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54 Pages

Cystic Fibrosis

Course: MEDICINE 350, Winter 2007
School: Medical College
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Word Count: 1488

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Fibrosis Advances Cystic and Asian Perspective Dr AS Paul 13 October 06 Cystic Fibrosis An Overview Asian Perspective Advances Cystic Fibrosis An Overview Epidemiology and Pathogenesis Most common severe AR disorder in Caucasians Carrier rate of 1:25/Incidence of 1:2500 Mutation affecting gene on long arm of chromosome 7 CFTR - Cystic fibrosis transmembrane conductance regulator a chloride channel- essential for salt and water movement across membranes. F508 most common mutation-67% UK Numerous others in the same region Increased sweat sodium chloride Increased potential difference across respiratory epithelium detected in the nose Increased viscosity of secretions/ciliary dysfunction/chronic infection and bronchiectasis Disorders in the gut epithelium/ pancreas/liver (malabsorption/DM/cirrhosis) Infertility in most men Lung fn normal at birth but deteriorates. Staph and Pseudomonas predominate Why is it so common? Carrier advantage in E coli diarrhea and cholera. Management Principles Lung Disease Maintaining function Monitoring bacteriology Transplant when appropriate Nutrition Nutritional support/ weight/enzymes GI Portal HT/Biliary cirrhosis Management Endocrine CFRD Osteporosis Fertility advice Psychosocial well being CF Pulmonary Sepsis Causes much mortality/morbidity Chronic colonization at an early age with bronchiectasis by 5 years FEV1 best marker of deterioration/ improves with antibiotics To assess decline/ exacerbation/ antibiotic response. Organisms Colonization changes over time. Goals Prevent Eradicate Control H influenzae/ S aureus/ P aeruginosa(non mucoid/ mucoid) Burkholderia cepacia/MRSA/NTM Antibiotics Higher doses and durations Clinical response guided by cultures Macrolides At home IV antibiotics/ usual course 2 wks Other pulmonary interventions Physiotherapy DNAse Oxygen and NIV Steroids: ABPA/ exacerbations/ terminally Immunization: influenza/ pneumococcal Transplant Life expectancy less than 2 years FEV1 less than 30% Hypoxia and hypercapnia Young female patients deteriorate faster Infection/ acute rejection Bronchiolitis obliterans 40% 1 year survival 58% Other pulmonary problems Pneumothorax ABPA Non-tuberculous mycobacteria CF asthma Haemoptysis Prognosis improving with better control of bronchial sepsis Median survival is about 40 years for those born in the nineties Gene therapy Asian Perspective Are North Indians Caucasian? 1:2500 White Americans 1:15000 Black Americans 1:31000 Asian Americans Unknown in Indians Low index of suspicion and therefore late diagnosis Cystic fibrosis in North Indian Children Singh M et al; Indian J Pediatr 2002; 69(7):627-629 Bhakoo 1968 Mehta 1969 Reddy 1970 Prasad 1990 Devanayagam 1990 Sarkar 1992 Kabra 1996 Singh 1998 Chandigarh Chandigarh Andhra New Delhi Madras Calcutta New Delhi Chandigarh 1 13 2 2 68 1 15 12 Cystic Fibrosis PGI (1995-1997) Clinical Characteristics Total patients 17 Mean age at presentation (Year): 4.78+3.42 Mean duration of symptoms(year) 4.05+ 2.1 Jammu and Kashmir , Panjab, UP, Rajasthan, HP Mean sweat Chloride concentration (meq/l)81.8 + 25. Abnormal CXR (Peribronchial thickening, cystic changes) 15/17 Abnormal CTchest, atelectasis, bronchiectasis (10) Patchy Malabsorption work up 4/6 Genetic mutations DF 508 3/10 cases Clinical diagnosis 14/17 cases Autopsy 3/17 Pulmonary disease alone 7/17 Pulm + GI 9/17 Pseudomonas colonization of the respiratory tract 12/17 Asian perspective DF 508 19-44% vs 70% UK CF Database 5274 children 88 from ISC ie 3.75% 63 Pakistani/12 Indian/7 Bangla/6 others Greater severity in Indians? When is CF a possibility? Meconium ileus at birth Persistent pneumonia Malabsorption and failure to thrive (appetite+) Both together Salt losing syndromes Obstructive azoospermia Confirmation Sweat chloride (> 60 mEq/L) Nasal potential difference measurements Mutation analysis No panel exists Suppportive lab tests Low Na+/ low Cl-/metabolic alkalosis Airway colonization Pancreatic function tests(Stool elastase1) Obstructive azoospermia CXR Sinus radiology CF is rare but. Early diagnosis is beneficial Negative Mutation analysis does not rule out the condition Clinical evaluation/sweat test/ancillary tests 15/381 were South Asian (20/248 709 873 US population) Higher than all previous estimates ? Inadequate awareness and diagnosis only in severe cases The prevalence and clinical characteristics of cystic fibrosis in South Asian Canadian immigrants M Mei-Zahav et al Arch Dis Child 2005;90:675-679 What is already known.. CF is rare in populations not of European Caucasian origin More severe disease has been reported in South Asian CF patients 508 is less prevalent in South Asians What this study adds Prevalence and clinical course of CF in children of South Asian origin is similar to that in the general Toronto population Previous reports reflect inadequate awareness of CF in this ethnic group 508 is confirmed to be lower in this group(41% vs 66%) Failure to thrive is a manifestation of CF Kwarshiorkor and marasmus are often treated without CF being considered a D/D Consider CF in severe PEM!! Cystic fibrosis presenting as kwashiorkor in a Sri Lankan infant M Mei-Zahav et al Arch Dis Child 2003;88:724-725 Cystic fibrosis in Asian Indians Powers et al Arch Pediatr Adolesc Med;150,May 1996 2 Asians referred with CF to a Chicago hospital in 1993 Survey of 116 US centers to estimate incidence 1:40 750 ( 20/815 000) Possibility of underdiagnosis alone. Cystic on ethnicity fibrosis in Asians IM Bowler et al Arch Dis Child 1993;68:120-2 Clinical course in 9 Pakistani immigrants Grew Pseudomonas earlier Worse PFTs Higher IgG levels Lower wt for age/wt for ht F508 4/9 vs 17/18 More severe clinical course Advances HRCT: A Potential Outcome Measure HRCT & volumetric CT detect CF changes earlier than global PFT. Scoring used to define severity, progression, evaluation of treatment. Composite CT/PFT scores Quantitative airway and air trapping measurements Therapeutic Trials Protein Rescue & Ion Transport Therapies Anti-inflammatory Therapies Anti-infection Therapies Nutritional/GI Therapies Mucus Clearance and Regulation Therapies Observational Studies Protein Rescue & Ion Transport Therapies TDN: Safety and Effectiveness of Curcumin in Adults with CF TDN: Oral PTC124 for Nonsense Mutation-Mediated CF TDN: Inhaled INS37217 (denufosol) to Correct Salt Transport in CF Anti-inflammatory Therapies Effect of Simvastatin on CF Airway Inflammation Effects of N-acetylcysteine Supplementation Safety and Tolerability of Oral Glutathione in CF Pilot Studies of Three AntiInflammatory Drugs (HCQ/MTX/Pioglitazone) Anti-infection Therapies Pilot: Comparing IV and Inhaled Antibiotics for Pseudomonas in Early CF (IV Ceftazidime + Tobramycin vs inhaled tobramycin for 2/4 wks) Antibiotic Susceptibility Testing Using the Standard vs. the Biofilm Method Phase II Azithromycin in Individuals with CF and B. cepacia Extremely resistant and produces intense inflammation Azithromycin has shown some promise when used long term Macrolides in CF 3 recent trials of azithromycin Improved FEV1 between 3.6-6.2% Decreased antibiotic use and exacerbations; wt gain Well tolerated Comparable with TOBI/DNAse Mechanism of action Anti-microbial Anti-inflammatory Interaction with CFTR: better for homozygotes ? Change in sputum rheology Additive to other therapies Phase III TDN: Treating Early P. aeruginosa Airway Infection in Young Patients with CF (EPIC Clinical Trial) TDN: Study of Risk Factors for Acquisition of P. aeruginosa and Early Anti-Pseudomonal Treatment (EPIC Observational Study) TDN: Two Trials of Aztreonam Inhalation in Individuals With CF and P. aeruginosa Lung Infections TDN: Follow-up Study of Long-term Azithromycin Tobramycin Inhalation Powder in CF Patients With P. aeruginosa Phase II Trial of Safety and Effectiveness of Inhaled Glutathione Mucus Clearance and Regulatory Therapies Aerosolized Surfactant and Hypertonic Saline for CF Lung Disease Lomucin (Talniflumate) to Reduce Mucus Overproduction Targeted Studies of Hypertonic Saline for CF Lung Disease Hypertonic Saline for Infants and Young Children With CF Advances in Gene therapy No other treatment options Easier for monogenic disorders 29 trials since 1993 Initial hopes for progress belied Ease of non-invasive access to lungs Delivery to relevant cells difficult Clinical Trials Adenoviruses used earlier Do not transfect airway epithelial cells Repeat admin not possible Adeno associated virus better Safety profile Broad tissue tropism Long duration of expression Superior escape from immune surveillance Moss RB et al:Repeated adeno-associated virus serotype 2 aerosol mediated CFTR gene transfer to the lungs of patients with CF.Chest 2004,125:509-521 Small improvements in function Reduction in IL-8 Seen after first dose only Mild disease: difficult to detect improvement Severe disease: poor transduction because of increased inflammation and sputum barrier. Konstan M et al: Single dose escalation study to evaluate safety of nasal administration of CFTR001 gene transfer vector to subjects with CF. Mol Ther 2004,7:S386 Smaller nonviral gene transfer agents Less than 25nm Nasal adm in 12 patients 7/12 showed correction in Cl transport(15d) No placebo group Spillover from treated nostril to control nostril Viral vectors Adenovirus mediated gene transfer poor in the absence of epithelial damage. No receptor on apical surface of airway cells Use of sodium caprate to open tight junctions to expose receptors on basolateral surfaces increased 25x Risk of systemic invasion by bacteria?? Immune response after first administration. Reduced in vectors depleted of all viral genes Sendai virus most efficient: cannot be repeated! Lentivirus pseudotyped with Ebola are efficient but need repetition. Non viral vectors Improving efficiency of these a major focus Adding sugars to polyplexes as airway cells express lectins which bind and internalise glycoconjugates Airway epithelial cell promoters to avoid CFTR expression in other cells eg FOXJ1 Physical delivery methods eg electroporation, magnetism, USG, vibration to enhance transfecton. Animal models Many CF knockout mouse models generated; gut disease more than lung disease. New models in ferrets, sheep,and pigs End point assays Reduction in decline in lung fn. Reduction in episodes of infection Large numbers required to study these end points Surrogate end points needed eg bacterial burden, inflammatory markers, imaging Gene therapy: current status Gene transfer to airway cells is inefficient Lung designed to keep foreign particles out New viral and non viral agents Physical delivery methods Surrogate end points Conclusion CF may be more common in our country than previously thought. Needs to be actively excluded in conditions as diverse as marasmus to bronchiectasis and infertility Thank you

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