Cystic fibrosis diagnosis and treatment

1. DIAGNOSIS
• The diagnosis of CF requires the demonstration of abnormally high
concentrations of sodium and chloride in the sweat of a person who has
the characteristic history and symptoms of CF. The most prominent clinical
features are chronic pulmonary disease and pancreatic insufficiency.
• The most compelling family history for the diagnosis CF in a sibling. If the
clinical picture and/or the family history support the diagnosis, and if two
sweat tests using the quantitative pilocarpine iontophoresis method are
clearly positive, the diagnosis of CF can be made with assurance.
• Identification of two pathologic mutations, in addition to the characteristic
clinical picture, is accepted as a criterion for the diagnosis

2. DIAGNOSTIC CRITERIA OF CF

4. NEONATAL SCREENING
• The initial stage of screening often uses the neonatal blood spot to
determine the concentration of immunoreactive trypsinogen. If this is
elevated, secondary screens vary in individual states from repeat
immunotrypsinogen determination to F508del or 25 to 32 mutation
screen. The screening programs have a sensitivity ranging from 87%
to 99%
• It has been proposed that infants who have a positive newborn
screen, but do not otherwise fulfill the criteria for a diagnosis of CF
should be termed as having “CFTR metabolic syndrome” and at a
minimum they should be followed in a CF center until their status can
be clarified

5. SWEAT CHLORIDE TEST
• The most consistent feature of CF is an abnormally high concentration
sodium and chloride in sweat. Measurement of the chloride
concentration is recommended for clinical testing.
• The only reliable sweat test is based on iontophoresis of pilocarpine,
followed by quantitative determination of the concentration of
chloride in an adequate, measured volume of sweat

6. The collection methods are the Gibson-Cooke procedure and the
Macroduct sweat collection system (Wescor, Logan, UT, USA). In both, the
sweat is stimulated by iontophoresis with pilocarpine, after which it is
collected with paper filter or gauze (Gibson-Cooke) or in a microbore tube
(Wescor). The sample is then analyzed to determine the concentration of
sodium chloride. The minimal acceptable sweat volume is 75 mg in the
Gibson-Cooke procedure and 15 mL for the Macroduct system.(5,9)

7. • In children, concentrations of chloride of less than 40 mEq/L are usually
• regardedas normal. However, the average of values for sodium and
chloride concentrations is about 20 mEq/L for normal subjects and 95
mEq/L for those with CF.
• In children, values between 40 and 60 mEq/L are traditionally considered
borderline elevated; such values call for further evaluation. As a result of
recent experience with CF newborn screening, it has been suggested that
sweat chloride values above30 mEq/L may be diagnostic in the first few
months of life.

8. • The concentration of sodium and chloride in sweat increases
gradually with age. Conditions other than CF in which the
concentrations of sodium and chloride in sweat are abnormally high
include malnutrition, adrenal insufficiency, hereditary nephrogenic
diabetes insipidus, ectodermal dysplasia, and fucosidosis.

9. GENETIC ANALYSIS
Genetic analysis can be used to confirm the diagnosis of CF. In
patients with minimal symptoms, the diagnosis of CF can be made
with certainty if two CF-associated alleles are present. As
mentioned previously, screening for 32 of the most common
alleles yields an overall sensitivity of 90% due to undetected alleles

10. NASAL POTENTIL DIFFERENCE
The nasal potential difference (NPD) test has been proposed to
provide evidence of abnormal function of the cystic fibrosis
transmembrane conductance regulator (CFTR), a receptor that
forms a chloride ion channel
The test is especially useful for patients who have normal chloride
concentrations in sweat tests and in whom 2 gene mutations
related to cystic fibrosis have not been detected.

11. A reading less than -40 mV is considered abnormal, as values under
that cut point are never found in healthy individuals. Two abnormal
NPD findings on separate days are required for a diagnosis of CFTR
dysfunction

12. CLINICAL EVALUATION

13. Chest x ray
• Peribronchial thickening, which is often most prominent in the upper
lobes of the lungs early in the course of the disease, usually
progresses to affect all lobes.
• In the advanced stage of pulmonary involvement, ring shadows, cystic
lesions, and nodular densities are increasingly apparent, as are areas
of bronchiectasis and atelectasis.
• The central pulmonaryartery often enlarges in the middle stages of
the disease, but the cardiac silhouette remains within normal limits
until the disease is far advanced

15. HRCT
• High-resolution computed tomography (HRCT) scans are more
sensitive than plain radiographs. The most common abnormalities
described are bronchiectasis, peribronchial thickening, mosaic
perfusion, air trapping, and mucus plugging.
• Early bronchiectasis is easily detected on the CT scan, even when
routine chest radiographs are normal.

17. Pulmonary performance
• In the fully developed clinical syndrome, all the pulmonary function
abnormalities seen in chronic bronchitis, emphysema, and asthma
may occur. However, one complicating regular feature of CF –
bronchiectasis – modifies pulmonary performance.
• Chronic, local infection and airway damage increase the compliance
of bronchiectatic airways, resulting in airway collapse during rapid
expirations or cough.
• The usefulness of pulmonary function testing in CF is twofold: Tracing
the natural history of the disease and assessing the value of
therapeutic interventions

18. • A variety of methods to measure infant pulmonary function have
been devised
• one method, the raised volume rapid thoraco abdominal compression
technique, requires sedation of infants but provides values most
similar to standard spirometric values, and has detected reduced
pulmonary function in infants with CF49 Nitrogen multiple breath
washout or lung clearance index, can be performed in preschool age
children and detects early ventilation in homogeneity that correlates
with airflow obstruction by spirometry

19. Obstruction in small airways
• Three factors interact in causing the obstruction:
• (1) Intrinsic disease of the smaller airways, often in association with
bronchiectasis in the proximal,larger airways;
• (2) viscid secretions, impaired ciliary action, and impaired cough; and
• (3) progressive decrease in lung elastic recoil
• Airway smooth muscle tone increases only slightly in CF. Exercise
elicits bronchodilation, followed shortly thereafter by
bronchoconstriction. Both the bronchodilation and
bronchoconstriction are far less impressive in CF than in asthma

20. • As with chronic bronchitis, emphysema, and asthma, RV in CF
increases. Thereafter, an increase in functional residual capacity and
sometimes in total lung capacity is seen.
• air trapping increases in severity and is manifest as an elevated ratio
of RV to total lung capacity.
• Early in the evolution of the pulmonary abnormalities in CF – that is,
when tests of small airway function alone are abnormal – ventilation–
perfusion abnormalities usually result in widening of the alveolar–
arterial oxygen gradient and an increase in the ratio of dead space to
tidal volume (Vd/Vt)

21. • The diffusing capacity for carbon monoxide (DlCO) is low at rest and
does not increase normally during exercise. This observation is
difficult to reconcile with the preservation of the gas-exchanging
surface of the lungs (in the absence of emphysema) until late in the
course of the disease.
• As obstructive disease of the airways progresses and exaggerates the
imbalances between alveolar ventilation and blood flow, arterial
hypoxemia develops; pulmonary hypertension, cor pulmonale, and
right ventricular failure follow, in turn.
• Late in the course of the disease, hypercapnia and respiratory
acidosis contribute to the final picture of respiratory failure

22. Sputum culture
• The unique respiratory flora isolated from sputum or oropharyngeal
cultures from patients with CF is helpful in establishing the diagnosis
and in guiding the antimicrobial therapy for acute exacerbations.
• The presence of mucoid Pseudomonas is important because
acquisition of mucoid Pseudomonas predicts more rapid progression
of CF lung disease.
• Similarly, acquisition of methicillin-resistant S. aureus is associated
with a decline in pulmonary function and worse survival.
• Infection with B. cepacia complex organisms may be aggressivewith
rapid deterioration of clinical status or may have an indolent course;
the presence of mucoid-positive organisms appears to be protective

23. • Chronic antibiotic therapy to suppress Pseudomonas has improved
clinical outcomes but has also led to a greater number of MDROs
identified in sputum, including S. maltophilia and A.xylosoxidans.
Chronic colonization with S. maltophilia, induces a serologic response
and independently correlates with progression in airflow obstruction
• Allergic bronchopulmonary aspergillosis (ABPA) complicates CF lung
disease and recent evidence suggests that Aspergillus fumigatus may
also be associated with airway infection or allergy-triggered asthma in
theabsence of ABPA.
• The prevalence of nontuberculous mycobacteria ranges from 7% to
24% with the most frequent species identified as Mycobacterium
avium complex and Mycobacterium abscessus

24. GASTROINTESTINAL TRACT

25. Pancreatic function
• The evaluation of pancreatic function is an important part of establishing
the diagnosis of CF, since almost 90% of patients have pancreatic
insufficiency.
• Currently the diagnosis of pancreatic insufficiency can be made by
measuring fecal elastase (FE)-1 levels and assessment of the degree of
malabsorption is best accomplished by the determination of the coefficient
of fat malabsorption.
• The FE-1 test is performed on a random single stool sample. It is easy to
obtain and in patients with CF, a human enzyme-linked immunosorbent
assay (ELISA) for FE has a sensitivity of 98% to 100% and a specificity of
93% to 100%, even while patients are taking pancreatic enzyme
supplements.

26. Cystic Fibrosis Related Diabetes
• Because the onset of CFRD is generally insidious, and FH tends to be a late
manifestation, annual CFRD screening with an oral glucose tolerance test
(OGTT) starting by age 10 is recommended.Based upon the fasting, 1-hour,
and 2-hour plasma glucose (PG0, PG1, and PG2) during the OGTT, the
following glucose tolerance categories are defined.
• • Normal glucose tolerance (NGT) = PG1 <200 mg/dL and PG2<140 mg/dl
Indeterminate = PG1 ≥200 mg/dL but PG2 <140 mg/dL
• impaired glucose tolerance (IGT) = PG2 ≥140 and <200 mg/dL
• • CFRD = PG2 ≥200 mg/dL
• Without FH = PG0 <126 mg/dL
• With FH = PG0 ≥126 mg/dL

27. • Contrary to what one might expect, isolated impaired fasting glucose
(PG0 100–125 mg/dL) is not associated with worse survival,
nutritional status, pulmonary function, or progression to CFRD.63
Over 10 years, FH occurs in 60% of patients with CFRD without FH at
baseline.
• While an elevated hemoglobin A1C (>6.5%) is consistent with CFRD,
the HbA1C tends to underestimate overall glucose intolerance in CF
patients and is not generally recommended for CFRD screening

28. Osteoporosis
• Patients with CF are at risk for vitamin D deficiency and osteoporosis.
• Annual serum 25-hydroxy vitamin D levels should be monitored.
• In addition, in all adults and children greater than 8 years with risk
factors for osteopenia including malnutrition, chronicglucocorticoid
use, moderate-to-severe airway obstruction (FEV1<50% predicted), or
history of fracture or delayed puberty, a DEXA scan should be
obtained to monitor bone mineral density

29. Semen analysis
• Occasionally, a man who is found to have aspermia during the course
of an evaluation for infertility is found to have CF.
• In men with CF, a complete semen analysis is part of the evaluation.
• Azoospermia is found in more than 98% of men with the disorder

30. Genetic analysis
• Patients homozygous for the most common mutation, F508del have
pancreatic insufficiency;patients with CF who have pancreatic insufficiency
tend to have a worse prognosis.
• F508del is one of the major mutations classified as disease causing; other
mutations are associated with CF-related disorders,and yet other
mutations have no known clinical importance or unknown significance
• Several mutations, including R117H, are associated with pancreatic
sufficiency and a mild phenotype. Interestingly, the phenotype of R117H is
linked to the expression of the polyT and polyTG intronic domains found 5’
to exon 9. A T5 polymorphism expressed with R117H results in congenital
bilateral absence of the vas deferens (CBAVD) or idiopathic pancreatitis,
and may be complicated by mild lung disease

31. • Certain alleles associated with CF (e.g., 3849+10kbC→T) are
associated with nasal polyposis and bronchiectasis but normal sweat
test results.
• For example, therapy for CF patients with the G551D mutation with
the CFTR potentiator ivacaftor results in astonishing improvements in
respiratory tract symptoms,weight gain, and shift from positive to
borderline sweat chloride values.

32. Treatment
• More than 90% of the patients with CF die from respiratory failure
pulmonary complications. The goals of treating the pulmonary disorder in
CF are to prevent and treat the complications of airway obstruction and
infection
• Chest physiotherapy:
“percussion and postural drainage” – performed regularly, is the most
widely prescribed method. In infants and young children, chest
physiotherapy is generally performed routinely, twice daily.
• Percussion and postural drainage technique has been modified to exclude
head-down positioning which increased the risk of GE reflux and increased
the duration of acute exacerbations of coughin infants.

33. • These alternative measures include the high-frequency chest-wall
oscillation (HFCWO) vest; the flutter device, a small pipe– like device
that produces an oscillating resistance during a forced expiratory
maneuver; the acapella device that produces both positive expiratory
pressure (PEP) and an oscillating resistance during forced expiratory
maneuver; PEP mask; intrapulmonary percussive ventilation
autogenic drainage and active cycle of breathing; and exercise

34. Mucolytics and Inhaled Hypertonic Saline
• A number of mucolytic agents have been tried over the years. One
that has endured is N-acetylcysteine. In the test tube, this agent is
quite effective in dissolving mucin components and in decreasing the
viscosity of sputum from patients with CF.
• One CF center which has a track record of outstanding CF outcomes
recommended using N-acetylcysteine in combination with sodium
cromolyn and albuterol (W. Warwick, personal communication)
• N-acetylcysteine was found to activate CFTR Cl− conductance in
cultured epithelial cells

35. • Pulmozyme, a DNA-cleaving enzyme, was approved for use in patients
with CF following a large phase III multicenter trial.
• Abnormal homeostasis of airway surface fluid results in dehydrated
secretions and impaired mucociliary clearance.
• As a strategy to improve airway surface hydration and airway
clearance, inhaled hypertonic therapy was evaluated. Patients with
CF, age 6 years and older, inhaled 7% hypertonic saline twice daily
following a bronchodilator for 48 weeks; results revealed only a
modest improvement in FEV1, but a significant reduction in the
number of pulmonary exacerbations and days lost from school or
work.

36. Bronchodilators and Anti-Inflammatory Agents
• Bronchodilators are often used in treating the pulmonary
manifestations of CF. Their use should be individualized.
• For example, in many patients, bronchospasm that is reversible with
bronchodilators at one point in the course of the illness may prove
refractory a short time later. Some patients undergo deterioration in
pulmonary function following use of bronchodilators. In infants who
are audibly wheezing, a bronchodilator can be tried.

37. • Corticosteroids have been used with good results in infants with severe
obstructive airway disease that does not respond to antibiotics and
bronchodilators and in patients with CF in whom the pulmonary disease is
complicated by severe asthma or allergic bronchopulmonary aspergillosis
(ABPA).
• Preliminary observations initially suggested that patients with CF would
benefit from long-term administration of alternate-day corticosteroids,
based on the presumption that corticosteroids would decrease the airway
inflammatory response.
• Subgroup analysis led to the suggestion that patients with moderately
severe obstructive airway disease and those with chronic Pseudomona
infection might benefit from treatment for periods of less than 1 year.

38. Antibiotics
• Two major innovations using antibiotics have been implemented as part of
the regimen of maintenance therapy for CF.
• First, inhaled therapies have been demonstrated to successfully eradicate
initialPseudomonas infection and postpone chronic colonization in three
large prospective trials of patients with CF in North America and in Europe.
• Second, chronic inhaled and/or oral antibiotic therapies successfully
decrease the progression of lung disease related to chronic Pseudomonas
infection. In addition to these therapies, it is important to emphasize that
person-to-person transmission of P.aeruginosa and other opportunistic
microbes is another source forchronic colonization

39. • Chronic airway colonization/infection with P. aeruginosa promotes
progression of lung disease. Hoiby et al. championed early treatment
of P. aeruginosa–positive sputum cultures with inhaled colistin and
oral ciprofloxacin, even in the absence of symptoms, as a modality to
prevent chronic colonization.
• The EPIC trial91 tested four randomized regimens: Cycled therapy
versus culture-driven therapy; and 28 days of inhaled tobramycin
inhalation solution (TIS) in the presence or absence of 14 days of oral
ciprofloxacin

40. • The ELITE study was an open label randomized study comparing 28 to
56 days of inhaled TIS which revealed approximately 90% eradication
at the end of therapy with 66% to 69% of patients having
Pseudomonas-free cultures at the end of the 27-month study.
• In addition, a trial comparing inhaled colistin and oral ciprofloxacin to
inhaled TIS and oral ciprofloxacin showed no difference between
regimens in eradication with approximately 62% to 65% of patients
with Pseudomonas-free cultures at 6 months

41. • Recently, inhaled aztreonam, 75 mg three times per day, was tested in an
open label study of cycling monthly regimen for patients with chronic P.
aeruginosa infection.
• Patients reported improved symptoms and pulmonary function during on-
therapy months with sustained weight gain over the 18-month duration of
the study.
• Azithromycin, 250 mg or 500 mg thric weekly, was evaluated in CF patients
colonized with P. aeruginosa.After 6 months of therapy, patients on
azithromycin had a modest improvement in FEV1 (6.2%), increased weight
gain, and decreased rates of pulmonary exacerbations.98 Although
macrolide antibiotics have been reported to have anti-inflammatory
properties,99 there is no direct evidence of azithromycin-induced anti-
inflammatory activity in CF

42. CFTR Potentiators and Correctors
• The most exciting breakthrough in CF therapies was announced in 2011
with the proof-of-concept demonstration that an oral drug, ivacaftor
corrected the physiologic impact of a CFTR mutation, G551D
• The G551D mutant CFTR protein is expressed at the cell surface but does
not conduct chloride or regulate other ion channels.
• In phase III randomized, placebo-controlled, double-blind trial for CF
patients with at least one copy of G551D mutation, ivacaftor®,
administered orally, 150 mg twice per day for 48 weeks, increased FEV1
percent predicted by 10.6%, decreased risk of pulmonary exacerbations by
55%, improved CF quality of life (CFQL) respiratory symptom scores by 8.6
points, decreased sweat chloride values by 48 mmol/L, and was associated
with an average 2.7-kg weight gain

43. • Currently, other mutations similar to G551D are being tested as
potential ivacaftor® targets. Importantly, other compounds that
potentially correct F508del CFTR are being tested.
• One lead compound, VX-809 has been reported to decrease sweat
chloride values in a dose-dependent manner.101 VX-809 will be
combined with ivacaftor® for complementary combined therapy to
enhance both processing and functioning of F508del-CFTR in
homozygous patients.