Determinants & Magnitude of Cystic Fibrosis in The Gaza Strip Amjad Fathi Hussein El-Shanti MD, MPH, Doctorate of Public Health (Epidemiology) Medical director of CFFC-Gaza April-2014

Contents Introduction: CF in Gaza Strip Conclusion Recommendations 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

What is cystic fibrosis (CF)? Definition What is cystic fibrosis (CF)? What is cystic fibrosis (CF)? A multisystem disease Autosomal recessive inheritance Cause: mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chromosome 7 codes for a c-AMP regulated chloride channel A multisystem disease Autosomal recessive inheritance Many functions still under investigation----CFTR 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: 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 C c CC Cc C Cc cc c

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: Gender Skin color and race Birth weight Consanguinity Socioeconomic status Environmental factors Patient adherence to prescribed medical regimens Genetic Factors: CFTR gene mutations 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 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 http://www.cysticfibrosismedicine.com/ htmldocs/CFText/genetics.htm

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 Defective Production II Defective Processing III Defective Regulation IV Defective Conductance V Reduced Amounts

CFTR and Airway Surface Liquid 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 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.

Pathophysiology of CF ? CFTR Dysfunction Disease manifestations Lungs 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 Age-specific prevalence of airway infections in patients with CF. Organisms reported to the U.S. Cystic Fibrosis Patient Registry, 2001 Early infections in CF airways are most frequently caused by S. aureus and H. influenzae. natural history study of patients with CF in the first 3 years of life, the mean age of detection of an antibody response to P. aeruginosa was approximately 15 months, whereas the mean ages of first positive upper and lower airway culture were approximately 21 and 23 months 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 S. aureus MRSA H. influenza S. maltophilia B. cepacia 80 60 Percent 40 20 0 to 1 2 to 5 6 to 10 11 to 17 18 to 24 25 to 34 35 to 44 45+ Age (years) Cystic Fibrosis Foundation Patient Registry Data. 2005

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 Biofilms are sessile communities of bacteria that form in aggregates on surfaces using a hydrated polymeric matrix of their own synthesis (Figures 6D and 6E). Some common clinical characteristics of biofilm infections have been identified: slow growth of organisms, stimulation of production of antibodies that are ineffective in clearing bacteria, inherent resistance to antibiotics, and an inability to eradicate biofilm infections even in hosts with intact immune systems (134–137). Gibson, RL, Burns, JL, and Ramsey, BW. AJRCCM 168 (918-951); 2003.

Pseudomonas genome http://www.pseudomonas.com/

Burkholderia cepacia complex B. cepacia syndrome: fevers, rapidly progressive necrotizing pneumonia, death Chronic cepacia infection decreased lung function and increased mortality Several closely related species termed genomovars1 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 Nine recognized genomovars Most common are II, III, V 1. Gibson, RL, Burns, JL, and Ramsey, BW. AJRCCM 168 (918-951); 2003.

Endobronchial disease Hyperinflation Peribronchial cuffing Bronchiectasis Diffuse fibrosis Atelectasis From: http://www.meddean.luc.edu/lumen/meded/elective/pulmonary/cf/cf_f.htm

Nasal Polyps 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 From: http://www.emedicine.com/ ped/topic1550.htm

Digital Clubbing 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 From: Fawcett et al., 2004

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 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 Hepatobiliary disease 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 Ursodiol increases bile flow {02} . In chronic cholestatic liver disease, ursodiol appears to reduce the detergent properties of the bile salts, thus reducing their cytotoxicity. Also, ursodiol may protect liver cells from the damaging activity of toxic bile acids (e.g., lithocholate, deoxycholate, and chenodeoxycholate), which increase in concentration in patients with chronic liver disease 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 Pregnancy and CF: 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 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 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

At least one of the following: 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 20 40 60 80 100 120 140 160 180 mEq/L 300 600 900 1200 1500 1800 240 Number of normal controls Number of patients with CF Controls n=4269 CF n=920 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 Analysis Sweat Stimulus & Collection

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 1601 CFTR mutations known to cause CF Only 25 mutations have a frequency > 0.1% G542X R347P 3849+10kbC  T Δ I507 R117H R1162X 1717-1G  A R553X 621+1G  T W1282X N1303K G551D 10 20 30 40 50 60 70 Frequency, % CF Genetic Analysis Consortium

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: to clear the abnormal and excess secretions and to control infections in the lungs, and 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

Macrolide Therapy for CF 4 12 24 28 -4 -2 2 5 Study Week Azithromycin Placebo 1 -1 -3 3 Change in FEV1 (% predicted) 8 16 20 Azithromycin in CF Improved FEV1 Fewer exacerbations of CF lung disease Uncertain mechanism of action Anti-inflammatory? Bacterial toxin or biofilm production? Saiman L, et al. JAMA. 2003;290:1749-56

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.

CF in Gaza Strip

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. Incidence rates of cystic fibrosis disease (Gaza, 2000- 2010)

Prevalence 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. Prevalence rates of cystic fibrosis disease (Gaza, 2000- 2010)

Magnitude of CF disease in GS Mortality The average annual mortality rate due to CF in the Gaza Strip through the last ten years (2000-2010) 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) Variable Cases (n= 100) Controls (n= 100) T-Test Average S.D T P Height (cm) 99.64 20.10 112.10 16.6 2 -4.78 0.000* HAZ -2.42 1.80 0.07 2.09 -9.01 Weight (kg) 14.70 5.84 19.89 7.44 -5.48 WAZ -2.48 1.05 -0.26 1.67 -11.28 WHZ -1.67 1.82 -0.02 2.06 -5.98 *Statistically significant

Average hemoglobin level of CF cases and controls (Gaza, 2010) 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 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 anti-Pseudomonas 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.