Transcript Slide 1

Amjad Fathi Hussein El-Shanti
MD, MPH, Doctorate of Public Health (Epidemiology)
Medical director of CFFC-Gaza
April-2014
Contents
• Introduction:
Definition of Cystic fibrosis (CF)
Epidemiology of CF ( Magnitude and Genotype Distribution)
Pathogenesis of CF
Clinical Manifestations of CF
Diagnosis of CF
Treatment
• CF in Gaza Strip
• Conclusion
• Recommendations
Definition
What
is cystic
fibrosis fibrosis
(CF)?
What
is cystic
(CF)?
• A multisystem disease
• Autosomal recessive inheritance
• Cause:
mutations
in the cystic fibrosis
•A
multisystem
disease
transmembrane conductance regulator (CFTR)
•Autosomal
recessive
inheritance
– chromosome
7
– codes for a c-AMP regulated chloride channel
Rosenstein, BJ and Zeitlin, PL. Cystic fibrosis. The Lancet.
351: 277-82.
Rosenstein, BJ and Zeitlin, PL. Cystic fibrosis. The Lancet. 351: 277-82.
Autosomal recessive inheritance in CF
Let C= normal CFTR
Let c= mutant CFTR
If mom and dad are both
carriers then:
C
C
c
c
CC
Cc
Cc
cc
• With mom and dad
carriers, then:
– 50% chance of having
child who is a carrier
– 25% chance of child
being affected
– 25% of child with no
mutant copies of CFTR
Definition
• Cystic Fibrosis (CF) or mucoviscidosis is an
inherited disease of the exocrine glands, primarily
affecting the GI and respiratory systems, and
usually characterized by COPD, exocrine
pancreatic insufficiency, and abnormally high
sweat electrolytes, causing progressive disability
and often, early death.
• It is caused by a mutation in a gene called the
Cystic Fibrosis Transmembrane Conductance
Regulator (CFTR).
Epidemiology of Cystic Fibrosis
Magnitude and genotypic distribution
• Birth prevalence is traditionally cited as 1 in 2,000
to 1 in 2,500 live births in Caucasian populations.
• For Non-Caucasian countries, the problem of
estimating birth prevalence of CF is even greater,
and good estimates are lacking.
Magnitude and genotypic distribution
• In UK, in 2003, the prevalence of CF was of 11.7
per 100,000.
• In Canada, the prevalence was 10.5 per 100,000
(based on 2002 patient registry data and 2005
population estimates).
Magnitude and Genotypic Distribution
• The incidence of CF among Arabs is estimated to
range from rare to as common as the Caucasian
populations.
• Reports indicated frequencies ranging from 1:5800
in Bahrain, to 1:2650 in Jordan.
• In Egypt, CF is more common than previously
anticipated with an incidence rate of 1:2664.
Magnitude and Genotypic Distribution
• The commonest mutation identified in the world is
DF508, which comprises 66% of global mutations,
followed by G451X and G551D which are
responsible for 2.4% and 1.6% of the mutations
respectively.
Magnitude and genotypic distribution:
• Survival and mortality rate are useful indicators of
clinical outcome, and are likely to be influenced by
a variety of factors.
• The CDR for CF in 2003 in the UK is only 0.17 per
100,000 general population.
• In USA, standardized mortality has been shown to
vary significantly with genotype, being as low as
4.4 per 1000 person-years at risk for certain
genotype combination and as high as 25 per 1000
for others.
Risk factors & determinants
• Non genetic factors:
1.
2.
3.
4.
5.
6.
7.
Gender
Skin color and race
Birth weight
Consanguinity
Socioeconomic status
Environmental factors
Patient adherence to prescribed medical regimens
• Genetic Factors:
1. CFTR gene mutations
2. Modifying genes
Pathogenesis of CF
Pathogenesis
• The CFTR gene is found in region q31.2 on the
long (q) arm of human chromosome 7.
CFTR Gene and Protein
Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management
of Pulmonary Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.
Pathogenesis
• The CFTR protein transports chloride ions (Cl-) ions
across the membranes of cells of the lungs, liver,
pancreas, digestive tract, reproductive tract, and skin.
• It is made up of five domains:
Types of mutations in CFTR
http://www.cysticfibrosismedicine.com/
htmldocs/CFText/genetics.htm
• Class I
– Defective protein production
• Class II
– Defects in processing
• ΔF508
• Class III
– CFTR reaches cell surface but
regulation is defective
(channel not activated)
• Class IV
– CFTR in membrane with
defective conduction
• Class V
– Decreased synthesis of CFTR
Pathogenesis
• Mutations in the CFTR gene have been classified into
five different groups according to the mechanism by
which they disrupt CFTR function.
Class
Effect on CFTR protein
Example of mutation
I
Shortened protein
W1282X
II
Protein fails to reach
cell membrane
ΔF508
III
Channel cannot be
regulated properly
G551D
IV
Reduced chloride
conductance
R117H
V
Reduced due to
incorrect splicing of
gene
3120+1G>A
5 Classes of CFTR Mutations
I
II
III
IV
V
Defective
Defective
Defective
Defective
Reduced
Production
Processing
Regulation
Conductance
Amounts
20
CFTR and Airway Surface Liquid
Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis
lung disease.
Airway surface liquid low volume hypothesis
• Mucus---helps clear airway of bacteria
• Clearance of mucus depends on
– Ciliary function
– Mucin secretion
– Volume of airway surface liquid (ASL)
• Forms periciliary liquid layer
• Dilutes mucus---facilates entrapment of bacteria and
clearance
• Optimal volume of ASL regulated by Na+ absorption
and Cl- secretion
Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease.
Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.
Airway surface liquid low volume hypothesis
• Normal CFTR inhibits a sodium channel (ENaC)
– Mutant CFTR----ENaC not inhibited
• Sodium absorption is increased
• Water follows sodium
• ASL volume decreases
• Normal CFTR will cause Cl- ions to be secreted
if the ASL fluid is low
– Mutant CFTR Cl- ions not secreted
Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis lung disease.
Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.
Airway surface liquid low volume hypothesis
• Cilia do not beat well when PCL volume is
depleted
• Mucins are not diluted and cannot be easily
swept up the airway
• Mucus becomes concentrated
• Results in increased adhesion to airway surface
• Promotes chronic infection
Donaldson,SH and Boucher,RC. Update on the pathogenesis of cystic fibrosis
lung disease.Current Opinion in Pulmonary Medicine. 9: 486-491; 2003.
From Mutation To Disease
The mutant form of CFTR
prevents chloride transport,
causing mucus build-up
Mucus clogs the airways
and disrupts the function
of
the pancreas & intestines.
25
Pathophysiology of CF
Disease manifestations
– Lungs
?
CFTR Dysfunction
– Sinuses
– Pancreas
– Liver
– Bones
– Vas deferens
Clinical Manifestations of
CF
Clinical Manifestations of CF
•
•
•
•
•
Chronic Sino-Pulmonary Disease
Nutritional deficiency/GI abnormality
Obstructive Azoospermia
Electrolyte abnormality
CF in a first degree relative
Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997.
Clinical Manifestations of CF
Chronic Sino-Pulmonary Disease
• Chronic infection with CF pathogens
• Endobronchial disease
– Cough/sputum production
– Air obstruction---wheezing; evidence of obstruction on
PFTs
– Chest x-ray anomalies
– Digital Clubbing
• Sinus disease
– Nasal Polyps
– CT or x-ray findings of sinus disease
Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic fibrosis.1997.
Infection
Gibson, RL, Burns, JL, and Ramsey, BW. Pathophysiology and Management of
Pulmonary Infections in Cystic Fibrosis. AJRCCM 168 (918-951); 2003.
Prevalence of Infections in CF Patients
100
P. aeruginosa
Percent
80
60
S. aureus
40
H. influenza
MRSA
20
S. maltophilia
B. cepacia
0
0 to 1
2 to 5
6 to 10
11 to 17
18 to 24
Age (years)
Cystic Fibrosis Foundation Patient Registry Data. 2005
25 to 34
35 to 44
45+
CF Infections---Pseudomonas aeruginosa
• 80% CF patients eventually infected with
pseudomonas
• Association between acquiring pseudomonas and
clinical status deterioration
• Form biofilms
• Relatively large genome
– Pseudomonae collected from sputa of CF patients have
been noted to have larger genomes than lab strains
Gibson, RL, Burns, JL, and Ramsey, BW. AJRCCM 168 (918-951); 2003.
Pseudomonas genome
http://www.pseudomonas.com/
Burkholderia cepacia complex
Holmes, A, Govan, J, and
Goldstein, R. Agricultural
Use of Burkholderia
(Pseudomonas) cepacia:
A Threat to Human
Health?
Emerging Infectious
Diseases. 4(2):221-227;
1998
• B. cepacia syndrome:
fevers, rapidly progressive
necrotizing pneumonia,
death
• Chronic cepacia infection
decreased lung function
and increased mortality
• Several closely related
species termed
genomovars1
1. Gibson, RL, Burns, JL, and Ramsey, BW.
AJRCCM 168 (918-951); 2003.
Endobronchial disease
•
•
•
•
•
From:
http://www.meddean.luc.edu/lumen/med
ed/elective/pulmonary/cf/cf_f.htm
Hyperinflation
Peribronchial cuffing
Bronchiectasis
Diffuse fibrosis
Atelectasis
Nasal Polyps
From: http://www.emedicine.com/
ped/topic1550.htm
• Benign lesions in nasal
airway
• If large enough, can be
associated with significant
nasal obstruction, drainage,
headaches, snoring
• Likely associated with
chronic inflammation
• May need surgical
intervention
• High recurrence rate
Digital Clubbing
From: Fawcett et al., 2004
• Bulbous swelling at end
of fingers
• Normal angle between
nail and nail bed lost
(Schamroth sign)
• Can be associated with
pulmonary disease,
cardiac disease,
ulcerative colitis, and
malignancies
Nutritional deficiency
• Pancreatic insufficiency
• Pancreatic enzymes stay in ducts and are activated
intraductally
– Autolysis of pancreas
– Inflammation, calcification, plugging of ducts,
fibrosis
• Malabsorption
– Failure to thrive
– Fat soluble vitamin deficiency
1. Davis, P. Cystic Fibrosis Since 1938. AJRCCM Articles in Press.
Doi: 10.1164/rccm.200505-840OE; 2005.
2. Quinton, P. Physiologic Basis of Cystic Fibrosis. Physiol Rev 79:3-22, 1999.
GI disease
• Intestinal abnormality
– Meconium ileus
– Distal intestinal obstruction syndrome (DIOS)
– Rectal prolapse
• Hepatobiliary disease
– Focal biliary cirrhosis
– Multilobular cirrhosis
• Pancreatic endocrine dysfunction
– Cystic fibrosis related diabetes
Cystic fibrosis related liver disease
• Focal inspissation of bile
– Obstructs biliary ductules
• Second leading cause of death in CF1
• Prevalence 9-37%1
• Spectrum of disease
– increased liver enzymes
– biliary cirrhosis
– portal hypertension
1. Efrati, O et al., Liver Cirrhosis and portal hypertension in CF.
European Journal of Gastroenterology and Hepatology. 15(10): 1073-1078; 2003.
Cystic fibrosis related diabetes mellitus
• Screening
– Oral glucose tolerance test (OGTT)
• Every two years in patients 10-16 years
• Any patient with random plasma glucose >180
• Fasting>=140 mg/dl
– initiate insulin treatment
• Fasting<140 and OGTT at 2 hrs>200 mg/dl
– Home glucose monitoring; consider insulin
• Fasting <140 and 2 hour 140-200
– Impaired glucose tolerance
• OGTT annually
• Fasting and 2 hour <140
– Normal glucose tolerance
Infertility
• Men
– Abnormal embryologic development of the
epididymal duct and vas deferens---may be
incomplete of absent1
– Congential bilateral absence of the vas deferens—
97-98% of men with CF 1
1. Lewis-Jones et al, Cystic fibrosis in infertility: screening before assisted reproduction: Opinion. Human
Reproduction 15(11): 2415-2417.
Infertility
• Women
– Lower fertility rate than non-CF women
– Viscid mucoid cervical secretions of low volume in
women with CF 1
• Pregnancy and CF:
– Goss et al, 2003---no significant difference in
survival in women who became pregnant with CF
compared to women who did not become
pregnant (after adjusting for disease severity)2
1.Quinton, P. Physiologic Basis of Cystic Fibrosis. Physiol Rev 79:3-22, 1999
2.Goss, CH, Rubenfeld, GD, Otto, K and Aitken, ML. The effect of pregnancy on survival in women
with cystic fibrosis. Chest 124(4):1460-68; 2003.
Electrolyte abnormality---history
• Dr. Paul di Sant’ Agnese
– 1949 NYC heat wave----noted CF infants to have a
higher rate of heat prostration than non-CF
• Showed that sodium and chloride concentration in CF
patients’ sweat was 5 times higher than in non-CF1
– Became basis for sweat chloride test
Davis, P. Cystic Fibrosis Since 1938. American Journal of Respiratory .1
and Critical Care Medicine Vol 173. pp. 475-482, (2006)
Electrolyte abnormality
• Clinically---hypochloremic metabolic
alkalosis
– CFTR on luminal side of sweat duct
• Chloride goes in from lumen via CFTR and out to
blood by other transporters
• Sodium goes in via ENaC
• Defective CFTR---Na and Cl- movement and
reabsoprtion into lumen impeded
Goodman, B and Percy, WH..CFTR in Teaching Membrane Transport. Adv
Physiol Educ. 29 (79-82); 2005
Genetic Determinants of severity of
disease
• The variability in disease severity in patients with CF is not a
consequence of relative preservation of pancreatic function but
is a result of different gene mutants, together with additional
factors, genetic and /or environmental.
• The location of a mutation along the CFTR gene has no direct
effect on severity of CF disease.
Diagnosis of Cystic Fibrosis
• One or more clinical manifestations of CF
PLUS
• Two CF mutations
OR
• Two positive quantative pilocarpine
iontophoresis sweat chloride values
OR
• An abnormal nasal transepithelial potential
difference value
Diagnostic criteria for cystic fibrosis
Part 1: Clinical Manifestation of Disease
• At least one of the following:
1) One or more clinical manifestations of CF
•
•
•
•
•
•
Meconium ileus
Chronic bronchitis / bronchiectasis
Chronic infection of the paranasal sinuses
Pancreatic insufficiency
Salt loss syndromes
Male infertility due to congenital bilateral absence of the vas deferens
2) Positive newborn screening test
3) History of CF in a sibling
Diagnostic Criteria for Cystic Fibrosis
Part 2: Laboratory evidence of CFTR abnormality
• At least one of the following:
1)
Elevated sweat chloride test
2)
Identification of a mutation in each CFTR gene known to cause CF
3)
In vivo demonstration of characteristic abnormalities in ion
transport across nasal epithelium (not widely available)
Sweat Test
Sweat Test for Diagnosis of CF
Controls
1500
n=4269
CF
1200
240
n=920
900
180
600
120
300
600
0
Number of patients with CF
Number of normal controls
1800
0
0
20
40
60
80
100
120
140
160
180
mEq/L
Shwachman H, Mahmoodian A. Mod Prob Pediatr 1967;10:158
A perspective on the Sweat Test
• The “sweat test” provides laboratory confirmation
of the clinical diagnosis of Cystic Fibrosis.
• This occurs because of an abnormally high salt
concentration in their eccrine sweat, ranging from
3-5 times higher than that of normal children.
A perspective on the Sweat Test
• The sweat Test was first described in 1959 by
Gibson & Cooke and remains the “ Gold
Standard” for the diagnosis of cystic fibrosis.
• In the majority of CF patients with typical
features and identified CFTR mutations, the
sweat test is diagnostic.
• In atypical forms, the sweat chloride levels
may fall into the intermediate range and there
are rare examples of patients with CF,
confirmed on genetic testing, who have a
normal sweat test.
SWEAT TESTING PROCEDURE
WESCOR MACRODUCT
Sweat Stimulus &
Collection
Sweat Analysis
Sweat chloride
–Positive Sweat chloride: 60-165 meq/L
–Borderline sweat chloride: 40-60 meq/L
–Normal sweat chloride: 0-40
Sweat chloride
• False positives:
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
Anorexia Nervosa
Autonomic dysfunction
Addison disease
Ectodermal dysplasia
Eczema
Edema
Fucosidosis
Glucose-6-Phosphate dehydrogenase deficiency
Glycogen storage disease Type 1
Hypothyroidism
Hypoparathyroidism
Malnutrition from various causes including HIV infection
Nephrogenic diabetes insipidus
Nepohrosis
Lab error (evaporation or contamination of sample)
Davis, P. Cystic Fibrosis Since 1938. AJRCCM Articles in Press.
Doi: 10.1164/rccm.200505-840OE; 2005.
Sweat Chloride
• False negatives:
–
–
–
–
Edema
Malnutrition
Some CF mutations
Sample diluted
Davis, P. Cystic Fibrosis Since 1938. AJRCCM Articles in Press.
Doi: 10.1164/rccm.200505-840OE; 2005.
Use of Genotyping to Diagnose CF
Population Frequency of Specific CFTR Mutations Causing CF
ΔF508
G542X
G551D
N1303K
W1282X
621+1G  T
R553X
1717-1G  A
R1162X
R117H
Δ I507
3849+10kbC  T
R347P
0
10
20
30
40
50
Frequency, %
CF Genetic Analysis Consortium
60
70
•
1601 CFTR
mutations known to
cause CF
•
Only 25 mutations
have a frequency >
0.1%
Genotyping for CF Diagnosis
• Current commercial screening tests
– Look for presence of between 25 - 100 mutations
– These will detect a CF allele only ~90% of time
• For a group of patients with known CF, genotyping would be
diagnostic in only ~81% of patients
•  Screening for most common mutations is not as sensitive
as sweat testing (98%) to diagnose classic CF
Genetic Diagnosis of CF
• Tests becoming commercially available for
detecting mutations more broadly
– PCR used to amplify all exons and surrounding
splice sites
– Heteroduplex formation screening and/or
sequencing
– Analysis for large deletions and duplications
Treatment
It gets more complicated......
Treatment
•The only way to cure CF would be to use gene
therapy to replace the defective gene or to give the
patient the normal form of the protein before
symptoms cause permanent damage.
• The major goal in treating CF is:
1. to clear the abnormal and excess secretions and
2. to control infections in the lungs, and
3. to prevent obstruction in the intestines.
• For patients with advanced stages of the disease, a lung
transplant operation may be necessary.
• Although treating the symptoms does not cure the
disease, it can greatly improve the quality of life for most
patients and has, over the years, increased the average
life span of CF patients to 30 years.
Treatment of Acute Exacerbations
of CF Lung Disease
• Antibiotic treatment
– Oral antibiotics
• If symptoms are mild, and
• Bacteria are susceptible
– Intravenous antibiotics otherwise
Management of Chronic Lung
Disease in Cystic Fibrosis
Aerosolized Antibiotics
• High dose tobramycin
proven for chronic
infection
–TOBI® 300 mg in 5 ml bid
every other month
Ramsey B, et al. NEJM 1999;340:23-30
Mucolytic Therapy for CF
• DNase
(Pulmozyme ®)
–Chronic use
improves FEV1 and
causes fewer
exacerbations
Fuchs HJ, et al. NEJM 1994;331:637-642
Bronchodilators in CF
• No studies in acute exacerbations but
routinely given
• Chronic use -- FEV1 improves acutely in some
patients
– b-adrenergic agonists (e.g. albuterol, salmeterol)
– Anticholinergic agents (ipratroprium bromide,
tiotroprium)
Anti-Inflammatory Treatment in CF
• Glucocorticoids
– Oral (prednisone)
• Preserves lung function, but too many adverse effects
– Inhaled
• Used for subgroup of with bronchial hyperreactivity
(asthma) symptoms
• Ibuprofen
– Beneficial for young patients
– No evidence for improvement in adults
• Azithromycin in CF
– Improved FEV1
– Fewer exacerbations of CF
lung disease
– Uncertain mechanism of
action
• Anti-inflammatory?
• Bacterial toxin or biofilm
production?
Change in FEV1 (% predicted)
Macrolide Therapy for CF
5
4
3
2
1
0
-1
-2
-3
-4
Azithromycin
Placebo
0
4
8
12
16
20
Study Week
Saiman L, et al. JAMA. 2003;290:1749-56
24
28
Nebulized Hypertonic Saline (7%)
• Effect on FEV1
– Randomized, double-blind,
placebo controlled trial
– N = 164
– Inhalation of 4 ml of 7% vs.
0.9% saline bid for 48 weeks
Elkins MR et al. N Engl J Med 2006;354:229-240
Effect of 7% Saline on Frequency of Pulmonary
Exacerbations
Elkins MR et al. N Engl J Med 2006;354:229-240
Physiotherapy for CF
• No studies in acute exacerbations
– But “standard of care” treatment
• Beneficial for chronic management
Gastrointestinal Treatment
Modified diet
• Due to pancreatic disorders, children with CF
require a modified diet, including vitamin
supplements (vitamins A, D, E, and K) and
pancreatic enzymes.
• Maintaining adequate nutrition is essential.
The diet calls for a high-caloric content (twice
what is considered normal for the child's age),
which is typically low in fat and high in
protein.
• Patients or their caregivers should consult
with their health care providers to determine
the most appropriate diet.
Gene Therapy
• Gene therapy is the use of
normal DNA to "correct" for the
damaged genes that cause
disease.
• In the case of CF, gene therapy
involves inhaling a spray that
delivers normal DNA to the
lungs.
• The goal is to replace the
defective CF gene in the lungs to
cure CF or slow the progression
of the disease.
Magnitude of CF disease in GS
• The average annual incidence rate of CF disease through the last ten years
(2000-2010) in the Gaza strip was 1.26 case per 5000 live births.
1.80
Incidence (per5000live births)
1.60
1.46
1.40
1.20
1.00
1.05
1.51
1.39
1.18 1.12 1.15
0.80
1.59
1.40
1.31
0.75
0.60
0.40
0.20
0.00
Years
Incidence rates of cystic fibrosis disease (Gaza, 2000- 2010)
Magnitude of CF disease in GS
• The average annual prevalence of CF disease through the last ten years in
Gaza strip was 3.72 cases per 100,000 population.
Prevelance (per 100,000 persons)
7.00
6.00
5.30
5.00
4.66
4.03
4.00
3.00
2.01
2.00
1.00
2.47 2.74
3.14
3.43
1.32
0.00
Years
Prevalence rates of cystic fibrosis disease (Gaza, 2000- 2010)
5.84
5.93
Magnitude of CF disease in GS
Mortality
• The average annual mortality rate due to CF in
the Gaza Strip through the last ten years (20002010) was 0.26 case per 100,000 populations.
• The average annual CFR of CF through the last
ten years was 9.18%.
Magnitude of CF disease in GS
CF diagnosis
• The mean age of CF cases at diagnosis was 6.05+6.57 months. (98%
of cases were infants at time of diagnosis).
Magnitude of CF disease in GS
Clinical manifestations and hospitalizations of CF patients
• All cases were recurrently admitted to hospital, The average
admission times was 3.51+1.63 times/year among cases.
Distribution of cystic fibrosis cases by the affected
systems (Gaza,2010)
Magnitude of CF disease in GS
Nutritional indicators of CF cases and controls
Average anthropometric measurements and nutritional indicators of cystic
fibrosis cases and controls (Gaza, 2010)
Cases (n= 100)
Variable
Height (cm)
HAZ
Weight (kg)
WAZ
WHZ
Controls (n= 100)
T-Test
Average
S.D
Average
S.D
T
99.64
20.10
112.10
16.6
2
-4.78
0.000*
2.09
-9.01
0.000*
7.44
-5.48
0.000*
1.67
-11.28
0.000*
2.06
-5.98
0.000*
-2.42
14.70
-2.48
-1.67
*Statistically significant
1.80
5.84
1.05
1.82
0.07
19.89
-0.26
-0.02
P
Magnitude of CF disease in GS
Nutritional indicators of CF cases and controls
• This difference was a statistically significant (t=-13.71, p =0.00).
Average hemoglobin level of CF cases and
controls (Gaza, 2010)
Risk factors associated with CF disease in GS
Sociodemographic factors
Distribution of cases and controls by sociodemographic factors (Gaza, 2010)
•
•
•
•
Male Gender (OR=2.35, 95% CI=1.26, 4.04, p=0.004).
Fair Skin Color (OR=5.43, 95% CI=2.11, 14.50, p=0.000).
Consanguinity (OR=13.20, 95% CI=5.94, 29.95, p=0.000).
North Gaza Governorate (OR=2.006,95%CI=1.04,3.853, p=0.035).
Genetic determinants of CF disease in GS
• The results of mutation testing revealed that 61% of known
mutation-CF cases have at least single allele of F508.
• Also 12.2% of known mutation-CF cases were of homo 3120+1kb
CFTR mutation.
• Also 14.7% of known mutation-CF cases were of homo N1303k
CFTR mutation, homo G85E CFTR mutation, and homo 3120del
18.6kb CFTR mutation equally.
Genetic determinants of CF disease in GS
CF disease Classes
CF Cases
No
%
Class I
2
4.9
Class II
21
51.2
Class III
0
0
Class IV
1
2.4
Class V
8
19.5
Compound
9
22
Total
41
100
• The majority of the cases was diagnosed during infantile
age and was diagnosed in Governmental Pediatric
Hospitals by both manifestations and sweat test.
• The anthropometric measurements and hemoglobin level
of CF cases in the GS reflected that short stature,
underweight, wasting and anemia were very common.
• About two thirds of known mutation of CF cases have at
least a single allele of DF508, which is considered of
severe type of CFTR mutations.
RECOMMENDATIONS
Recommendations concerning CF services
• Neonatal screening programs for CF disease should be set up.
• The importance of establishing a reliable diagnosis of CF using a
properly conducted sweat test. In addition, diagnostic radiology,
and laboratory facilities.
• Integration of genetic counseling and services for CF cases’
families into primary health care.
• Setting an expanded comprehensive health educational program for
families of CF cases’, old CF cases, and general public about CF and
strengthening the nutrition program for the public.
• Supplies of pancreatic enzymes and basic antibiotics, including antiPseudomonas agents for CF patients free of charge .
• It is essential for health authorities to know the magnitude of the
problem if they are to make appropriate provisions for CF care.
• It is important to establish and maintain a national CF registry in
order to identify and predict the need for services and to monitor
survival trends.
Recommendations for improving socioeconomic &
environmental status
• Increasing the situation of women in the community by
encouraging the high education of girls, and involving the women
in all fields and works.
• Increasing community awareness and counseling concerning the
effect of early marriage and consanguineous marriage.
• Campaigns aiming at educating families on the importance of
clean drinking water as well as advising mothers to take
compensatory measures such as additional nutrition intakes.
• Local authorities should inform the public about local
concentrations of air pollutants, possible effects on health, and
the action taken to minimize any health risks.