Bateman, Eric

Ramsay, Michelle

Zar, Heather J

English

AJOL - African Journals Online

EDITORIALEDITORIALNEW ADVANCES IN CYSTICFIBROSIS - IMPLICATIONS FORDEVELOPING COUNTRIESThere has been substantial progress in the understanding ofcystic fibrosis (CF) in the past decade. The discovery of thegene in 1989 provided an important impetus to understandingthe molecular basis of CF a.'1d its pathogenesis, and offered ameans of diagnosing the disease. Perhaps more importantly itbroadened our concept of the clinical spectrum of CF and gaverise to new options for treating this potentially devastatingdisease.CF is caused by a mutation in a single gene on the long armof chromosome 7 that encodes the cystic fibrosistransmembrane regulator (CFfR)l The basic defect in CF is analteration in the regulation of ion transport across the apicalmembranes of epithelial cells. Mutations in the CF geneproduce dysfunctional or absent CFTR, resulting in defectivechloride and sodium absorption in the respiratory, gastro-intestinal and reproductive tracts.' To date over 700 mutationshave been reported, the most common of which is the M508mutation, present in 82% and 53% of CF genes of white(European origin) and coloured (mixed ancestry) South Africanpatients, respectively.' This mutation has not been identified inblack South Africans, in whom other mutations, such as3120+1G->A, predominate. This mutation was shown to bepresent in 4 out of 6 CFTR genes from 3 black CF patients'Studies on the carrier status of healthy black South Africansindicate that CF is likely to be much more common in thispopulation than was formerly recognised5 Genotyping hasthus afforded a broader view of the extent of CF in the SouthAfrican population and has improved the accuracy of prenataldiagnosis and genetic counselling. Although the sweat testremains the standard method for diagnosis, genotyping hasimproved the ability to diagnose CF, particularly when theclinical presentation is atypical or the sweat test normal orequivocal.'Respiratory disease is the primary cause of morbidity andmortality in CF. Lung disease results from two processes -chronic endobronchial infection and neutrophil-dominatedairway inflammation. Conventional therapy has focused onclearance of lower airway secretions (using physiotherapytechniques and bronchodilators), antibiotic administration andmaintenance of adequate nutrition (using pancreatic enzymereplacements and nutritional supplements). Several new andeffective therapies for CF lung disease have been developed.7For chronic endobronchial Pseudomonas aeruginosa infection,aerosolised antibiotic therapy, particularly the aminoglycosides,has resulted in improved pulmonary function, reduced needfor intravenous antibiotics and decreased duration ofhospitalisation.s" The development of quinolone antibiotics,principally ciprofloxacin, has offered an effective oral therapyfor susceptible P aeruginosa lO Anti-inflammatory therapy withibuprofen may slow the progression of CF lung disease byreducing airway inflammation, particularly when used inyoung patients with mild disease. l1 Inhaled recombinanthuman deoxyribonuclease (rhDNase I), a treatment thatdecreases sputum viscosity by cleaving extracellular DNAoriginating from inflammatory cells, has reduced the frequencyof severe respiratory exacerbations and the annualdeterioration in pulmonary function." Recent data suggest thatnebulised hypertonic saline may produce similarimprovements in lung function, although further confirmationof this is awaited. l3 Lung transplantation, an option for CFpatients with end-stage pulmonary disease in some overseascentres, may improve both quality of life and survival."Although this has been performed in South Africa, cost andlack of experience in postoperative care of these patients maylimit the success of this procedure.Potential future therapies for CF lung disease include otheranti-inflammatory agents, modulators of ion transport, andgene replacement therapy. Aerosolised anti-proteases such assecretory leucocyte protease inhibitor and a,-antitrypsin mayprevent lung damage resulting from neutrophil elastase.Inhibitors of neutrophil chemotaxis such as pentoxifylline mayprevent the influx of neutrophils and the development of floridairway inflammation and lung injury. Activators of alternativechloride channels such as uridine triphosphate, or sodiumchannel antagonists such as arniloride, may normalise thedefect in ion secretion and absorption. Gene therapy in theform of adenoviral vectors and liposomes has been used todeliver the complementary DNA for CFTR into the respiratorytract of adults with CFls Although it appears that the CFTRgene can be transduced into the respiratory epithelium usingeither of these methods, the clinical benefit, duration of effect,long-term outcome and side-effects of such therapy await fullevaluation.Although the development of new therapies has improvedthe outlook of patients with CF, the major impact on survivalhas resulted from the application of standard, conventionaltreatmellts given early in the disease. Key factors influencingprognosis include early diagnosis, maintenance of optimalnutrition and aggressive treatment of pulmonary infections.Patients diagnosed and referred to a CF centre before the age of1 year have better lung function at 14 years than those I':'PJCJIdiagnosed later!' - timely diagnosis and referral of CF ~patients is therefore essential. The impact of P. aeruginosainfection on lung function is apparent from the accompanyingpaper by Zar et al.,!7 and the benefit of antipseudomonaltreatment has been demonstrated in a number of studies.7".!SThe ability of the community or patient to afford relativelyEDITORIALcostly long-term, lifelong care also impacts directly onoutcome. ewer treatments such as rhD ase appear to offerimproved outcome, but at considerable additional cost.The question of what should be considered minimalacceptable treatment of CF in developing countries is anevocative and controversial question. Firstly, the value of a CFcentre where a multidisciplinary team including doctors,physiotherapists, nutritionists and social workers can providesupport for all the important aspects of this disease must beemphasised. These clinics require co-ordination and a suitablelocation in large regional centres. Secondly, provision ofstandard conventional therapy including antibiotics, pancreaticenzyme replacement therapy and nutritional support needs tobe assured, as these constitute basic care for CF patients.Thirdly, treatment for CF-associated complications such asdiabetes should be provided. It is gratifying to note that theprognosis for South African children, although not as good asfor orth American patients," has improved significantly withthis approach.'" As a result the majority of CF patients born in1998 can be expected to survive into adulthood. A consensusdocument on the care of CF patients is currently beingcompiled by the medical and scientific advisory committee ofthe South African Cystic Fibrosis Association (SACFA), andwill soon be available.Assurance of continued lifelong care is a serious concern forall patients with chronic diseases, particularly for those who,like CF sufferers, require a variety of costly drugs. The cost ofrhD ase, transplantation, and in time possibly gene therapyplace these treatments beyond the reach of State funding, butmay be accommodated within the cover of some privatemedical aid schemes. CF clinics and support groups need tocontinue their important advocacy role in ensuring continuedgovernmental, medical aid and private support.Heather J ZarDepartment of Paediatrics and Child HealthUniversity of Cape TownEric BatemanDepartment ofMedicineUniversity of Cape TownMichelle RamsayChainrum: South African Cystic Fibrosis AssociationDepartment ofHuman GeneticsSouth African Institute for Medical Research and School of PathologyUniversity of the WitwatersrandJohannesburg1. Collins fS. Cystic fibrosis: molecular biology and therapeutic implications. Scirnce 1992; 256:n4-719.2. Welsh MJ, Smith AE. Molecular mechanisms of CFrR chloride channel dysfunction in cysticfibrosis. Czlll993; 73: 1251-1254.3. Herbert IS, Retief AE. The frequency of the delta F508 mutation in the cystic fibrosis genes of71 unrelated South African cystic fibrosis patients. 5 AIr Med 11992; 82: 13-15.4. Caries S, Desgeorges M. Goldman A. tI al. First report of CFrR mutations in black cysticfibrosis patients of southern African origin. I Med Gmd 1996; 33: 802-804.August 199 , Val. 88, No. 8 SAMJ5. Ramsay M, Caries 5, Desgeorges M, d al. CFTR mutations in black cystic fibrosis patients ofSouthern African origin. Is, I Med Sci 1996; 32: suppl. 5231.6. Stem RC. The diagnosis of cystic fibrosis. N Engl JMed 1997; 336: 487-491.7. Ramsey BW. Management of pulmonary disease in patients with cystic fibrosis. N Engl JMed1996; 335: 179-188.Ramsey BW, Dorkin Ht, Eisenberg JD. Efficacy of aerosolized tobramycin in patients withcystic fibrosis. N Engl JMed 1993; 328: 17-10-1746.9. PathoGenesis Corp. Results of phase m trials of TOBI in cystic fibrosis patients. Availablefrom: www.pslgroup.com/dg/l99cb.htm10. Hodson ME. Roberts CM, Butland RlA. Smith Ml, Batten le. Oral ciprofloxacin comparedwith intravenous treatment for Pseudomonas aeruginosa infection in adults with cystic fibrosis.LAncet 1987; 1: 235-237.11. Konstan MW, Byard PJ, Hoppel CL. Da\rl.s PA. Effect of high-dose ibuprofen in patients withcystic fibrosis. N Engl JMed 1995; 332: 848-854.12. Fuchs HJ, Borowitz OS, Christiansen OH, et al. Effect of aerosolized recombinant humanDNase on exacerbation of respiratory symptoms and on pulmonary function in patients withcystic fibrosis. N Engl JMed 1994; 331: 637-6-12.13. Eng PA. Morton J, Douglass lA, et al. Short-term efficacy of ultrasonically nebulizedhypertonic saline in cystic fibrosis. Pediatr Pulmonoll996; 21: 77-83.14. Caine N, Sharples l. Smyth R. et al. Survival and quality of life of cystic fibrosis patientsbefore and after heart-lung transplantation. Transplant Proc 1991; 23: 1203-1204.15. Knowles MR, Hohneker KW, Zhou Z, et al. A controlled trial of adenoviral-vector-mediatedgene transfer in the nasal epithelium of patients with cystic fibrosis. N Engl / Med 1995; 333:823-831.16. Weller PH. Implications of early infection and inflammation in cystic fibrosis - a review ofnew and potential interventions. Pediatr Pulmonol 1997; 24: 14-3-145.17. Zar HJ, Moore B, Argent A, et al. Lung function in South African children with cystic fibrosis.5 Afr Med J1998; 88: 992-995.lB. Frederiksen B, Koch C, Hoiby . Antibiotic treatment of initial colonization with PseudOmotUlSaeruginosa postpones chronic infection and prevents deterioration of pulmonary function incystic fibrosis. Pediat, Pulmonoll997; 23: 330-335.19. FitzSimmons se. The changing epidemiology of cystic fibrosis. JPediatr 1993; 122: 1·920. Westwood ATR The prognosis of cystic fibrosis in the Western Cape region of South Africa. /Paediat, Child Heillth 1996; 32: 323-236.

New advances in cystic fibrosis - implications for developing countries

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New advances in cystic fibrosis - implications for developing countries

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