulmonary function and fewer
exacerbations of lung disease requiring hospitalization
over a 4-year period.
• However, widespread use of oral or inhaled
corticosteroids should be avoided.
ANTI-INFLAMMATORY THERAPY WITH
• A study of high-dose ibuprofen over 4 years
indicated that CF patients younger than age 13
years with mild lung disease have remarkable
slowing of decline of lung function (eightfold) as
compared with placebo control subjects.
• No effect was documented in patients older than
13 years. There were few side effects, but most of
the eldely patients were taking antacids or H2receptor blockers.
OTHER RESPIRATORY THERAPIES
• Mucolytics, expectorants, and cough suppressants
have been used for relief of chest symptoms.
• Expectorants, which assist in the elimination of airway
secretions during cough, probably do not achieve
• Long-term administration of iodides to patients with CF
has been associated with a high incidence of goiter
• Mucolytics such as N-acetylcysteine are injurious to
respiratory epithelium and promote bronchitis when
SYSTEMIC AGENTS DESIGNED TO
RESTORE CYSTIC FIBROSIS
• Two classes of small molecule therapeutics are under
development for treatment of CFTR mutant protein.
• The first class is aimed to improve the maturation of
misfolded mutant CFTR (e.g., F508 CFTR). A first such
compound, VX809, is in phase I testing.
• The second class is aimed at mutant CFTRs that have
normally folded, and are targeted to the apical
membrane, but function poorly. VX770 is currently in
phase II clinical testing.
GENE TRANSFER TECHNOLOGY
• It is technically possible using genetically engineered
viral vectors to transfer the wild-type CFTR gene to
respiratory epithelial cells in vitro, where it can be
expressed at least for days to weeks.
• Work is ongoing at the laboratory level on adenoassociated virus–, lentiviral-, and paramyxoviral-based
vectors for this purpose.
• Approximately 90% of patients with CF require
mealtime pancreatic enzymes, packaged as granules
that are coated with acid-resistant material to
promote delivery to the small intestine.
• Capsules containing 4000 to 24,000 units of lipase are
• Numbers of capsules taken should be adjusted based
on weight gain, presence or absence of abdominal
cramping, and the character of stools.
• Dosage should be limited to current guidelines (~2500
lipase units/kg/meal), because a large total daily dose
of enzymes has been associated with fibrosing
• Vitamins A and D are supplied by a daily multiple
vitamin preparation. Vitamin E, 100 to 200 units daily.
• Vitamin K is given sporadically to treat bleeding
complications or to correct prolonged prothrombin
• Other vitamins and trace minerals may be deficient
and require supplementation on a selective basis.
• As with any chronic disease, compliance with therapy
and ability to function fully are highly dependent on
the patient's attitude.
• Approaches that promote a positive self-concept and
foster the ability of patients to take control of their
medical management, and enable them to
participate fully in life events, are likely to promote wellbeing and perhaps longevity.
TREATMENT OF LUNG
• Hypercapnic and hypoxemic respiratory failure in CF are
primarily due to progressive obstructive airway disease with
alveolar hypoventilation and ventilation-perfusion
• Low-flow oxygen is effective at relieving nocturnal,
exertional, and resting hypoxemia and does not usually
cause significant hypercapnia.
• The use of supplemental oxygen in children has been
discouraged because nocturnal oxygen did not improve
survival or prevent the development of cor pulmonale in
one controlled trial.
• Supplemental oxygen in accordance with the guidelines
established for chronic obstructive pulmonary disease is
recommended for adults to avoid development of
TREATMENT OF LUNG
• Diuretics, inotropic agents, and theophylline produce
few benefits and are rarely used.
• Cor pulmonale is a late complication of airway
obstruction, and no treatment options beyond those for
the primary disease processes are effective.
• Ventilatory assistance is effective in CF patients with
acute respiratory failure caused by reversible insults but
produces few long-term benefits in patients with
respiratory failure due to irreversible lung damage
caused by CF bronchiectasis.
• The airway disease generally progresses, however, and
long-term ventilatory support is rarely feasible.
TREATMENT OF LUNG
• Atelectasis is best treated by vigorous standard
therapy, including airway clearance and antibiotics.
• ABPA responds to standard doses of systemic
corticosteroids. Inhaled steroids and the oral antifungal
agent itraconazole may prove to be useful.
• Pneumothorax can be observed for spontaneous
resolution if small and minimally symptomatic.
• A pneumothorax more than 20% of the hemithorax
volume, compromising ventilation or causing
hypotension, requires tube drainage.
• Recurrences are very common and may require
thoracoscopic talc poudrage or surgical pleural
TREATMENT OF LUNG
• Hemoptysis requires treatment of airway infection and
supplemental vitamin K if the prothrombin time is
prolonged due to inadequate absorption.
• Massive hemoptysis may resolve with such conservative
therapy and modest cough suppression for 1 to 2 days.
• Bronchial artery embolization provides more definitive
control, which usually persists for more than 6 months.
• Lung transplantation has become an accepted
therapy for respiratory failure secondary to CF.
• Heartlung transplant has been largely replaced by
sequential double-lung transplant because of limited
• The transplanted lungs remain free of CF, but are
subject to secondary infection, acute rejection, and
chronic rejection (bronchiolitis obliterans syndrome).
• The 5-year survival is 48%, as good as that of lung
transplant recipients with other causes of lung disease.
• Living lobar transplantation is an effective alternative
to conventional cadaveric lung transplants.