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Fibrosis quistica
- 1. Fibrosis Quística Dr. José Luis Lezana Fernández Clínica de Fibrosis Quística Hospital Infantil de México Federico Gómez. Asociación Mexicana de Fibrosis Quística A.C.
- 3. Fibrosis Quística Andersen D. Cystic Fibrosis of the pancreas and its relation to celiac disease: clinical and pathological study. Am J Dis Child 1938;56:344-99
- 4. Herencia Autosómico Recesiva X X X X X X X X X X X X 25% 50% 25%
- 5. Proteína Reguladora de Conductancia Transmembranal en FQ: CFTR Riordan JR, et al. Science. 1989. Rommens JM, et al. Science. 1989. Kerem B, et al. Science. 1989. Cromosoma 7, región q31 CFTR gene CFTR proteína (estructura primaria) CN
- 6. Genetica del CFTR • Mas de 1,300 mutaciones identificadas • ΔF508 es la mutación mas común …I I F G… …ATCATCTTTGGT… — ——— Ratjen F, et al. Lancet. 2003. CFTR gene
- 7. Proteína CFTR Riordan JR, et al. Science. 1989. Ratjen F, et al. Lancet. 2003. Collins FS. Science. 1992. Vankeerberghen A, et al. J Cyst Fibros. 2002. • 1480 aminoácidos • MW ~170 kD • Miembro de la superfamilia ATP-binding cassette (ABC) • Un dominio regulador (R) • Se localiza en la membrana apical de células epiteliales • 2 dominios transmembranales que atraviesan la membrana 6 veces (MSD) • 2 dominios de unión a Nucleótidos (NDB)
- 8. V Alternative splicing 3849+10kbC→T Missense A455E Síntesis reducida IV Missense R117H Conductancia alterada III Missense G551D Bloqueo regulación II AA deletion ∆F508 Bloqueo en proceso Normal I Nonsense G542X Frameshift 394delTT Splice junction 1717-1G→A Sin síntesis Consecuencias Moleculares de las Mutaciones CFTR Vankeerberghen A, et al. J Cyst Fibros. 2002. http://www.genet.sickkids.on.ca/cftr/ CFTR
- 9. Definición Fibrosis Quística es una enfermedad multiorgánica causada por mutaciones que afectan la proteína Reguladora de Conductancia Transmembranal (CFTR) en un gene situado en el brazo largo del cromosoma 7 (región q,31).
- 10. Propiedades Fisiológicas del CFTR Ratjen F, et al. Lancet. 2003. Pier GB. Curr Opin Microbiol. 2002. CFTRCFTR Canal de Cl– Canal de Cl– Regulador de ENaC Regulador de ENaC Regulador de pH endosomal Regulador de pH endosomal Interacción con otras proteínas celulares Interacción con otras proteínas celulares Receptor para P aeruginosa? Receptor para P aeruginosa?
- 11. Fibrosis Quística Población Frecuencia Frecuencia TN Blanca (U.S.) 1 en 1,900 - 3,700 1 en 3,400 - 3,800 Hispanos (U.S.) 1 en 8,000 - 9,000 Afro-Americanos 1 en 15,300 Nativos Americanos 1 en 40,000 Asiáticos (U.S./U.K.) 1 en 10,000 Blanca (U.K.) 1 en 2,400 - 3,000 1 en 2,200 - 3,200 Israel 1 en 5,000 Sur de Europa 1 en 2,000 - 4,000 México desconocido Cystic Fibrosis. R. Yankaskas. Lippincot-Raven Publ. 1999.
- 12. Prevalencia de la mutaciónPrevalencia de la mutación ∆∆F508F508 en distintos grupos étnicosen distintos grupos étnicos Grupo Etnico Mutación ∆F508 (% de alelos) Caucásicos 70 Afro Americanos 48 Hispanos 46 Asia Americanos 30 Judíos Ashkenazi 30 Wang D, et al. Am J Clin Pathol. 2002.
- 13. Prevalencia de la MutaciónPrevalencia de la Mutación ∆∆F508F508 en 97 Pacientes Mexicanosen 97 Pacientes Mexicanos Mutación (% de alelos) ∆F508 40.72 G542X 8.18 ∆I507, S549N 2.57 N1303K 2.06 406-1-GA, I148T, R75X 1.54 Orozco L, y cols., Hum Genet 2000;106:360-365
- 14. Prevalencia de la MutaciónPrevalencia de la Mutación ∆∆F508F508 en 97 Pacientes Mexicanosen 97 Pacientes Mexicanos Mutación (% de alelos) 2055del9-A, 935delA, I596T, 3199del6, 2183AA-G 1.03 G551D, R553X,1924del7, R117H, W1098C, G551S, 1078del7, Y1092X,G85E, W1204X, 3849+10Kbc-T, 1716G-A, 846delT, P750L, 4160insGGGG, H199Y, V754M, R75Q, L558S,297-1G-A, W1069X 0.51 Orozco L, y cols., Hum Genet 2000;106:360-365 74.58% de los alelos caracterizados con 34 mutaciones
- 15. Fibrosis Quística; Definición Ratjen F, et al. Lancet. 2003. Collins FS. Science. 1992. Fibrosis Quística es una enfermedad genética, multiorgánica y progresiva, causada por mutaciones que afectan la proteína Reguladora de Conductancia Transmembranal (CFTR) en un gene situado en el brazo largo del cromosoma 7 (región q,31).
- 17. Fisiopatología de la EnfermedadFisiopatología de la Enfermedad Pulmonar en FQPulmonar en FQ Defecto en el gene CFTR Defecto/deficiente proteína CFTR Alteración iónica en la superficie de la vía aérea Obstrucción Bronquial Infección InflamaciónInflamación Bronquiectasias Konstan MW, et al. Pediatr Pulmonol. 1997.
- 18. El Pulmón en Fibrosis QuísticaEl Pulmón en Fibrosis Quística
- 19. PMN LTB4, IL-8 IgG (Fc) unión CR1, C3bi unión Falla de opsonofagocitosis (persistencia bacteriana) ↑ secreción de moco degradación Elastina Tapones en VA Daño estructuralDaño estructural BronquiectasiasBronquiectasias IL-8 Epitelial ADNO2 - H2O2 . ElastasaElastasa Neutrofilos en la Enfermedad de laNeutrofilos en la Enfermedad de la Vía Aérea en FQVía Aérea en FQ Konstan MW, et al. Pediatr Pulmonol. 1997.
- 21. Diagnóstico de FQDiagnóstico de FQ Rosenstein BJ, et al. J Pediatr. 1998. El diagnóstico de FQ se establece con :El diagnóstico de FQ se establece con : Uno de los siguientes:Uno de los siguientes: MAS una prueba positiva:MAS una prueba positiva: >1 característica fenotípica de FQ 2 determinaciones positivas de cloro en sudor Antecedente de FQ 2 mutaciones del gene CFTR identificadas Tamiz neonatal positivo Diferencia de potencial de membrana nasal anormal
- 22. Características Típicas y AtípicasCaracterísticas Típicas y Atípicas de Fibrosis Quísticade Fibrosis Quística Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic Fibrosis. 1997. Rosenstein BJ, et al. J Pediatr. 1998. Knowles MR, et al. N Engl J Med. 2002. Sinusitis crónica Infección crónica grave Insuficiencia pancreática Niveles de Cl en sudor elevados Azoospermia obstructiva Sinusitis crónica Infección crónica Suficiencia pancreática Niveles de Cl en sudor normales Azoospermia obstructiva Típicas Atípicas Enfermedad hepatobiliar grave Ileo meconial al nacer Función hepatobiliar normal Ausencia de ileo meconial
- 23. Clínica Diagnóstica para FQClínica Diagnóstica para FQ Enfermedad sinopulmonar crónicaEnfermedad sinopulmonar crónica Colonización/infección persistente con patógenosColonización/infección persistente con patógenos típicos en FQ incluyendotípicos en FQ incluyendo:: Staphylococcus aureus Pseudomonas aeruginosa (mucoide/no mucoide) Haemophilus influenzae no tipificable Burkholderia cepacia Enfermedad endobronquial manifestada por:Enfermedad endobronquial manifestada por: Tos y producción de esputo Atrapamiento de aire y disnea Anormalidades radiológicas Patrón obstructivo en las PFR Acropaquias Clinical Practice Guidelines for Cystic Fibrosis. CFF 1997
- 24. Clínica Diagnóstica para FQClínica Diagnóstica para FQ Clinical Practice Guidelines for Cystic Fibrosis. CFF 1997 Enfermedad sinusal crónica:Enfermedad sinusal crónica: Pólipos nasales Cambios radiográficos Anormalidades Gastrointestinales/nutricionalesAnormalidades Gastrointestinales/nutricionales Anormalidades intestinales:Anormalidades intestinales: Ileo meconial Insuficiencia pancreática oxócrina SOID Prolapso rectal Pancreatitis recurrente
- 25. Clínica Diagnóstica para FQClínica Diagnóstica para FQ Clinical Practice Guidelines for Cystic Fibrosis. CFF 1997 Enfermedad hepatobiliar crónica con evidenciaEnfermedad hepatobiliar crónica con evidencia clínica y/o de laboratorio:clínica y/o de laboratorio: Cirrosis biliar focal Cirrosis multilobular Falla para crecer (desnutrición proteíco-calórica).Falla para crecer (desnutrición proteíco-calórica). Edema – hipoproteinemia.Edema – hipoproteinemia. Deficiencia de vitaminas liposolubles.Deficiencia de vitaminas liposolubles.
- 26. Clínica Diagnóstica para FQClínica Diagnóstica para FQ Clinical Practice Guidelines for Cystic Fibrosis. CFF 1997 Enfermedad sinusal crónica:Enfermedad sinusal crónica: Pólipos nasales Cambios radiográficos Anormalidades Gastrointestinales/nutricionalesAnormalidades Gastrointestinales/nutricionales Anormalidades intestinales:Anormalidades intestinales: Ileo meconial Insuficiencia pancreática oxócrina SOID Prolapso rectal Pancreatitis recurrente
- 27. Clínica Diagnóstica para FQClínica Diagnóstica para FQ Clinical Practice Guidelines for Cystic Fibrosis. CFF 1997 Enfermedad hepatobiliar crónica con evidenciaEnfermedad hepatobiliar crónica con evidencia clínica y/o de laboratorio:clínica y/o de laboratorio: Cirrosis biliar focal Cirrosis multilobular Falla para crecer (desnutrición proteíco-calórica).Falla para crecer (desnutrición proteíco-calórica). Edema – hipoproteinemia.Edema – hipoproteinemia. Deficiencia de vitaminas liposolubles.Deficiencia de vitaminas liposolubles.
- 28. Clínica Diagnóstica para FQClínica Diagnóstica para FQ Clinical Practice Guidelines for Cystic Fibrosis. CFF 1997 Azoospermia obstructiva.Azoospermia obstructiva. Síndromes perdedores de sal.Síndromes perdedores de sal. Depleción aguda de sal.Depleción aguda de sal. Alcalosis metabólica crónica.Alcalosis metabólica crónica.
- 29. La Rx-tórax puede no detectar el dañoLa Rx-tórax puede no detectar el daño pulmonar tempranopulmonar temprano • Masculino FQ 7 años • La Rx-tórax no refleja la gravedad de la enfermedad • La gravedad del compromiso pulmonar se hizo evidente por necropsia
- 31. La HRCT detecta el daño antes de laLa HRCT detecta el daño antes de la caída en la función pulmonarcaída en la función pulmonar • FEV1 99% • FVC 92% • Radio FEV1/FVC 90% • FEF25-75 95% • CT muestra áreas localizadas de enfermedad pulmonar avanzada
- 32. Fibrosis Quística La anormalidad del CFTR para el Diagnóstico
- 33. Cifras de Cloro en sudor elevado por el método QIPT (Gibson y Cooke). Identificar la mutación CFTR en ambos alelos. Alteración en el potencial de membrana nasal. Cystic Fibrosis in Adults. Lippincott-Raven Publishers, 1999 Evidencia de Disfunción del CFTREvidencia de Disfunción del CFTR
- 34. Análisis Mutacional del ADNAnálisis Mutacional del ADN • >1300 mutaciones identificadas del CFTR Mutación ∆F508 en 70% de los alelos 15 a 20 otras mutaciones comunes en el 2% a 15% de los alelos CFTR • Análisis mutacional del ADN: 90% sensibilidad en población Caucásica Poblaciones No-Caucasicas requieren diferentes páneles (kits de mutaciones) Un paciente con 2 copias mutadas es FQ En ausencia de cuadro clínico, historia familiar, o prueba de sudor positiva, el análisis de mutaciones no es diagnóstico Rosenstein BJ, et al. J Pediatr. 1998. Wang D, et al. Am J Clin Pathol. 2002.
- 35. Evidencia de Anormalidad del CFTR:Evidencia de Anormalidad del CFTR: Diferencia de Potencial Nasal (NPD)Diferencia de Potencial Nasal (NPD) • Alto NPD basalAlto NPD basal Rosenstein BJ, et al. J Pediatr. 1998.Wang D, et al. Am J Clin Pathol. 2002. NPD(mV) NORMALNORMAL 0 –10 –20 –30 –40 –50 –60 –1 0 1 2 3 4 5 6 7 8 Tiempo (minutos) 9 Amiloride Amiloride 0 Cl– Amiloride 0 Cl– Amiloride Iso 0 Cl– Amiloride Iso 0 Cl– Amiloride NPD(mV) FIBROSIS QUÍSTICAFIBROSIS QUÍSTICA 0 –10 –20 –30 –40 –50 –60 –70 –1 0 1 2 3 4 5 6 7 8 Tiempo (minutos) 9 • Mayor caida enMayor caida en NPD después deNPD después de perfundir amilorideperfundir amiloride • Sin respuesta a laSin respuesta a la perfusión de unaperfusión de una sol. libre de Clsol. libre de Cl oo IsoproterenolIsoproterenol Paciente con FQ:Paciente con FQ:
- 36. Welsh MJ. Tenth Annual North American CF Conference; October 1996. Fisiopatología de la alteración del CFTRFisiopatología de la alteración del CFTR en la Glándula del Sudoren la Glándula del Sudor
- 37. Evidencia de Anormalidad del CFTR:Evidencia de Anormalidad del CFTR: Prueba del SudorPrueba del Sudor • Iontoforesis Cuantitativa con Pilocarpina (QPIT); se requieren 2 resultados positivos – Titulación del Cloro en sudor – <40 mmol/L = negativo; 40-59 = dudoso; >60 positivo FQ – Cantidad mínima de sudor 75 mg en 30 minutos • Pruebas cualitativas (screening) : NO diagnósticas – Conductividad: Wescor Sweat Chek o Advanced Instruments – Electrodo Orion para cloro – Scandipharm CF Indicator System chloride patch – Osmolaridad Cystic Fibrosis Foundation. Center Director Committee. 1993. National Committee for Clinical Laboratory Standards C34-A2. Wayne (PA) 2000. LeGrys VA. J Pediatr. 1996.
- 38. Dr. José Luis Lezana-Fernández, Dr. Mario H. Vargas, Dr. José Karam- Bechara, Dra. Ruth S. Aldana-Vergara, Dra. María E.Y. Furuya. Journal of Cystic Fibrosis 2003;2:1-7 Estudio Comparativo entre Conductividad y Clorimetría enEstudio Comparativo entre Conductividad y Clorimetría en 3834 sujetos con sospecha clínica de Fibrosis Quística.3834 sujetos con sospecha clínica de Fibrosis Quística.
- 39. Método de Conductividad Es un método analítico que expresa la concentraciónEs un método analítico que expresa la concentración molar equivalente en conductiancia de una soluciónmolar equivalente en conductiancia de una solución de NaClde NaCl VENTAJAS CON RESPECTO A TITULACION ClVENTAJAS CON RESPECTO A TITULACION Cl Más sencillo y rápidoMás sencillo y rápido Requiere menos muestra de sudor (15 µ)Requiere menos muestra de sudor (15 µ) Menor posibilidad de erroresMenor posibilidad de errores DESVENTAJAS CON RESPECTO A TITULACION ClDESVENTAJAS CON RESPECTO A TITULACION Cl No aceptado como método Dx definitivoNo aceptado como método Dx definitivo
- 40. Objetivo TITULACION DE CLORO CONDUCTIVIDAD Evaluar la eficacia y precisión del método de conductividad comparado con la titulación de Cl para el diagnóstico de FQ > 60 mmol / L 40- 60 mmol / L < 40 mmol / L FQ No – FQ DUDOSOS ? ? ? ? ? ? Lezana y cols. J of Cystic Fibrosis 2003;2:1-7
- 41. AMFQ 1990-2000 7933 2972 Un solo método 38343834 587 Repetición Conductividad + Titulación de Cl 540 Muestra insuficiente FQ 294FQ 294 51.4% femeninos 0.1 a 28 años (2.5 años)0.1 a 54 años de edad Lezana y cols. J of Cystic Fibrosis 2003;2:1-7 Material y Métodos
- 42. Distribución de Sujetos con y sin FQ Lezana y cols. J of Cystic Fibrosis 2003;2:1-7
- 43. Curva ROC Lezana y cols. J of Cystic Fibrosis 2003;2:1-7 98 99 100 0 1 2 FALSOS POSITIVOS (%) VERDADEROSPOSITIVOS(%) 0 20 40 60 80 100 0 20 40 60 80 100
- 44. Resultados:Resultados: Valores de Corte para CONFIRMAR FQValores de Corte para CONFIRMAR FQ TITULACION DE CLORO CONDUCTIVIDAD FQ No – FQ > 60 mmol / L DUDOSOS ≥ 90 mmol / L Titulación de cloro Conductividad Valor de corte (mmol/L) FQ (n=294) No-FQ * (n=3540) Sensibilidad (%) Especificidad (%) VPP (%) VPN (%) Kappa ≥92 291 3540 98.98 100.00 100.00 99.92 0.994 ≥91 292 3540 99.32 100.00 100.00 99.94 0.996 ≥90 † 293 3540 99.66 100.00 100.00 99.97 0.998 ≥89 293 3539 99.66 99.97 99.66 99.97 0.996 ≥88 293 3535 99.66 99.86 98.32 99.97 0.989 *Incluye valor negativo (< 40 mmol/L CL) y valor equívoco (40- a 60 mmol/L). † Mejor valor de corte. VPP = valor predictivo positivo. VPN = valor predictivo negativo.
- 45. Resultados:Resultados: Valores de Corte para EXCLUIR FQValores de Corte para EXCLUIR FQ TITULACION DE CLORO CONDUCTIVIDAD FQ No – FQ < 40 mmol / L DUDOSOS < 75 mmol / L Titulación de cloroConductividad Valor de corte (mmol/L) No-FQ (n=3457) No excluye FQ* (n=377) Sensibilidad (%) Especificidad (%) VPP (%) VPN (%) Kappa <85 3451 302 99.83 80.11 97.87 98.05 0.870 <80 3445 329 99.65 87.27 98.63 96.48 0.908 <75 † 3431 352 99.25 93.37 99.28 93.12 0.925 <70 3418 362 98.87 96.02 99.56 90.27 0.923 <65 3364 373 97.31 98.94 99.88 80.04 0.871 *Incluye sujetos positivos (>60 mmol/L Cl - ) y valores equívocos (40 -60 mmol/L Cl - ). † Mejor valor de corte. VPP= valor predictivo positivo, VPN = valor predictivo negativo.
- 46. Conclusiones Nuestro estudio en una gran muestra de pacientes (3834) demuestra que el método de conductividad para diagnóstico de FQ correlaciona con la titulación de Cl, discriminando adecuadamente los positivos de aquellos negativos. Valores de corte propuestos: a) Positivos ≥ 90 mmol/L ( > 60 mmol/L Cl / titulación ) b) Dudosos 75 – 90 mmol/L ( 40 a 60 mmol/L Cl / titulación) c) Negativos < 75 mmol/L ( < 40 mmol/L Cl / titulación ) Lezana y cols. J of Cystic Fibrosis 2003;2:1-7
- 48. Abordaje MultidisciplinarioAbordaje Multidisciplinario Objetivos del Equipo MultidisciplinarioObjetivos del Equipo Multidisciplinario • Promover y enfatizar la necesidad de crear conciencia de un manejo temprano y agresivo para prevenir el deterioro clínico del paciente • Proporcionar conocimiento y apoyo al paciente y su familia con herramientas que mejoren los tratamientos actuales y aseguren una mejor calidad y esperanza de vida.
- 49. Recommendaciones para Manejo Nutricional Rutinario • Medidas antropométricas en cada visita, incluir conducta alimentaria y preferencias • Prevención y riesgo de falla nutricional • Intervención temprana para pacientes con riesgo • Manejo agresivo de la falla nutricional • Dosis óptimas de enzimas pancreáticas • Dieta con contenido normal de grasa y TCM • Vigilancia de complicaciones GI Mantener Crecimiento y Nutrición: Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic Fibrosis. 1997.
- 50. Recomendaciones para el ManejoRecomendaciones para el Manejo Respiratorio RutinarioRespiratorio Rutinario • Intervención nutricional temprana, Enzimas sustitutivas, Inhaloterapia, Fisioterapia, DNasa • Tratamiento temprano de la infección pulmonar • Inmunizaciones completas • Cultivos cada 4 meses • Espirometría 2 veces al año y Pletismografía anual American Academy of Pediatrics. Red Book. 2003. Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic Fibrosis. 1997. Mantener la función pulmonar:
- 51. Lineamientos GeneralesLineamientos Generales Curr Opin Pulm Med 2003 Tratamiento respiratorio: Inhaloterapia/fisioterapia B2, mucolíticos Dnasa, antibióticos Tratamiento digestivo: Dieta Enzimas pancreáticas Vitaminas liposolubles Otros: Suplementación de electrolitos Manejo de la complicaciones
- 52. Fibrosis Quística Manejo del Proceso Infeccioso Pulmonar Los Antibióticos, utilizados en Fibrosis Quística desde 1959, han mejorado de manera dramática el pronostico y las espectativas de vida en los pacientes. Curr Opin Pulm Med 2003
- 53. Evolución de la Infección porEvolución de la Infección por Ps.aeruginosaPs.aeruginosa Curr Opin Pulm Med 2003 Cultivo de Ps. aeruginosa en la vía aérea Negativo Intermitente Crónico Ac. séricos Ps.a. Adaptación genética de Ps.a. ¿ Selección clonal Ps.a. Ps.a. mucoide Nacimiento Cultivos + - Cultivos +
- 54. Patogénesis de la Infección porPatogénesis de la Infección por Ps.aeruginosaPs.aeruginosa Hipótesis de losHipótesis de los eventos patogénicoseventos patogénicos que conducen a laque conducen a la colonización crónicacolonización crónica porpor Ps. aeruginosa.Ps. aeruginosa. Am J Respir Crit Care Med 2003
- 55. Objetvios del Tratamiento AntimicrobianoObjetvios del Tratamiento Antimicrobiano Curr Opin Pulm Med 2003 Reducción en la carga bacteriana Disminuir marcadores de inflamación Mejoría en las PFR Mejoría en la condición clínica Disminución en la migración de PMN Reducción en la carga bacteriana Biosíntesis de factores de virulencia y alginato Disminuir marcadores de inflamación Disminución en la producción de elastasa
- 56. Manejo Inicial de la InfecciónManejo Inicial de la Infección Asintomática porAsintomática por P. aeruginosaP. aeruginosa Colonización temprana por Ps aeruginosa Ciprofloxacina + TOBI 2 semanas Cultivo + Ps a Ciprofloxaciona + TOBI 3 meses Colonización sintomática por Ps a Tratamiento IV 14 a 21 días Am J Respir Crit Care Med 2003
- 57. Clínica de Exacerbación PulmonarClínica de Exacerbación Pulmonar Am J Respir Crit Care Med 2003 Incremento de la tos.Incremento de la tos. Incremento en la producción de esputo o cambio en suIncremento en la producción de esputo o cambio en su apariencia.apariencia. Pérdida de peso > 5% o disminución en la ingesta.Pérdida de peso > 5% o disminución en la ingesta. Incremento en el trabajo respiratorio.Incremento en el trabajo respiratorio. Disminución en la tolerancia al ejercicio.Disminución en la tolerancia al ejercicio. Nuevos hallazgos en el examen físico y la Rx de tórax.Nuevos hallazgos en el examen físico y la Rx de tórax. DisminuciónDisminución ≥≥ 10% en el VEF1 con respecto al valor previo.10% en el VEF1 con respecto al valor previo. Disminución en la saturación de O2Disminución en la saturación de O2 ≥≥ 10% del valor previo.10% del valor previo. FiebreFiebre ≥≥ 38 grados C.38 grados C.
- 58. Exacerbación Leve a ModeradaExacerbación Leve a Moderada Am J Respir Crit Care Med 2003 Staphylococcus aureusStaphylococcus aureus DicloxacilinaDicloxacilina CefalexinaCefalexina Amoxicilina/ClavulanatoAmoxicilina/Clavulanato ClindamicinaClindamicina Haemophilus influenzaeHaemophilus influenzae AmoxicilinaAmoxicilina Amoxicilina/ClavulanatoAmoxicilina/Clavulanato CefuroximaCefuroxima CefiximaCefixima LoracarbefLoracarbef
- 59. Exacerbación Leve a ModeradaExacerbación Leve a Moderada Am J Respir Crit Care Med 2003 Pseudomonas aeruginosaPseudomonas aeruginosa CiprofloxacinaCiprofloxacina ++ Tobramicina inhaladaTobramicina inhalada Colistin inhaladoColistin inhalado Burkholderia cepaciaBurkholderia cepacia Trimetoprim/sulfametoxazolTrimetoprim/sulfametoxazol DoxiciclinaDoxiciclina MinociclinaMinociclina
- 60. Exacerbación Moderada a GraveExacerbación Moderada a Grave Am J Respir Crit Care Med 2003 Staphylococcus aureusStaphylococcus aureus Cefazolina o Dicloxacilina,Cefazolina o Dicloxacilina, Vancomicina,Vancomicina, Linezolid.Linezolid. Pseudomonas aeruginosaPseudomonas aeruginosa CeftazidimaCeftazidima Ticarcilina TobramicinaTicarcilina Tobramicina Piperacilina + AmikacinaPiperacilina + Amikacina Imipenem GentamicinaImipenem Gentamicina MeropenemMeropenem AztreonamAztreonam Multirresistente + Ciprofloxacina Multirresistente + Ciprofloxacina
- 61. Excerbación Moderada a Grave Burkholderia cepaciaBurkholderia cepacia MinociclinaMinociclina AmikacinaAmikacina Meropenem + CeftazidimaMeropenem + Ceftazidima CloranfenicolCloranfenicol SM/TMSM/TM TobramicinaTobramicina Multirresistente Meropenem + Tobramicina + Ceftazidima SMX/TMP Cloranfenicol Aztreonam Am J Respir Crit Care Med 2003
- 62. Excerbación Moderada a GraveExcerbación Moderada a Grave Stenotrophomonas malthop.Stenotrophomonas malthop. Achromobacter xylosoxidansAchromobacter xylosoxidans Ticarcilina/Clavulanato + Aztreonam, SMX/TMPTicarcilina/Clavulanato + Aztreonam, SMX/TMP Cloranfenicol + MinociclinaCloranfenicol + Minociclina Ciprofloxacina + Imipenem oCiprofloxacina + Imipenem o MeropenemMeropenem Am J Respir Crit Care Med 2003
- 64. Terapias para Disminuír la Inflamación Pulmonar en FQ • Inhibir señales pro-inflamatoriasInhibir señales pro-inflamatorias – Cytoquinas: TNF, IL-1Cytoquinas: TNF, IL-1 – Quimioatrayentes: IL-8, LTBQuimioatrayentes: IL-8, LTB44, C5a, C5a • Inhibir la respuesta de PMNInhibir la respuesta de PMN – ActivacionActivacion – Adhesión: CD11b/CD18, ICAM-1Adhesión: CD11b/CD18, ICAM-1 • Neutralizando productos de PMNNeutralizando productos de PMN – Elastasa y otras proteasasElastasa y otras proteasas – AntiOxidantes; B caroteno, glutatiónAntiOxidantes; B caroteno, glutatión – DNA y actina (DNasa y Gelsolin)DNA y actina (DNasa y Gelsolin) Konstan MW, et al. Adv Drug Deliv Rev. 2002.
- 65. Propiedades Anti-inflamatorias de los Corticosteroides Efecto en genes blancoEfecto en genes blanco Efectos fisiológicos FQEfectos fisiológicos FQ ↓ IL-1, TNF-α, GM-CSF ↓ IL-3, IL-4, IL-5, IL-8 ↓ Citoquinas-mediadas por inflamación ↓ Fosfolipasa A2 ↓ Ciclooxigenasa tipo 2 ↑ Lipocortina-1 ↓ Prostaglandinas ↓ Leukotrienos ↓ Moléculas de adhesión Reducen la infiltración de PMN ↑ Endonucleasas Inducción de apoptosis en linfocitos y eosinófilos Adapted from: Janeway CA, et al. Immunobiology. c2001.
- 66. Prednisona en FQ Autores Auerbach Eigen Duración del estudio 4 a. 4 a. Número de sujetos 45 285 Edad, años 1-12 6-14 Dósis mg/kg/día 2 1 Pronóstico ↑ Función pulmonar ↑ Crecimiento ↓ Hospitalizaciones ↑ Función pulmonar ↓ Crecimiento ↔ Hospitalizationes Efectos adversosEfectos adversos NingunoNinguno Retardo en crecimeintoRetardo en crecimeinto diabetes, y cataratasdiabetes, y cataratas Auerbach HS, et al. Lancet. 1985. Eigen H, et al. J Pediatr. 1995.
- 67. Función Pulmonar (VEF1%) en Terapia con Prednisona PlaceboPlacebo 1 mg/kg1 mg/kg 2 mg/kg2 mg/kg PP ** Final delFinal del estudioestudio 7676 8585 7676 0.040.04 6-7 años6-7 años despuésdespués 7171 7171 6666 0.510.51 Lai H-C, et al. N Engl J Med. 2000.* Dosis baja vs dosis alta o placebo
- 68. Conclusiones en Relación a la Terapia con Prednisona en FQ • Proporciona cierto beneficio en la funciónProporciona cierto beneficio en la función pulmonar durante el tratamientopulmonar durante el tratamiento • El beneficio desaparece al descontinuarlaEl beneficio desaparece al descontinuarla • Los efectos adversos serios limitan su usoLos efectos adversos serios limitan su uso • Los efectos adversos persisten al descontinuarlaLos efectos adversos persisten al descontinuarla • El riesgo de la terapia con esteroide sistémicoEl riesgo de la terapia con esteroide sistémico sobrepasa el beneficio en pacientes con FQsobrepasa el beneficio en pacientes con FQ
- 69. Pueden los Esteroides Inhalados ser una Buena Alternativa • Su uso se ha incrementado (25% to 45%)Su uso se ha incrementado (25% to 45%) • No se ha demostrado su eficacia para retardar laNo se ha demostrado su eficacia para retardar la progresión del daño pulmonarprogresión del daño pulmonar – Estudios de corta duración, con muestra pequeña deEstudios de corta duración, con muestra pequeña de pacientes y no controladospacientes y no controlados • No se ha establecido su perfil de seguridadNo se ha establecido su perfil de seguridad • Se requieren estudios para evaluar eficacia y seguridadSe requieren estudios para evaluar eficacia y seguridad Dezateux C, et al. Cochrane Database Syst Rev. 2000.
- 70. Ibuprofeno • Inhibe la activación, adhesión, quimiotaxis yInhibe la activación, adhesión, quimiotaxis y degranulación de PMN (FN-degranulación de PMN (FN-κκB)B) • Efectivo en modelos animales con infecciónEfectivo en modelos animales con infección crónica porcrónica por PseudomonasPseudomonas • Efectivo en diversos estudios clínicos enEfectivo en diversos estudios clínicos en pacientes con FQpacientes con FQ • Mayor seguridad que los esteroides sistémicosMayor seguridad que los esteroides sistémicos
- 71. Estudio Clínico Ibuprofeno • 2-años randomizado, doble- ciego, placebo-controlado multicéntrico • 145 pacientes: 6-18 años, FEV1 >60% predictivo • Ibuprofeno 20-30 mg/kg BID vs placebo • Variable primaria: tasa de cambio annual en la función pulmonar (FEV1 y FVC) Lands LC, et al. 16th Annual NACFC. 2002. –4 –3 –2 –1 0 Ibuprofeno Placebo P <0.05 P = 0.14 FEV1 FVC Tasadedescensoannual(%pred)
- 72. Efecto del TratamientoEfecto del Tratamiento Antinflamatorio con IbuprofenoAntinflamatorio con Ibuprofeno Konstan MW, et al. N Engl J Med. 1995. Ibuprofeno Placebo 0 -1 1 -2 -3 -4 FEV1 Peso Ideal CaídaAnnualFEV1(%/año) * * *P = .02 ibuprofen vs placebo • 85 pacientes (5-39 años) • Enf. Pulmonar leve (FEV1 ≥60% predictivo) • Dosis 20-30 mg/kg/dosis durante 4 años
- 73. Barreras Potenciales para el Uso de Ibuprofeno • El efecto benéfico en la función pulmonar noEl efecto benéfico en la función pulmonar no está completamente aceptadoestá completamente aceptado • SeguridadSeguridad • Pobre adherencia puede incrementar laPobre adherencia puede incrementar la migración de PMNmigración de PMN • Establecer la dosis individual por pruebas deEstablecer la dosis individual por pruebas de farmacocinética es complejofarmacocinética es complejo Konstan M, et al. N Engl J Med. 1995. Konstan M, et al. J Pediatr. 1991.
- 74. Efecto Anti-inflamatorio de la rhDNasa N = 105 Media edad 11.8 a. FEV1 >80% N = 46; rhDNase 2.5 mg/2 N = 39; sin tratamiento N = 20; controles N = 85; PMN Basal elevados N = 20; PMN Basal normales 3 años •• LBA al ingreso, 18 months, and 36 monthsLBA al ingreso, 18 months, and 36 months •• Variables: neutrofilos, IL-8, elastasa, mieloperoxidasa,Variables: neutrofilos, IL-8, elastasa, mieloperoxidasa, FEVFEV11, FVC, FEF, FVC, FEF25-7525-75 Paul K, et al. Am J Respir Crit Care Med. 2004.
- 75. Paul K, et al. Am J Respir Crit Care Med. 2004. Efecto de la rhDNasa en la Inflamación Tratamiento con rhDNase Sin tratamiento 0 10 20 30 40 50 60 70 PMN(%) 0 0.2 0.4 0.6 0.8 1 1.2 IL-8(ng/mL) 0 0.01 0.02 0.03 0.04 0.05 0.06 0.07 Elastasa(U) PMN % IL-8 Elastasa P <0.02P <0.02 P <0.007 NS NS NS 0 3 0 3 0 3 0 3 0 3 0 3 Año Año Año
- 76. –4 –3 –2 –1 0Tasadedeterioroanual(%pred/año n = 20 n = 46 n = 39 Paul K, et al. Am J Respir Crit Care Med. 2004. Efecto de la rhDNasa en el FEV1 Control rhDNasa-tratados Sin tratamiento
- 77. Efecto de la Dornase Alfa en la Función Pulmonar y RiesgoEfecto de la Dornase Alfa en la Función Pulmonar y Riesgo de Exacerbaciones en Pacientes con FQ y Enfermedadde Exacerbaciones en Pacientes con FQ y Enfermedad Pulmonar Leve (239 pacientes)Pulmonar Leve (239 pacientes) Quan JM, et al. J Pediatr. 2001. Dornasa Alfa Placebo CambioenFEV1 (%predictivodesdeelbasal 5 0 12 24 36 48 60 72 84 96 Semanas –5 –4 –3 –2 –1 0 1 2 3 4 70 75 80 85 90 95 100 0 12 24 36 48 60 72 84 96 Semanas %libredeexacerbaciones * P = .006 vs placebo † P = .048 vs placebo * †
- 78. -10 -5 0 5 10 15 20 Cambio%predictivoFEV1 14.1% 5.5% 15.9% –7.2% 5.5% –2.6% 10.3% 14.3% 4.5% Efecto de la Terapia Supresiva conTobramicinaEfecto de la Terapia Supresiva conTobramicina Inhalada para Infección Crónica porInhalada para Infección Crónica por P. aeruginosaP. aeruginosa Tobramicina Placebo 6-12 n=113 13-17 n=120 ≥18 n=229 6-12 n=36 13-17 n=26 ≥18 n=49 Semana 20 del estudio controlado Semana 92 de exposición Grupos de Edad PP=0.08=0.08 PP<0.001<0.001 PP<0.001<0.001 Moss RB, et al.: 13th Annual NACFC. 1999.
- 79. Dr. José Luis Lezana-Fernández,Dr. José Luis Lezana-Fernández, Dr. Mario H. Vargas, Dr. José Karam-Dr. Mario H. Vargas, Dr. José Karam- Bechara, Dra. Ruth S. Aldana-Vergara, Dra. María E.Y. Furuya.Bechara, Dra. Ruth S. Aldana-Vergara, Dra. María E.Y. Furuya. Asociación Mexicana de Fibrosis Quística, A.CAsociación Mexicana de Fibrosis Quística, A.C Hospital Infantil de México Federico GómezHospital Infantil de México Federico Gómez Hospital de Pediatría, Centro Médico Nacional Siglo XXI, IMSSHospital de Pediatría, Centro Médico Nacional Siglo XXI, IMSS Tasa de deterioro anual de la funciónTasa de deterioro anual de la función respiratoria en pacientes con fibrosis quísticarespiratoria en pacientes con fibrosis quística
- 80. La afección pulmonar es la principal causa de morbi-La afección pulmonar es la principal causa de morbi- mortalidad en FQ.mortalidad en FQ. Su extensión y progresión varían ampliamente de unSu extensión y progresión varían ampliamente de un individuo a otro.individuo a otro. La evaluación periódica de la función pulmonar esLa evaluación periódica de la función pulmonar es fundamental en el manejo y seguimiento de FQ.fundamental en el manejo y seguimiento de FQ. El VEFEl VEF11 es el parámetroes el parámetro que mejor predice laque mejor predice la morbi-mortalidad.morbi-mortalidad. VEF1 Capacidadvital 1 seg AntecedentesAntecedentes
- 81. ObjetivosObjetivos Conocer la tasa anual de deterioro delConocer la tasa anual de deterioro del VEFVEF11 (volumen espiratorio forzado en el(volumen espiratorio forzado en el primer segundo) en una población deprimer segundo) en una población de pacientes con fibrosis quística.pacientes con fibrosis quística. Identificar los factores asociados a laIdentificar los factores asociados a la tasatasa de deterioro del VEFde deterioro del VEF11 y a la supervivencia.y a la supervivencia.
- 82. 388 pacientes 66 2222 EDAD (años)EDAD (años) 1010 1414 1818 VEF1 inicial Excluidos 241 pacientes 178 perdidos o fallecidos 63 sin espirometría <11 años 1987 - 20021987 - 2002 Incluidos 147 pacientesIncluidos 147 pacientes Material y métodosMaterial y métodos 2 a 14 años de seguimiento2 a 14 años de seguimiento
- 83. ResultadosResultados TotalTotal No. pacientesNo. pacientes 147 Edad de Dx.Edad de Dx. 4.0 ± 0.2 Edad 1Edad 1erer VEFVEF11 7.3 ± 0.1 Años seg.Años seg. 6.9 ± 0.3 Estudios/añoEstudios/año 4.8 ± 0.3 Insuf. pancreáticaInsuf. pancreática 82 % Ileo meconialIleo meconial 7 % promedio ± EE 5,896 estudios espirométricos revisados TotalTotal Genotipo:Genotipo: 119119 ∆∆ F508/F508/ ∆∆ F508F508 16 % ∆∆ F508/ otroF508/ otro 45 % otro/otrootro/otro 40 % Ps. aeruginosaPs. aeruginosa 83 % Staph. aureusStaph. aureus 30 % FallecimientosFallecimientos 25 %
- 84. Descenso anual global del VEFDescenso anual global del VEF11 CaídaCaída anualanual No.No. pac.pac. SeguimientSeguimient oo (x años)(x años) SitioSitio AutoresAutores -2 % 215 4 Cleveland, EUA Davis y col. 1997 -3 % 344 13 Toronto, Canadá Corey y col. 1997 -2.6 % 81 10 Holanda Dankert–Roelse 1995 -3.47*-3.47* 147 6.9 México Lezana y col. * - 3.47 ± 0.16 % (- 0.46 a -11.0 %)
- 85. Factores que afectan el VEFFactores que afectan el VEF11 inicialinicial (promedio(promedio ±± EE)EE) CondiciónCondición nn VEFVEF11 al ingresoal ingreso pp P. aeruginosaP. aeruginosa ++ -- 115115 3232 70.7970.79 ± 1.85± 1.85 90.87 ± 2.3390.87 ± 2.33 < 10< 10-8-8 Funciòn pancreáticaFunciòn pancreática insuficienteinsuficiente suficientesuficiente 121121 2626 70.9970.99 ± 1.76± 1.76 94.56 ± 2.2294.56 ± 2.22 < 10< 10-7-7 GéneroGénero femeninofemenino masculinomasculino 7070 7777 70.3570.35 ± 2.28± 2.28 79.53 ± 2.3379.53 ± 2.33 0.0060.006 Ileo meconialIleo meconial ++ -- 1111 136136 51.9951.99 ± 3.37± 3.37 77.03 ± 1.6977.03 ± 1.69 < 10< 10-4-4
- 86. CondiciónCondición nn VEFVEF11 al ingresoal ingreso pp GenotipoGenotipo ΔΔ F508/F508/ΔΔ F508F508 ΔΔ F508/otroF508/otro otro/otrootro/otro 1919 5353 4747 61.68 ± 4.5461.68 ± 4.54 73.98 ± 2.7473.98 ± 2.74 81.63 ± 2.7881.63 ± 2.78 0.048*0.048* 0.0006*0.0006* * Comparado con* Comparado con ΔΔ F508/F508/ ΔΔ F508F508 Factores que afectan el VEFFactores que afectan el VEF11 inicialinicial (promedio(promedio ±± EE)EE)
- 87. Dr. José Luis Lezana-Fernández, Dr.Rodolfo Boites-Velarde, MC AlfonsoDr. José Luis Lezana-Fernández, Dr.Rodolfo Boites-Velarde, MC Alfonso Reyes, Dr. Miguel Angel Lezana-FernándezReyes, Dr. Miguel Angel Lezana-Fernández Análisis Epidemiológico en 521 Pacientes conAnálisis Epidemiológico en 521 Pacientes con Fibrosis Quística desde 1982Fibrosis Quística desde 1982
- 88. Análisis EpidemiológicoAnálisis Epidemiológico en 521 Pacientes Mexicanosen 521 Pacientes Mexicanos Sobrevida promedioSobrevida promedio FemeninoFemenino MasculinoMasculino 16.5 años (0-23 a.)16.5 años (0-23 a.) 14.9 años (0-21 a.)14.9 años (0-21 a.) 18.1 años (0-23 a.)18.1 años (0-23 a.) 0.040.04 Edad promedio DxEdad promedio Dx FemeninoFemenino MasculinoMasculino 2.85 a. (2.59-3.11 a.)2.85 a. (2.59-3.11 a.) 2.96 a. (2.59-3.33 a.)2.96 a. (2.59-3.33 a.) 2.73 a. (2.36-3.10 a.)2.73 a. (2.36-3.10 a.) NSNS GéneroGénero FemeninoFemenino MasculinoMasculino 254 pacientes254 pacientes 267 pacientes267 pacientes NSNS Ileo meconialIleo meconial 52 (9.9 %)52 (9.9 %)
- 89. Análisis EpidemiológicoAnálisis Epidemiológico en 521 Pacientes Mexicanosen 521 Pacientes Mexicanos InsuficientesInsuficientes pancreáticospancreáticos 83.9 % (411)83.9 % (411) 490 est. disponibles490 est. disponibles Ps. aeruginosaPs. aeruginosa 60 % (285)60 % (285) 475 est. disponibles475 est. disponibles Edo. Nutricional (490)Edo. Nutricional (490) 00 11 22 33 145 (29.1%)145 (29.1%) 156 (31.3%*)156 (31.3%*) 121 (24.2%*)121 (24.2%*) 77 (15.4%*)77 (15.4%*) * 71% de los pacientes con desnutrición al ingreso* 71% de los pacientes con desnutrición al ingreso
- 90. Análisis Epidemiológico; Estado Nutricional-Análisis Epidemiológico; Estado Nutricional- Función Pancreática (490 pacientes)Función Pancreática (490 pacientes) % Desnutrición% Desnutrición (490 pacientes)(490 pacientes) IPIP SPSP TotalTotal 00 11 22 33 53.1% (76)53.1% (76) 92.6% (138)92.6% (138) 99.2% (120)99.2% (120) 100.0% (77)100.0% (77) 46.9% (67)46.9% (67) 7.4% (11)*7.4% (11)* 0.8% (1)*0.8% (1)* 0.0% (0)*0.0% (0)* 143143 149149 121121 7777 TOTALTOTAL 83.9% (411)83.9% (411) 16.1% (79)16.1% (79) 490490 ** PP <0.005<0.005
- 91. Análisis Epidemiológico; Estado Nutricional-Análisis Epidemiológico; Estado Nutricional- Cultivo +Cultivo + Ps. aeruginosaPs. aeruginosa (474 pacientes)(474 pacientes) 57.6% de los pacientes con IP tuvieron cultivos positivos57.6% de los pacientes con IP tuvieron cultivos positivos parapara Ps. aeruginosaPs. aeruginosa. Solamente el 2.1% de los SP con cultivo. Solamente el 2.1% de los SP con cultivo positivo.positivo. % Desnutrición% Desnutrición (474 pacientes)(474 pacientes) CultivoCultivo negativonegativo CultivoCultivo positivopositivo TOTALTOTAL 00 11 22 33 109 (76.2%)109 (76.2%) 56 (39.2%)56 (39.2%) 15 (13.2%)15 (13.2%) 10 (13.5%)10 (13.5%) 34 (23.8%)*34 (23.8%)* 87 (60.8%)*87 (60.8%)* 99 (86.8%)*99 (86.8%)* 64 (86.5%)*64 (86.5%)* 143143 143143 114114 7474 TOTALTOTAL ** PP <0.005<0.005 190 (40.1%)190 (40.1%) 284 (59.9%)284 (59.9%) 474 (100%)474 (100%)
- 92. Análisis Epidemiológico;Análisis Epidemiológico; Estado Nutricional-GéneroEstado Nutricional-Género (499 pacientes)(499 pacientes) % Desnutrición% Desnutrición (499 pacientes)(499 pacientes) MasculinoMasculino FemeninoFemenino TOTALTOTAL 00 11 22 33 81 (55.9%)81 (55.9%) 81 (51.9%)81 (51.9%) 48 (39.7%)48 (39.7%) 35 (45.5%)35 (45.5%) 64 (44.1%)*64 (44.1%)* 75 (48.1%)*75 (48.1%)* 73 (60.3%)*73 (60.3%)* 42 (54.1%)*42 (54.1%)* 145145 156156 121121 7777 TOTALTOTAL ** PP 0.0490.049 245 (49.1%)245 (49.1%) 254 (50.9%)254 (50.9%) 499 (100%)499 (100%)
- 93. Análisis Epidemiológico; Función deAnálisis Epidemiológico; Función de Supervivencia (general y por género)Supervivencia (general y por género)
- 94. Análisis Epidemiológico; Función deAnálisis Epidemiológico; Función de Supervivencia (IP e infección porSupervivencia (IP e infección por PseudomonasPseudomonas))
- 95. 1.0 0.8 0.6 0.4 0.2 0 ProbabilidaddeSobrevida 0 10 20 30 40 50 60 Edad (Años) Ileo Meconial Screening Historia familiar Síntomas El DiagnosticoTemprano Mejora la Sobrevida Lai HJ, et al. Am J Epidemiol. 2004.
Hinweis der Redaktion
- CF Diagnosis and Newborn Screening Cystic fibrosis (CF) is carried as an autosomal recessive trait and affects about 1 in 2500 Caucasian newborns. CF is characterized by viscous mucous secretions that become difficult to clear and disrupt the normal function of organs, particularly the lungs and pancreas. In the lung, these abnormal secretions foster a vicious cycle of airway obstruction, infection, and inflammation that results in irreversible changes such as bronchiectasis. Early diagnosis allows early intervention to prevent or delay progression of disease and the development of associated complications. Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science. 1992;256:774-779. Tiddens HA. Detecting early structural lung damage in cystic fibrosis. Pediatr Pulmonol. 2002;34:228-231.
- CF Diagnosis and Newborn Screening Cystic fibrosis (CF) is carried as an autosomal recessive trait and affects about 1 in 2500 Caucasian newborns. CF is characterized by viscous mucous secretions that become difficult to clear and disrupt the normal function of organs, particularly the lungs and pancreas. In the lung, these abnormal secretions foster a vicious cycle of airway obstruction, infection, and inflammation that results in irreversible changes such as bronchiectasis. Early diagnosis allows early intervention to prevent or delay progression of disease and the development of associated complications. Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science. 1992;256:774-779. Tiddens HA. Detecting early structural lung damage in cystic fibrosis. Pediatr Pulmonol. 2002;34:228-231.
- Cystic Fibrosis Cystic fibrosis (CF) is a genetic disease caused by defects in a single gene inherited in an autosomal recessive manner. The frequency of CF varies across ethnic groups. It is most common in populations of Northern European descent, in which approximately 1 in 25 individuals are heterozygote carriers of the defective gene and 1 in 2500 newborns are affected by CF. CF is a multisystem disease with a wide spectrum of severity. It primarily affects the respiratory tract; however, most patients also have gastrointestinal involvement (eg, pancreatic insufficiency, intestinal obstruction at birth, and/or liver disease) and fertility complications, especially males. CF is a progressive disease, the most salient feature of which is chronic respiratory disease, which is characterized by abnormally thick airway secretions colonized with bacterial species including S aureus, H influenzae, and most commonly, P aeruginosa. This presentation will discuss aspects of the molecular genetics and pathophysiology of CF; however, it is important to realize that the clinical manifestations and complications were identified before the precise determination of the gene locus and the DNA sequence/mutations that produce the disease. We are now better able to explain, through mutational analysis, the clinical features and broad clinical spectrum of CF, including less severe “variants” of CF. Ratjen F, Doring G. Cystic fibrosis. Lancet. 2003;361:681-689. Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science. 1992;256:774-779.
- Cystic Fibrosis Cystic fibrosis (CF) is a genetic disease caused by defects in a single gene inherited in an autosomal recessive manner. The frequency of CF varies across ethnic groups. It is most common in populations of Northern European descent, in which approximately 1 in 25 individuals are heterozygote carriers of the defective gene and 1 in 2500 newborns are affected by CF. CF is a multisystem disease with a wide spectrum of severity. It primarily affects the respiratory tract; however, most patients also have gastrointestinal involvement (eg, pancreatic insufficiency, intestinal obstruction at birth, and/or liver disease) and fertility complications, especially males. CF is a progressive disease, the most salient feature of which is chronic respiratory disease, which is characterized by abnormally thick airway secretions colonized with bacterial species including S aureus, H influenzae, and most commonly, P aeruginosa. This presentation will discuss aspects of the molecular genetics and pathophysiology of CF; however, it is important to realize that the clinical manifestations and complications were identified before the precise determination of the gene locus and the DNA sequence/mutations that produce the disease. We are now better able to explain, through mutational analysis, the clinical features and broad clinical spectrum of CF, including less severe “variants” of CF. Ratjen F, Doring G. Cystic fibrosis. Lancet. 2003;361:681-689. Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science. 1992;256:774-779.
- CF Transmembrane Conductance Regulator Protein: CFTR The gene responsible for CF was sequenced in 1989. It is located on chromosome 7, in band q31. This gene encodes a protein product called the cystic fibrosis transmembrane conductance regulator (CFTR). The CFTR gene is large, spanning ~250 kB of DNA and comprising 27 exons (top, dark bands), with a messenger RNA transcript of ~6.5 kB. The predicted protein product (bottom) shows strong resemblance to known membrane-associated proteins and is likely involved in transmembrane ion transport, hence its designation, “cystic fibrosis transmembrane conductance regulator” (CFTR). The structure and function of the CFTR protein and its role in the pathophysiology of CF are discussed in greater detail in the following slides. Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science . 1989;245(4922):1066-1073. Rommens JM, Iannuzzi MC, Kerem B, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science . 1989;245(4922):1059-1065. Kerem B, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science . 1989;245(4922):1073-1080.
- Genetics of CFTR More than 1000 mutations in the CFTR gene have now been identified.The most common mutation is designated Δ F508 , which accounts for approximately 70% of all CF alleles. A deletion of 3 base pairs in exon 10 results in the loss of the normally present phenylalanine (amino acid code F) at position 508 in the protein. Ratjen F, Doring G. Cystic fibrosis. Lancet. 2003;361:681-689.
- CFTR Protein The CFTR protein is a 1480 amino acid polypeptide which, in its mature form, has a molecular weight of approximately 170 kD. It is a member of the ATP-binding cassette (ABC) superfamily, which includes other ATPases. CFTR is expressed primarily in epithelial cells lining exocrine glands, with the highest expression in the pancreas, salivary glands, sweat glands, intestine, and reproductive tract. The CFTR protein comprises: 2 hydrophobic 6-span membrane-spanning domains (MSD), 2 cytoplasmic nucleotide-binding domains that bind and hydrolyze ATP, and A large, highly charged, central domain predicted to contain several cyclic AMP-dependent protein kinase (PKA) phosphorylation targets and therefore designated the regulatory, or R, unit The R unit is unique to CFTR, although the general structure of the CFTR protein is similar to that of other ABC superfamily members. The unfolded CFTR polypeptide is N-glycosylated in the endoplasmic reticulum and folded into its tertiary structure. The glycosylation groups are further modified in the Golgi apparatus to form the mature protein, which localizes primarily to the apical cell membrane. CFTR is also present and active in intracellular membranes. Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245(4922):1066-1073. Ratjen F, Doring G. Cystic fibrosis. Lancet. 2003;361:681-689. Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science. 1992;256:774-779. Vankeerberghen A, Cuppens H, Cassiman JJ. The cystic fibrosis transmembrane conductance regulator: an intriguing protein with pleiotropic functions. J Cyst Fibros. 2002;1:13-29.
- Molecular Consequences of CFTR Mutations CF mutations result in the loss of functional CFTR and can be classified into 6 groups, 5 of which are shown here with examples: Class I mutations result in CFTR not being synthesized at all, for example: Nonsense mutation G542X: the codon for glycine (G) at position 542 is replaced with a STOP codon (X), resulting in premature termination of protein translation. Frameshift mutation 394delTT: deletion of 2 T nucleotides from position 394, resulting in a frameshift during mRNA translation leading to premature termination of the protein. Splice junction mutation 1717-1G A: a nucleotide change from G to A at 1717-1, resulting in an mRNA splicing defect and failure to synthesize the protein. Class II mutations cause defective processing of CFTR. Amino acid deletion Δ F508: this classic mutation involves deletion of 3 base pairs in exon 10, resulting in loss of phenylalanine (F) at position 508 (in the first nucleotide-binding domain) leading to defective processing of CFTR in the endoplasmic reticulum and, ultimately, to intracellular degradation. Class III mutations block regulation of CFTR activity. Missense mutation G551D: glycine (G) at position 551 changes to aspartic acid (D). Class IV mutations alter the conductive properties of CFTR. Missense mutation R117H: arginine (R) at position 482 changes to histidine (H). Class V mutations reduce the level of CFTR protein synthesis. Missense mutation A455E: alanine (A) at position 455 changes to glutamic acid (E). Alternative splicing mutation 3849+10kbC T: a nucleotide change from C to T in a fragment 10kB from exon 19, resulting in creation of a splice acceptor site leading to alternative mRNA splicing. Class VI mutations (not shown) alter the ability of CFTR to regulate other proteins. The nature of the underlying CFTR mutation can influence the phenotype of CF. For example, class I, II, and III mutations are associated with pancreatic insufficiency, whereas class IV to VI are not; class IV mutations are generally associated with a relatively mild phenotype. Vankeerberghen A, Cuppens H, Cassiman JJ. The cystic fibrosis transmembrane conductance regulator: an intriguing protein with pleiotropic functions. J Cyst Fibros. 2002;1:13-29. Cystic fibrosis mutation database at http://www.genet.sickkids.on.ca/cftr/
- Physiologic Properties of CFTR CFTR has pleiotropic functions in the regulation of epithelial physiology. CFTR acts as an ion channel with a high specificity for chloride ions. The regulation of CFTR chloride channel activity is complex, involving phosphorylation of the R domain and subsequent binding of ATP to the nucleotide-binding domains. Hydrolysis of ATP by the nucleotide-binding domains causes the chloride channel to open, allowing chloride ions to flow according to the electrochemical gradient across the membrane. CFTR is also a negative regulator of the amiloride-sensitive epithelial sodium channel (ENaC). In the presence of CFTR, stimulation of ENaC by cAMP causes a reduction in sodium channel activity, resulting in reduced epithelial absorption of sodium ions. CFTR is involved in the regulation of endosomal pH. CFTR is involved in chloride transport across intracellular membranes, resulting in the acidification of organelles such as the Golgi, prelysosomes, and endosomes that is necessary for their normal activity. CFTR also interacts with a wide variety of other cellular proteins, including other ion and fluid channels, and other transporter proteins. Wild-type CFTR may also interact directly with P aeruginosa to eradicate infection. Mutant CFTR, however, may be capable of binding to the bacteria but unable to degrade them. Thus, mutant CFTR may encourage bacterial colonization in the airways. Ratjen F, Doring G. Cystic fibrosis. Lancet. 2003;361:681-689. Pier GB. CFTR mutations and host susceptibility to Pseudomonas aeruginosa lung infection. Curr Opin Microbiol . 2002;5:81-86 .
- Physiologic Properties of CFTR CFTR has pleiotropic functions in the regulation of epithelial physiology. CFTR acts as an ion channel with a high specificity for chloride ions. The regulation of CFTR chloride channel activity is complex, involving phosphorylation of the R domain and subsequent binding of ATP to the nucleotide-binding domains. Hydrolysis of ATP by the nucleotide-binding domains causes the chloride channel to open, allowing chloride ions to flow according to the electrochemical gradient across the membrane. CFTR is also a negative regulator of the amiloride-sensitive epithelial sodium channel (ENaC). In the presence of CFTR, stimulation of ENaC by cAMP causes a reduction in sodium channel activity, resulting in reduced epithelial absorption of sodium ions. CFTR is involved in the regulation of endosomal pH. CFTR is involved in chloride transport across intracellular membranes, resulting in the acidification of organelles such as the Golgi, prelysosomes, and endosomes that is necessary for their normal activity. CFTR also interacts with a wide variety of other cellular proteins, including other ion and fluid channels, and other transporter proteins. Wild-type CFTR may also interact directly with P aeruginosa to eradicate infection. Mutant CFTR, however, may be capable of binding to the bacteria but unable to degrade them. Thus, mutant CFTR may encourage bacterial colonization in the airways. Ratjen F, Doring G. Cystic fibrosis. Lancet. 2003;361:681-689. Pier GB. CFTR mutations and host susceptibility to Pseudomonas aeruginosa lung infection. Curr Opin Microbiol . 2002;5:81-86 .
- Cystic Fibrosis Cystic fibrosis (CF) is a genetic disease caused by defects in a single gene inherited in an autosomal recessive manner. The frequency of CF varies across ethnic groups. It is most common in populations of Northern European descent, in which approximately 1 in 25 individuals are heterozygote carriers of the defective gene and 1 in 2500 newborns are affected by CF. CF is a multisystem disease with a wide spectrum of severity. It primarily affects the respiratory tract; however, most patients also have gastrointestinal involvement (eg, pancreatic insufficiency, intestinal obstruction at birth, and/or liver disease) and fertility complications, especially males. CF is a progressive disease, the most salient feature of which is chronic respiratory disease, which is characterized by abnormally thick airway secretions colonized with bacterial species including S aureus, H influenzae, and most commonly, P aeruginosa. This presentation will discuss aspects of the molecular genetics and pathophysiology of CF; however, it is important to realize that the clinical manifestations and complications were identified before the precise determination of the gene locus and the DNA sequence/mutations that produce the disease. We are now better able to explain, through mutational analysis, the clinical features and broad clinical spectrum of CF, including less severe “variants” of CF. Ratjen F, Doring G. Cystic fibrosis. Lancet. 2003;361:681-689. Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science. 1992;256:774-779.
- Prevalence of F508 Mutation Varies in Ethnic Groups The mutation detection rate varies across ethnic groups depending on the frequencies of the common mutations used in the mutational analysis screen. This slide shows the prevalence of the F508 mutation across different ethnic groups in the US. F508 is most prevalent among Caucasians, comprising 70% of the CF mutations in this group. The prevalence rate drops to 48% for African Americans and to 46% for Hispanics. The mutation is least prevalent among Asian Americans and Ashkenazi Jews, where it constitutes only 30% of the CF mutations. Delayed CF diagnosis has been reported in children of ethnic minorities. Customizing mutation analysis screens might improve genotyping sensitivity in different ethnic backgrounds, although this is not yet routine clinical practice. Wang D, Freedman SD. Laboratory tests for the diagnosis of cystic fibrosis. Am J Clin Pathol . 2002;117:S109-S115.
- Prevalence of F508 Mutation Varies in Ethnic Groups The mutation detection rate varies across ethnic groups depending on the frequencies of the common mutations used in the mutational analysis screen. This slide shows the prevalence of the F508 mutation across different ethnic groups in the US. F508 is most prevalent among Caucasians, comprising 70% of the CF mutations in this group. The prevalence rate drops to 48% for African Americans and to 46% for Hispanics. The mutation is least prevalent among Asian Americans and Ashkenazi Jews, where it constitutes only 30% of the CF mutations. Delayed CF diagnosis has been reported in children of ethnic minorities. Customizing mutation analysis screens might improve genotyping sensitivity in different ethnic backgrounds, although this is not yet routine clinical practice. Wang D, Freedman SD. Laboratory tests for the diagnosis of cystic fibrosis. Am J Clin Pathol . 2002;117:S109-S115.
- Prevalence of F508 Mutation Varies in Ethnic Groups The mutation detection rate varies across ethnic groups depending on the frequencies of the common mutations used in the mutational analysis screen. This slide shows the prevalence of the F508 mutation across different ethnic groups in the US. F508 is most prevalent among Caucasians, comprising 70% of the CF mutations in this group. The prevalence rate drops to 48% for African Americans and to 46% for Hispanics. The mutation is least prevalent among Asian Americans and Ashkenazi Jews, where it constitutes only 30% of the CF mutations. Delayed CF diagnosis has been reported in children of ethnic minorities. Customizing mutation analysis screens might improve genotyping sensitivity in different ethnic backgrounds, although this is not yet routine clinical practice. Wang D, Freedman SD. Laboratory tests for the diagnosis of cystic fibrosis. Am J Clin Pathol . 2002;117:S109-S115.
- Cystic Fibrosis Cystic fibrosis (CF) is a genetic disease caused by defects in a single gene inherited in an autosomal recessive manner. The frequency of CF varies across ethnic groups. It is most common in populations of Northern European descent, in which approximately 1 in 25 individuals are heterozygote carriers of the defective gene and 1 in 2500 newborns are affected by CF. CF is a multisystem disease with a wide spectrum of severity. It primarily affects the respiratory tract; however, most patients also have gastrointestinal involvement (eg, pancreatic insufficiency, intestinal obstruction at birth, and/or liver disease) and fertility complications, especially males. CF is a progressive disease, the most salient feature of which is chronic respiratory disease, which is characterized by abnormally thick airway secretions colonized with bacterial species including S aureus, H influenzae, and most commonly, P aeruginosa. This presentation will discuss aspects of the molecular genetics and pathophysiology of CF; however, it is important to realize that the clinical manifestations and complications were identified before the precise determination of the gene locus and the DNA sequence/mutations that produce the disease. We are now better able to explain, through mutational analysis, the clinical features and broad clinical spectrum of CF, including less severe “variants” of CF. Ratjen F, Doring G. Cystic fibrosis. Lancet. 2003;361:681-689. Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science. 1992;256:774-779.
- CF Diagnosis and Newborn Screening Cystic fibrosis (CF) is carried as an autosomal recessive trait and affects about 1 in 2500 Caucasian newborns. CF is characterized by viscous mucous secretions that become difficult to clear and disrupt the normal function of organs, particularly the lungs and pancreas. In the lung, these abnormal secretions foster a vicious cycle of airway obstruction, infection, and inflammation that results in irreversible changes such as bronchiectasis. Early diagnosis allows early intervention to prevent or delay progression of disease and the development of associated complications. Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science. 1992;256:774-779. Tiddens HA. Detecting early structural lung damage in cystic fibrosis. Pediatr Pulmonol. 2002;34:228-231.
- Role of Inflammation in the Pathophysiology of CF Lung Disease This schematic is a representation of the pathophysiology of cystic fibrosis (CF) lung disease. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The expression of a defective or deficient CFTR protein disrupts the flow of ions across epithelial cell membranes in the airways, leading to impaired water movement across the membrane, the formation of thick mucus secretions, and an abnormal airway surface environment. This thick, viscous mucus obstructs the bronchi and promotes bacterial infection, which provokes a robust inflammatory response by the immune system. Inflammatory cells, especially neutrophils, infiltrate the airways and contribute to further bronchial obstruction when they degenerate and release DNA and actin into the airways. In addition, neutrophils release elastase, which in excess causes cellular damage to lung tissue. Repeated cycles of bronchial obstruction, infection, and inflammation (curved arrows) eventually lead to permanent structural lung damage and bronchiectasis. Konstan MW, Berger M. Current understanding of the inflammatory process in cystic fibrosis —onset and etiology. Pediatr Pulmonol. 24:137-142, 1997.
- The Lung in Cystic Fibrosis Airway obstruction, infection, and inflammation can be seen in this histologic slide from a CF patient. Thick, viscous secretions obstruct the lumen of this airway. On higher magnification, bacteria could be seen in these secretions and at the surface of the epithelium. Neutrophils are visible in the lumen, as well as in the peribronchial space. The alveoli are relatively spared, even in this patient with advanced disease. Photo courtesy of M. Konstan.
- The Role of Neutrophils in CF Airway Disease The inflammatory response is provoked by an initial infection or an intrinsic predisposition of CF airways to inflammation and results in the infiltration of the airways by polymorphonuclear (PMN) cells (click for animation), such as neutrophils, which secrete elastase (click), a proteolytic enzyme. PMNs release chemoattractants, LTB 4 and IL-8 (click), which recruit more PMN to the airways (click). PMNs also release DNA and oxidants, O 2 – and H 2 O 2 , which lead to the plugging of airways and to structural damage, respectively. Elastase contributes to the pathophysiology of CF lung disease in several ways: Direct inhibition of mucociliary clearance (because it is a potent mucus secretagogue) (click) Destruction of elastin in airway walls (click) Degradation of immunoglobulins and complement fragments critical to the opsonophagocytosis (engulfment and destruction) of bacteria Synthesis of IL-8 (click) Konstan MW, Berger M. Current understanding of the inflammatory process in cystic fibrosis —onset and etiology. Pediatr Pulmonol. 1997;24:137-142.
- CF Diagnosis and Newborn Screening Cystic fibrosis (CF) is carried as an autosomal recessive trait and affects about 1 in 2500 Caucasian newborns. CF is characterized by viscous mucous secretions that become difficult to clear and disrupt the normal function of organs, particularly the lungs and pancreas. In the lung, these abnormal secretions foster a vicious cycle of airway obstruction, infection, and inflammation that results in irreversible changes such as bronchiectasis. Early diagnosis allows early intervention to prevent or delay progression of disease and the development of associated complications. Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science. 1992;256:774-779. Tiddens HA. Detecting early structural lung damage in cystic fibrosis. Pediatr Pulmonol. 2002;34:228-231.
- Diagnosis of CF Cystic fibrosis experts developed a consensus statement establishing guidelines for the diagnosis of CF. A CF diagnosis can be established if a patient has: One or more of the typical phenotypic features described (slide 3) OR a sibling with CF, which gives the patient a 1 in 4 chance of having CF Half-siblings are also at risk for CF and should be clinically monitored and, if appropriate, sweat tested OR a positive newborn screening (NBS) These infants may be asymptomatic, but a positive NBS test is highly predictive of CF disease PLUS laboratory evidence of cystic fibrosis transmembrane regulator protein (CFTR) abnormality (1 of the following): Elevated sweat chloride concentration of >60 mmol/L (or >40 mmol/L if under 3 months old) on 2 separate occasions OR the presence of 2 identified CFTR mutations OR abnormal ion transport across the nasal epithelium detected by nasal potential difference (PD) testing Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. J Pediatr . 1998;132:589-595.
- Typical Phenotypic Features of CF Typically, affected patients exhibit chronic sinopulmonary disease, involving persistent colonization or infection with Staphylococcus aureus , Haemophilus influenzae , Pseudomonas aeruginosa, and/or Burkholderia cepacia . There may also be evidence of nasal polyps or digital clubbing. Gastrointestinal abnormalities may be present, such as chronic hepatobiliary disease manifested by biliary or multilobular cirrhosis, pancreatic insufficiency, or meconium ileus at birth. Salt-loss syndromes may produce elevated sweat chloride values. Most males with CF have obstructive azoospermia (lack of spermatozoa in the semen as a result of congenital bilateral absence of the vas deferens). In atypical CF, disease symptoms are less severe and fewer organ systems are affected. In particular, atypical patients are pancreatic sufficient and may have normal or slightly elevated borderline sweat chloride values. Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic Fibrosis. 1997. Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. J Pediatr . 1998;132:589-595. Knowles MR, Durie PR. What is cystic fibrosis? N Engl J Med . 2002;347:439-442.
- Diagnosis of CF Cystic fibrosis experts developed a consensus statement establishing guidelines for the diagnosis of CF. A CF diagnosis can be established if a patient has: One or more of the typical phenotypic features described (slide 3) OR a sibling with CF, which gives the patient a 1 in 4 chance of having CF Half-siblings are also at risk for CF and should be clinically monitored and, if appropriate, sweat tested OR a positive newborn screening (NBS) These infants may be asymptomatic, but a positive NBS test is highly predictive of CF disease PLUS laboratory evidence of cystic fibrosis transmembrane regulator protein (CFTR) abnormality (1 of the following): Elevated sweat chloride concentration of >60 mmol/L (or >40 mmol/L if under 3 months old) on 2 separate occasions OR the presence of 2 identified CFTR mutations OR abnormal ion transport across the nasal epithelium detected by nasal potential difference (PD) testing Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. J Pediatr . 1998;132:589-595.
- Diagnosis of CF Cystic fibrosis experts developed a consensus statement establishing guidelines for the diagnosis of CF. A CF diagnosis can be established if a patient has: One or more of the typical phenotypic features described (slide 3) OR a sibling with CF, which gives the patient a 1 in 4 chance of having CF Half-siblings are also at risk for CF and should be clinically monitored and, if appropriate, sweat tested OR a positive newborn screening (NBS) These infants may be asymptomatic, but a positive NBS test is highly predictive of CF disease PLUS laboratory evidence of cystic fibrosis transmembrane regulator protein (CFTR) abnormality (1 of the following): Elevated sweat chloride concentration of >60 mmol/L (or >40 mmol/L if under 3 months old) on 2 separate occasions OR the presence of 2 identified CFTR mutations OR abnormal ion transport across the nasal epithelium detected by nasal potential difference (PD) testing Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. J Pediatr . 1998;132:589-595.
- Diagnosis of CF Cystic fibrosis experts developed a consensus statement establishing guidelines for the diagnosis of CF. A CF diagnosis can be established if a patient has: One or more of the typical phenotypic features described (slide 3) OR a sibling with CF, which gives the patient a 1 in 4 chance of having CF Half-siblings are also at risk for CF and should be clinically monitored and, if appropriate, sweat tested OR a positive newborn screening (NBS) These infants may be asymptomatic, but a positive NBS test is highly predictive of CF disease PLUS laboratory evidence of cystic fibrosis transmembrane regulator protein (CFTR) abnormality (1 of the following): Elevated sweat chloride concentration of >60 mmol/L (or >40 mmol/L if under 3 months old) on 2 separate occasions OR the presence of 2 identified CFTR mutations OR abnormal ion transport across the nasal epithelium detected by nasal potential difference (PD) testing Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. J Pediatr . 1998;132:589-595.
- Diagnosis of CF Cystic fibrosis experts developed a consensus statement establishing guidelines for the diagnosis of CF. A CF diagnosis can be established if a patient has: One or more of the typical phenotypic features described (slide 3) OR a sibling with CF, which gives the patient a 1 in 4 chance of having CF Half-siblings are also at risk for CF and should be clinically monitored and, if appropriate, sweat tested OR a positive newborn screening (NBS) These infants may be asymptomatic, but a positive NBS test is highly predictive of CF disease PLUS laboratory evidence of cystic fibrosis transmembrane regulator protein (CFTR) abnormality (1 of the following): Elevated sweat chloride concentration of >60 mmol/L (or >40 mmol/L if under 3 months old) on 2 separate occasions OR the presence of 2 identified CFTR mutations OR abnormal ion transport across the nasal epithelium detected by nasal potential difference (PD) testing Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. J Pediatr . 1998;132:589-595.
- Diagnosis of CF Cystic fibrosis experts developed a consensus statement establishing guidelines for the diagnosis of CF. A CF diagnosis can be established if a patient has: One or more of the typical phenotypic features described (slide 3) OR a sibling with CF, which gives the patient a 1 in 4 chance of having CF Half-siblings are also at risk for CF and should be clinically monitored and, if appropriate, sweat tested OR a positive newborn screening (NBS) These infants may be asymptomatic, but a positive NBS test is highly predictive of CF disease PLUS laboratory evidence of cystic fibrosis transmembrane regulator protein (CFTR) abnormality (1 of the following): Elevated sweat chloride concentration of >60 mmol/L (or >40 mmol/L if under 3 months old) on 2 separate occasions OR the presence of 2 identified CFTR mutations OR abnormal ion transport across the nasal epithelium detected by nasal potential difference (PD) testing Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. J Pediatr . 1998;132:589-595.
- Diagnosis of CF Cystic fibrosis experts developed a consensus statement establishing guidelines for the diagnosis of CF. A CF diagnosis can be established if a patient has: One or more of the typical phenotypic features described (slide 3) OR a sibling with CF, which gives the patient a 1 in 4 chance of having CF Half-siblings are also at risk for CF and should be clinically monitored and, if appropriate, sweat tested OR a positive newborn screening (NBS) These infants may be asymptomatic, but a positive NBS test is highly predictive of CF disease PLUS laboratory evidence of cystic fibrosis transmembrane regulator protein (CFTR) abnormality (1 of the following): Elevated sweat chloride concentration of >60 mmol/L (or >40 mmol/L if under 3 months old) on 2 separate occasions OR the presence of 2 identified CFTR mutations OR abnormal ion transport across the nasal epithelium detected by nasal potential difference (PD) testing Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. J Pediatr . 1998;132:589-595.
- Chest X-Ray May Not Detect Early Lung Damage Although lung damage can precede a decline in lung function, early lung damage may not always be detectable on standard chest x-rays (CXRs). This slide shows 2 CXRs of a 7-year-old CF patient and pictures of the patient’s severely damaged lung. The extent of lung damage is not evident in the CXRs. This case demonstrates that CXR may not be sensitive to early structural changes in CF lung disease. Photos courtesy of M. Woo.
- CT Scans Detect Damage Before Decline in Lung Function Structural lung damage can occur well before the onset of decline in lung function. This slide shows a high-resolution computed tomography (HRCT) scan of the lungs of a CF patient. Note the dotted occlusions in the left lung and larger areas of opacity in the right lung. Despite the presence of these abnormalities, this patient had normal spirometry (FEV 1 99%; FVC 92%; FEF 25-75 95% of predicted). This observation confirms that structural lung damage precedes the deterioration of lung function and suggests that HRCT can detect early changes in lung structure. Furthermore, monitoring lung health solely by pulmonary function tests may not accurately reflect progressive lung disease. Without an accurate assessment of lung disease progression, the initiation of therapies may be delayed. Tiddens HA. Detecting early structural lung disease in cystic fibrosis. Pediatr Pulmonol. 2002;34:228-231.
- CF Diagnosis and Newborn Screening Cystic fibrosis (CF) is carried as an autosomal recessive trait and affects about 1 in 2500 Caucasian newborns. CF is characterized by viscous mucous secretions that become difficult to clear and disrupt the normal function of organs, particularly the lungs and pancreas. In the lung, these abnormal secretions foster a vicious cycle of airway obstruction, infection, and inflammation that results in irreversible changes such as bronchiectasis. Early diagnosis allows early intervention to prevent or delay progression of disease and the development of associated complications. Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science. 1992;256:774-779. Tiddens HA. Detecting early structural lung damage in cystic fibrosis. Pediatr Pulmonol. 2002;34:228-231.
- DNA Mutational Analysis Mutations in CFTR result in defective Cl – and Na + transport across epithelial membranes, producing viscous mucous secretions that can disrupt normal organ function. Over 1000 mutations have been identified, and the number continues to grow. The F508 mutation of this gene accounts for 70% of all CF mutant alleles. 15 to 20 other common mutations account for 2% to 15% of CF mutant alleles. DNA mutational analysis screens for the F508 and other common CF gene mutations. A screen of 70 common CF mutations achieves 90% sensitivity in the US Caucasian population. Non-Caucasian patients may require a separate panel of alleles to be screened. A variety of test panels are available for commercial or research use. An infant who has 2 copies of the same mutation on each of his/her chromosomes or 1 copy of 2 different mutations on each chromosome is likely to have CF. DNA testing also identifies infants with a mutation on only 1 chromosome (ie, carriers). Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. J Pediatr. 1998;132:589-595. Wang D, Freedman SD. Laboratory tests for the diagnosis of cystic fibrosis. Am J Clin Pathol. 2002;117:S109-S115.
- Evidence of CFTR Abnormality: Nasal Potential Difference The nasal potential difference (NPD) test detects abnormal ion transport across the nasal epithelium. Nasal epithelia regulate the transport of ions across the membrane, which in turn generates an electrical potential that can be measured. CF causes ion transport abnormalities that yield a different pattern of NPD than normal ion transport. The following 3 abnormalities of nasal ion transport characterize CF: A higher basal NPD generated by a relative increase in sodium transport and decrease in chloride transport across the membrane (although an absence of raised NPD does not rule out CF) A greater inhibition of the NPD after nasal perfusion with amiloride, a sodium channel blocker, reflecting an inhibition of the accelerated sodium transport Unchanged NPD after perfusion of the nasal epithelium with a chloride- free solution coupled with the beta agonist isoproterenol (this reflects the reduction or absence of CFTR-dependent chloride secretion) Like the sweat test, NPD measurements should be repeated on at least 2 separate occasions. Figures redrawn from Rosenstein BJ, Cutting GR. The diagnosis of cystic fibrosis: a consensus statement. J Pediatr . 1998;132:589-595, with permission from Elsevier. Wang D, Freedman SD. Laboratory tests for the diagnosis of cystic fibrosis. Am J Clin Pathol . 2002;117:S109-S115.
- Evidence of CFTR Abnormality: Sweat Test A qualitative sweat test is a nondiagnostic screening test for CF. A positive or borderline result warrants quantitative testing. Examples of qualitative tests are the Wescor Sweat Chek conductivity analyzer, the Advanced Instruments conductivity analyzer, the Orion skin electrode for chloride, the Scandipharm CF Indicator System chloride patch, and sweat osmolality measurements. The pilocarpine iontophoresis test (QPIT) is a quantitative sweat test. Collected sweat is weighed, and the chloride or sodium concentration is quantified. <40 mmol/L = negative; 40-59 = borderline; >60 = positive ( however, healthy adults can have concentrations >60 mmol/L) Minimum sweat weight required is 75 mg obtained over 30 minutes (to ensure an average sweat rate >1 g/m 2 /min). False positive rate: up to 15% CF diagnosis should be based on at least 2 positive sweat test results. Approximately 98% of patients with CF have sweat chloride concentrations >60 mmol/L. When concentrations are <60 mmol/L, diagnosis can be confirmed by genotype, nasal potential difference testing, or clinical presentation. LeGrys VA. Sweat testing for the diagnosis of cystic fibrosis: practical considerations J Pediatr . 1996;129:892-897. Farrell PM, Koscik RE. Sweat chloride concentrations in infants homozygous or heterozygous for F508 cystic fibrosis. Pediatrics . 1996;97:524-528.
- CF Diagnosis and Newborn Screening Cystic fibrosis (CF) is carried as an autosomal recessive trait and affects about 1 in 2500 Caucasian newborns. CF is characterized by viscous mucous secretions that become difficult to clear and disrupt the normal function of organs, particularly the lungs and pancreas. In the lung, these abnormal secretions foster a vicious cycle of airway obstruction, infection, and inflammation that results in irreversible changes such as bronchiectasis. Early diagnosis allows early intervention to prevent or delay progression of disease and the development of associated complications. Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science. 1992;256:774-779. Tiddens HA. Detecting early structural lung damage in cystic fibrosis. Pediatr Pulmonol. 2002;34:228-231.
- Goals of CF Care Goals of the multidisciplinary team approach: The first goal of care emphasizes the need to change the culture in CF treatment from being reactive to proactive to focus on preventing health status decline. The second goal recognizes that the success of treatment depends on the patient and family understanding the significance of prevention and having the knowledge and tools to successfully implement these early strategies.
- Recommendations for Routine Care and Screening The clinical practice guidelines developed by the CFF highlight the importance of maintaining growth and nutrition in the routine care of infants and children with CF. Routine care should incorporate frequent assessment of growth and nutrition, including behavioral issues associated with eating, and screening for nutritional risk to prevent nutritional failure. If needed, patients at risk should receive early intervention, and patients with nutritional failure should receive aggressive intervention. Optimal enzyme dosing should be maintained. Regular monitoring for gastrointestinal complications, including reflux and bacterial overgrowth, is also important. Attention should be paid to new abdominal symptoms such as nausea, vomiting, early satiety, or pain, which may indicate GI problems requiring further evaluation. Cystic Fibrosis Foundation. Clinical Practice Guidelines for Cystic Fibrosis. 1997.
- Recommendations for Routine Care and Screening Important components of routine medical care for children with CF include early intervention with therapies of known value (daily airway clearance, mucolytics, antibiotics, and nutritional supplementation) and early treatment of pulmonary infections. Immunization against respiratory pathogens can prevent respiratory complications. Certain vaccines, including pneumococcus, H influenzae, and influenza, are clearly indicated for infants with CF. Finally, quarterly surveillance for bacterial infection is recommended. More frequent surveillance cultures should be considered with illness or change in symptoms. Biannual pulmonary function testing is recommended. American Academy of Pediatrics. Influenza. In: Pickering LK, ed. Red Book: 2003 Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003:382-391. American Academy of Pediatrics. Pneumococcal infections. Ibid:490-500. American Academy of Pediatrics. Haemophilus influenzae infections. Ibid:293-301. Cystic Fibrosis Foundation. Clinical practice guidelines for cystic fibrosis . 1997.
- Why Is Infection Control Important? The life expectancy of patients with cystic fibrosis (CF) has increased steadily over the last 2 decades, and the predicted survival age is now 33.4 years. 1 Repeated respiratory infections are a primary concern for patients with CF, as cycles of infection and inflammation can damage the lungs and decrease lung function. 1 Acquisition of Pseudomonas aeruginosa (Pa) is associated with decreased survival. In addition, new pathogens are emerging as survival increases, and different patterns of infection are associated with this increase in survival. The use of multiple courses of antibiotics (oral, aerosol, IV) to treat infections may encourage the emergence of multidrug-resistant pathogens. 2 1 Cystic Fibrosis Foundation. Patient Registry Annual Data Report. 2002. Bethesda, Maryland. 2 Saiman L, Siegel J. Infection control in cystic fibrosis. Clin Microbiol Rev. 2004;17:57-71.
- CF Diagnosis and Newborn Screening Cystic fibrosis (CF) is carried as an autosomal recessive trait and affects about 1 in 2500 Caucasian newborns. CF is characterized by viscous mucous secretions that become difficult to clear and disrupt the normal function of organs, particularly the lungs and pancreas. In the lung, these abnormal secretions foster a vicious cycle of airway obstruction, infection, and inflammation that results in irreversible changes such as bronchiectasis. Early diagnosis allows early intervention to prevent or delay progression of disease and the development of associated complications. Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science. 1992;256:774-779. Tiddens HA. Detecting early structural lung damage in cystic fibrosis. Pediatr Pulmonol. 2002;34:228-231.
- Why Is Infection Control Important? The life expectancy of patients with cystic fibrosis (CF) has increased steadily over the last 2 decades, and the predicted survival age is now 33.4 years. 1 Repeated respiratory infections are a primary concern for patients with CF, as cycles of infection and inflammation can damage the lungs and decrease lung function. 1 Acquisition of Pseudomonas aeruginosa (Pa) is associated with decreased survival. In addition, new pathogens are emerging as survival increases, and different patterns of infection are associated with this increase in survival. The use of multiple courses of antibiotics (oral, aerosol, IV) to treat infections may encourage the emergence of multidrug-resistant pathogens. 2 1 Cystic Fibrosis Foundation. Patient Registry Annual Data Report. 2002. Bethesda, Maryland. 2 Saiman L, Siegel J. Infection control in cystic fibrosis. Clin Microbiol Rev. 2004;17:57-71.
- Why Is Infection Control Important? The life expectancy of patients with cystic fibrosis (CF) has increased steadily over the last 2 decades, and the predicted survival age is now 33.4 years. 1 Repeated respiratory infections are a primary concern for patients with CF, as cycles of infection and inflammation can damage the lungs and decrease lung function. 1 Acquisition of Pseudomonas aeruginosa (Pa) is associated with decreased survival. In addition, new pathogens are emerging as survival increases, and different patterns of infection are associated with this increase in survival. The use of multiple courses of antibiotics (oral, aerosol, IV) to treat infections may encourage the emergence of multidrug-resistant pathogens. 2 1 Cystic Fibrosis Foundation. Patient Registry Annual Data Report. 2002. Bethesda, Maryland. 2 Saiman L, Siegel J. Infection control in cystic fibrosis. Clin Microbiol Rev. 2004;17:57-71.
- Why Is Infection Control Important? The life expectancy of patients with cystic fibrosis (CF) has increased steadily over the last 2 decades, and the predicted survival age is now 33.4 years. 1 Repeated respiratory infections are a primary concern for patients with CF, as cycles of infection and inflammation can damage the lungs and decrease lung function. 1 Acquisition of Pseudomonas aeruginosa (Pa) is associated with decreased survival. In addition, new pathogens are emerging as survival increases, and different patterns of infection are associated with this increase in survival. The use of multiple courses of antibiotics (oral, aerosol, IV) to treat infections may encourage the emergence of multidrug-resistant pathogens. 2 1 Cystic Fibrosis Foundation. Patient Registry Annual Data Report. 2002. Bethesda, Maryland. 2 Saiman L, Siegel J. Infection control in cystic fibrosis. Clin Microbiol Rev. 2004;17:57-71.
- Effect of Anti-inflammatory Treatment with Ibuprofen Inflammation of the airways is another component of CF lung disease that can be targeted to improve patient outcomes. This 4-year, randomized, double-blind, placebo-controlled trial in 85 patients (aged 5-39 years) with mild CF lung disease (FEV 1 ≥60% of predicted) demonstrated that long-term, high-dose ibuprofen (20-30 mg/kg) significantly slowed the progression of lung function decline and preserved body weight. Progression of lung disease was measured by the annual rate of decline of FEV 1 , FVC, and FEF 25-75 Rate of change in body weight was measured relative to ideal body weight (IBW). Patients tolerated twice-daily treatment well. Conjunctivitis and epistaxis were the only adverse events reported. Abdominal pain, an adverse event usually associated with high-dose ibuprofen use, is a common symptom in CF and did not worsen in ibuprofen-treated patients, as compared with those receiving placebo. Both lung function and weight-for-age are factors predicting long-term survival of CF patients. In its ability to preserve lung function and body weight, ibuprofen may impact survival outcomes of CF patients. Konstan MW, Byard PJ, Hoppel CL, et al. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med. 1995;332:848-854.
- Effect of Anti-inflammatory Treatment with Ibuprofen Inflammation of the airways is another component of CF lung disease that can be targeted to improve patient outcomes. This 4-year, randomized, double-blind, placebo-controlled trial in 85 patients (aged 5-39 years) with mild CF lung disease (FEV 1 ≥60% of predicted) demonstrated that long-term, high-dose ibuprofen (20-30 mg/kg) significantly slowed the progression of lung function decline and preserved body weight. Progression of lung disease was measured by the annual rate of decline of FEV 1 , FVC, and FEF 25-75 Rate of change in body weight was measured relative to ideal body weight (IBW). Patients tolerated twice-daily treatment well. Conjunctivitis and epistaxis were the only adverse events reported. Abdominal pain, an adverse event usually associated with high-dose ibuprofen use, is a common symptom in CF and did not worsen in ibuprofen-treated patients, as compared with those receiving placebo. Both lung function and weight-for-age are factors predicting long-term survival of CF patients. In its ability to preserve lung function and body weight, ibuprofen may impact survival outcomes of CF patients. Konstan MW, Byard PJ, Hoppel CL, et al. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med. 1995;332:848-854.
- Effect of Anti-inflammatory Treatment with Ibuprofen Inflammation of the airways is another component of CF lung disease that can be targeted to improve patient outcomes. This 4-year, randomized, double-blind, placebo-controlled trial in 85 patients (aged 5-39 years) with mild CF lung disease (FEV 1 ≥60% of predicted) demonstrated that long-term, high-dose ibuprofen (20-30 mg/kg) significantly slowed the progression of lung function decline and preserved body weight. Progression of lung disease was measured by the annual rate of decline of FEV 1 , FVC, and FEF 25-75 Rate of change in body weight was measured relative to ideal body weight (IBW). Patients tolerated twice-daily treatment well. Conjunctivitis and epistaxis were the only adverse events reported. Abdominal pain, an adverse event usually associated with high-dose ibuprofen use, is a common symptom in CF and did not worsen in ibuprofen-treated patients, as compared with those receiving placebo. Both lung function and weight-for-age are factors predicting long-term survival of CF patients. In its ability to preserve lung function and body weight, ibuprofen may impact survival outcomes of CF patients. Konstan MW, Byard PJ, Hoppel CL, et al. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med. 1995;332:848-854.
- Effect of Anti-inflammatory Treatment with Ibuprofen Inflammation of the airways is another component of CF lung disease that can be targeted to improve patient outcomes. This 4-year, randomized, double-blind, placebo-controlled trial in 85 patients (aged 5-39 years) with mild CF lung disease (FEV 1 ≥60% of predicted) demonstrated that long-term, high-dose ibuprofen (20-30 mg/kg) significantly slowed the progression of lung function decline and preserved body weight. Progression of lung disease was measured by the annual rate of decline of FEV 1 , FVC, and FEF 25-75 Rate of change in body weight was measured relative to ideal body weight (IBW). Patients tolerated twice-daily treatment well. Conjunctivitis and epistaxis were the only adverse events reported. Abdominal pain, an adverse event usually associated with high-dose ibuprofen use, is a common symptom in CF and did not worsen in ibuprofen-treated patients, as compared with those receiving placebo. Both lung function and weight-for-age are factors predicting long-term survival of CF patients. In its ability to preserve lung function and body weight, ibuprofen may impact survival outcomes of CF patients. Konstan MW, Byard PJ, Hoppel CL, et al. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med. 1995;332:848-854.
- Effect of Anti-inflammatory Treatment with Ibuprofen Inflammation of the airways is another component of CF lung disease that can be targeted to improve patient outcomes. This 4-year, randomized, double-blind, placebo-controlled trial in 85 patients (aged 5-39 years) with mild CF lung disease (FEV 1 ≥60% of predicted) demonstrated that long-term, high-dose ibuprofen (20-30 mg/kg) significantly slowed the progression of lung function decline and preserved body weight. Progression of lung disease was measured by the annual rate of decline of FEV 1 , FVC, and FEF 25-75 Rate of change in body weight was measured relative to ideal body weight (IBW). Patients tolerated twice-daily treatment well. Conjunctivitis and epistaxis were the only adverse events reported. Abdominal pain, an adverse event usually associated with high-dose ibuprofen use, is a common symptom in CF and did not worsen in ibuprofen-treated patients, as compared with those receiving placebo. Both lung function and weight-for-age are factors predicting long-term survival of CF patients. In its ability to preserve lung function and body weight, ibuprofen may impact survival outcomes of CF patients. Konstan MW, Byard PJ, Hoppel CL, et al. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med. 1995;332:848-854.
- Recommendations for Routine Care and Screening Important components of routine medical care for children with CF include early intervention with therapies of known value (daily airway clearance, mucolytics, antibiotics, and nutritional supplementation) and early treatment of pulmonary infections. Immunization against respiratory pathogens can prevent respiratory complications. Certain vaccines, including pneumococcus, H influenzae, and influenza, are clearly indicated for infants with CF. Finally, quarterly surveillance for bacterial infection is recommended. More frequent surveillance cultures should be considered with illness or change in symptoms. Biannual pulmonary function testing is recommended. American Academy of Pediatrics. Influenza. In: Pickering LK, ed. Red Book: 2003 Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003:382-391. American Academy of Pediatrics. Pneumococcal infections. Ibid:490-500. American Academy of Pediatrics. Haemophilus influenzae infections. Ibid:293-301. Cystic Fibrosis Foundation. Clinical practice guidelines for cystic fibrosis . 1997.
- Recommendations for Routine Care and Screening Important components of routine medical care for children with CF include early intervention with therapies of known value (daily airway clearance, mucolytics, antibiotics, and nutritional supplementation) and early treatment of pulmonary infections. Immunization against respiratory pathogens can prevent respiratory complications. Certain vaccines, including pneumococcus, H influenzae, and influenza, are clearly indicated for infants with CF. Finally, quarterly surveillance for bacterial infection is recommended. More frequent surveillance cultures should be considered with illness or change in symptoms. Biannual pulmonary function testing is recommended. American Academy of Pediatrics. Influenza. In: Pickering LK, ed. Red Book: 2003 Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003:382-391. American Academy of Pediatrics. Pneumococcal infections. Ibid:490-500. American Academy of Pediatrics. Haemophilus influenzae infections. Ibid:293-301. Cystic Fibrosis Foundation. Clinical practice guidelines for cystic fibrosis . 1997.
- CF Diagnosis and Newborn Screening Cystic fibrosis (CF) is carried as an autosomal recessive trait and affects about 1 in 2500 Caucasian newborns. CF is characterized by viscous mucous secretions that become difficult to clear and disrupt the normal function of organs, particularly the lungs and pancreas. In the lung, these abnormal secretions foster a vicious cycle of airway obstruction, infection, and inflammation that results in irreversible changes such as bronchiectasis. Early diagnosis allows early intervention to prevent or delay progression of disease and the development of associated complications. Collins FS. Cystic fibrosis: molecular biology and therapeutic implications. Science. 1992;256:774-779. Tiddens HA. Detecting early structural lung damage in cystic fibrosis. Pediatr Pulmonol. 2002;34:228-231.
- Approaches to Decreasing Inflammation in the CF Lung Several approaches can be taken to decrease inflammation in the CF lung, each targeting a different component of the inflammatory response. Pro-inflammatory signals, such as cytokine priming (TNF, IL-1) and chemoattractant secretion (IL-8, LTB 4 , C5a), can be inhibited; this prevents the inflammatory response from being amplified once it is initiated. Activation of PMN infiltration of the airways can be targeted for inhibition, as well as the adhesion of neutrophils to epithelial cells through adhesion molecules such as CD11b/CD18 and ICAM-1. Finally, the activities of PMN products, such as elastase and other proteases, oxidants, and DNA and actin can be neutralized. This would prevent substantial lung obstruction and structural damage. Konstan MW, Davis PB. Pharmacological approach for the discovery and development of new anti-inflammatory agents for the treatment of cystic fibrosis. Adv Drug Deliv Rev. 2002; 54:1409-1423.
- Anti-inflammatory Properties of Corticosteroids The anti-inflammatory properties of corticosteroids are conferred by their ability to directly modulate transcription of genes involved in the inflammatory response. Corticosteroids, after diffusion across the cell membrane, bind to corticosteroid receptors and, as a complex, translocate into the nucleus to regulate gene transcription. As a result, corticosteroids affect a large number of gene targets producing a variety of physiologic effects, including the suppression of cytokine-mediated inflammation, nitric oxide production, prostaglandin and leukotriene production, and PMN infiltration. Adapted from: Janeway CA, Travers P, Walport M, Shlomchik M. Immunobiology. 5th ed. New York and London: Garland Publishing; c2001.
- Prednisone Trials in CF Two clinical trials of prednisone therapy have been conducted in CF patients. Auerbach study: 4-year, randomized, double-blind, placebo-controlled study N = 45, ages 1 to 12 years Prednisone 2 mg/kg every other day (QOD) Improved pulmonary function and growth; fewer hospitalizations No adverse events Eigen study: 4-year, randomized, double-blind, placebo-controlled study N = 285, ages 6 to 14 years Prednisone 1 or 2 mg/kg QOD Improved pulmonary function; no reduction in hospitalizations Adverse events: growth retardation, diabetes, and cataracts Despite the same duration of therapy at similar doses, Auerbach documented increased growth, fewer hospitalizations, and no adverse events in prednisone-treated patients, while Eigen noted no change in rate of hospitalization and significant adverse events in the high-dose group, which led to the early termination of this treatment arm. The differences in treatment outcome may be accounted for by the sample size and/or differences in patient characteristics. Auerbach HS, Williams M, Kirkpatrick JA, Colten HR. Alternate-day prednisone reduces morbidity and improves pulmonary function in cystic fibrosis. Lancet . 1985;2:686-688. Eigen H, Rosenstein BJ, FitzSimmons S, Schidlow DV. A multicenter study of alternate-day prednisone therapy in patients with cystic fibrosis. Cystic Fibrosis Foundation Prednisone Trial Group. J Pediatr . 1995;126:515-523.
- Lung Function (FEV 1 % Predicted) After Prednisone Therapy In this same group of patients, lung function (FEV 1 , % predicted) is compared at the end of the study 1 and 6 to 7 years after prednisone was discontinued. 2 At the end of the Eigen study, FEV 1 was significantly better in the low-dose group as compared to both the high-dose and placebo groups ( P = 0.04). However, this difference was no longer evident 6 to 7 years following termination of prednisone therapy ( P = 0.51). 1 Eigen H, Rosenstein BJ, FitzSimmons S, Schidlow DV. A multicenter study of alternate-day prednisone therapy in patients with cystic fibrosis. Cystic Fibrosis Foundation Prednisone Trial Group. J Pediatr . 1995;126:515-523 2 Lai H-C, FitzSimmons SC, Allen DB, et al. Risk of persistent growth impairment after alternate-day prednisone treatment in children with cystic fibrosis. N Engl J Med . 2000;342:851-859.
- Summary of Systemic Prednisone Therapy in CF To summarize the conclusions drawn from studies of systemic prednisone therapy in CF patients: Prednisone therapy provides some benefits to lung function during treatment, resulting in significant preservation of FEV 1 and FVC. Unfortunately, these benefits do not persist after discontinuation of the drug. Indeed, there may be accelerated decline following drug discontinuation. It is currently unclear whether the benefit of this drug is not related to its anti-inflammatory effect but rather to an increase in -adrenergic response and an anti-airway reactivity effect. Severe adverse effects of drug therapy, including diabetes, cataracts, growth retardation, limit its use. Once initiated, these adverse effects, including growth failure in boys, tend to be long-lasting. The risks of systemic steroid therapy appear to outweigh the benefits for patients with CF. Auerbach HS, Williams M, Kirkpatrick JA, Colten HR. Alternate-day prednisone reduces morbidity and improves pulmonary function in cystic fibrosis. Lancet . 1985;2:686-688. Eigen H, Rosenstein BJ, FitzSimmons S, Schidlow DV. A multicenter study of alternate-day prednisone therapy in patients with cystic fibrosis. Cystic Fibrosis Foundation Prednisone Trial Group. J Pediatr . 1995;126:515-523. Lai H-C, FitzSimmons SC, Allen DB, et al. Risk of persistent growth impairment after alternate-day prednisone treatment in children with cystic fibrosis. N Engl J Med . 2000;342:851-859.
- Could Inhaled Corticosteroids Be a Good Alternative to Prednisone? Oral corticosteroid therapy, such as prednisone, can be beneficial to the preservation of lung function in CF patients, but the occurrence of serious adverse events limits its therapeutic utility. Could inhaled corticosteroids be a good alternative to prednisone? A recent systematic review of randomized, double-blind, controlled studies of beclomethasone, budesonide, or fluticasone concluded that: Efficacy in slowing the progression of lung disease was not demonstrated, in part due to the short duration and small sample size of several studies. A positive safety profile has not been established for any of these inhaled corticosteroids. Further studies are required to fully evaluate the efficacy and safety of inhaled corticosteroid therapy in CF patients. Dezateux C, Walters S, Balfour-Lynn I. Inhaled corticosteroids for cystic fibrosis. Cochrane Database Syst Rev . 2000;(2):CD001915.
- Rationale for Ibuprofen Use Ibuprofen provides an alternative anti-inflammatory approach to inhaled or systemic corticosteroids. What is the rationale for its use in CF? Ibuprofen inhibits the activation, adhesion, chemotaxis, and degranulation of PMN by inhibiting the activation of NF- B, the synthesis and release of cytokines and eicosanoids (prostaglandins and leukotrienes), and the expression of adhesion molecules on the PMN cell surface. Early research has demonstrated the efficacy of ibuprofen in attenuating inflammatory response in an animal model of chronic Pseudomonas infection. Subsequently, this efficacy was demonstrated in a 4-year clinical trial in CF patients, which will be discussed in upcoming slides. Because the occurrence of adverse events in this clinical trial was not significantly more frequent in the treated group (compared with placebo), ibuprofen is considered a safer alternative to systemic corticosteroids. Konstan MW, Vargo KM, Davis PB. Ibuprofen attenuates the inflammatory response to Pseudomonas aeruginosa in a rat model of chronic pulmonary infection. Implications for antiinflammatory therapy in cystic fibrosis Am Rev Respir Dis . 1990;141:186-192. Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med . 1995;332:848-854.
- The Trans-Canadian Ibuprofen Trial Lands and colleagues conducted a 2-year, randomized, double-blind, placebo-controlled, multicenter trial of ibuprofen use in 145 CF children 6 to 18 years of age with mild lung disease (FEV 1 >60% of predicted), who received either placebo or ibuprofen (20-30 mg/kg BID). The primary outcome measure was the annual rate of change in FEV 1 (% of predicted). As shown in the graph, the annual rate of decline in FVC, but not FEV 1 , was significantly reduced in the ibuprofen group, compared with the placebo group. The differences in results between this trial and the Konstan trial (Konstan MW, et al. N Engl J Med . 1995;332:848-854), which showed a significant reduction in the rate of decline in FEV 1 and FVC, may be due to the difference in study duration, the number of study participants, or the mean age of the study participants. Lands LC. 16th Annual NACFC. 2002.
- Effect of Anti-inflammatory Treatment with Ibuprofen Inflammation of the airways is another component of CF lung disease that can be targeted to improve patient outcomes. This 4-year, randomized, double-blind, placebo-controlled trial in 85 patients (aged 5-39 years) with mild CF lung disease (FEV 1 ≥60% of predicted) demonstrated that long-term, high-dose ibuprofen (20-30 mg/kg) significantly slowed the progression of lung function decline and preserved body weight. Progression of lung disease was measured by the annual rate of decline of FEV 1 , FVC, and FEF 25-75 Rate of change in body weight was measured relative to ideal body weight (IBW). Patients tolerated twice-daily treatment well. Conjunctivitis and epistaxis were the only adverse events reported. Abdominal pain, an adverse event usually associated with high-dose ibuprofen use, is a common symptom in CF and did not worsen in ibuprofen-treated patients, as compared with those receiving placebo. Both lung function and weight-for-age are factors predicting long-term survival of CF patients. In its ability to preserve lung function and body weight, ibuprofen may impact survival outcomes of CF patients. Konstan MW, Byard PJ, Hoppel CL, et al. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med. 1995;332:848-854.
- Potential Barriers to Ibuprofen Use Although evidence supports the use of ibuprofen in patients with mild disease (FEV 1 ≥60% of predicted), especially those <13 years of age, the overall rate of ibuprofen use across all CF centers nationwide is 4.7%. Potential barriers to ibuprofen use may include: Beneficial effect on lung function is not fully accepted by clinicians Concerns may persist regarding safety, although the clinical trial showed no significant increase in adverse events in ibuprofen-treated patients Poor adherence may actually increase PMN migration Pharmacokinetic assessment (drug concentrations) are logistically difficult but necessary to prevent overdosage Lack of marketing by pharmaceutical industry Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med . 1995;332:848-854. Konstan MW, Hoppel CL, Chai B, Davis PB. Ibuprofen in children with cystic fibrosis: pharmacokinetics and adverse effects. J Pediatr . 1991;118:956-964.
- Bronchoalveolar Lavage in the Evaluation of Anti-inflammatory Treatment: The BEAT Study To evaluate the effect of rhDNase on inflammatory markers and lung function, Paul and colleagues conducted a randomized study in CF patients (mean age 11.8 years) with mild lung disease (FEV 1 >80% of predicted). Patients (N = 105) were stratified based on neutrophil levels (elevated or normal) found at baseline bronchoalveolar lavage (BAL). Those with elevated baseline neutrophil levels (n = 85) were randomized to receive either rhDNase (2.5 mg QD; n = 46) or no treatment (n = 39) for 3 years. Patients with normal baseline neutrophil levels (n = 20) also received no treatment for 3 years. BAL was performed again at 18 months and 36 months of the study. Outcome measures included: Neutrophil levels IL-8, elastase, and myeloperoxidase levels Lung function (FEV 1 , FVC, and FEF 25-75 ) Paul K, Rietschel E, Ballmann M, et al. Effect of treatment with dornase alpha on airway inflammation in patients with cystic fibrosis. Am J Respir Crit Care Med . 2004;169:719-725.
- The BEAT Study: Effect of rhDNase on Inflammation Patients with elevated baseline neutrophil levels who were treated with rhDNase therapy for 3 years experienced no statistically significant changes in neutrophil, IL-8, and elastase levels. In contrast, patients with elevated baseline neutrophil levels who were not treated for 3 years experienced a significant increase in all of these inflammatory markers. Thus, rhDNase treatment stabilized inflammation in patients with elevated baseline neutrophil levels. Paul K, Rietschel E, Ballmann M, et al. Effect of treatment with dornase alpha on airway inflammation in patients with cystic fibrosis. Am J Respir Crit Care Med . 2004;169:719-725.
- The BEAT Study: Effect of rhDNase on FEV 1 Decline Although the rate of decline in FEV 1 was not significantly different between study groups, the rate of decline in FEV 1 of the untreated group (–3.26% of predicted/year) was greater than that of the control (–2.12% of predicted/year) and rhDNase-treated (–1.99% of predicted/year) groups. Taken together with the results of rhDNase treatment on inflammation, stabilization of inflammation in patients with elevated baseline neutrophils is associated with a rate of decline in FEV 1 similar to that of patients with normal baseline neutrophils. Paul K, Rietschel E, Ballmann M, et al. Effect of treatment with dornase alpha on airway inflammation in patients with cystic fibrosis. Am J Respir Crit Care Med . 2004;169:719-725.
- Effects of Dornase Alfa on Lung Function and RTEs in Patients with Mild CF This slide summarizes the effect of dornase alfa (2.5 mg QD) on lung function and the frequency of RTEs in 239 patients (mean age 8.3 ± 1.4 years) with mild CF (mean FEV 1 96% ± 15% of predicted) . Left: Mean change in FEV 1 from baseline during 96 weeks of dornase alfa or placebo. Patients in the treatment arm experienced an improvement in FEV 1 within the first 3 weeks of treatment. Mean treatment effect for the entire study period was 3.2% of predicted ( P = .006). Right: Kaplan-Meier survival curve of the percentage of patients in the dornase alfa and placebo groups who were free of RTEs during the 96 weeks of study. Overall, there was a 34% reduction in the risk of RTE in the dornase-treated group ( P = .048). The results of this study demonstrate the effectiveness of dornase alfa in reducing RTE events. Each RTE is equivalent to a 12% drop in FEV 1 , according to the Liou survivorship model. Thus, the use of dornase alfa may impact survival outcome of CF patients. Figures adapted from Quan JM, Tiddens HAWM, Sy JP, et al. A two-year, randomized, placebo-controlled trial of dornase alfa in young patients with cystic fibrosis with mild lung function abnormalities. J Pediatr . 2001;139:813-820, with permission from Elsevier.
- Effect of Inhaled Tobramycin Suppressive Therapy for Chronic P aeruginosa Infection Moss and colleagues conducted a multicenter, placebo-controlled study with an open-label, follow-on study to examine the effects of inhaled tobramycin suppressive therapy in patients chronically infected with P aeruginosa . Patients were stratified by age: child (6-12 years old; n = 113 ), adolescent (13-17 years; n = 120), or adult ( ≥18 years; n = 229) Patients received twice daily tobramycin (300 mg BID) or placebo in addition to all standard IV and oral antibiotic medications necessary for 24 weeks in a 28-days-on, 28-days-off schedule Subsequently, all patients received open-label tobramycin (300 mg BID) (in addition to all standard medications) for a maximum of 72 weeks in a 28-days-on, 28-days-off schedule At week 20 of the controlled trial, the FEV 1 treatment effect (mean change from week 0 relative to the placebo group) for the child, adolescent, and adult groups was 8.6% ( P = .08), 23.1% ( P < .001), and 8.1% ( P < .001), respectively. By 92 weeks, the treatment effect achieved in the child, adolescent, and adult groups was 10.3%, 14.3%, and –4.5%, respectively. Moss RB, Kylstra JW, Gibson R. Who benefits more? An analysis of FEV 1 and weight in adolescent (ages 13-17) CF patients using TOBI ® (Tobramycin Solution for Inhalation). Poster presented at: 13th Annual North American Cystic Fibrosis Conference; October 7-10, 1999; Seattle, WA.
- Prevalence of F508 Mutation Varies in Ethnic Groups The mutation detection rate varies across ethnic groups depending on the frequencies of the common mutations used in the mutational analysis screen. This slide shows the prevalence of the F508 mutation across different ethnic groups in the US. F508 is most prevalent among Caucasians, comprising 70% of the CF mutations in this group. The prevalence rate drops to 48% for African Americans and to 46% for Hispanics. The mutation is least prevalent among Asian Americans and Ashkenazi Jews, where it constitutes only 30% of the CF mutations. Delayed CF diagnosis has been reported in children of ethnic minorities. Customizing mutation analysis screens might improve genotyping sensitivity in different ethnic backgrounds, although this is not yet routine clinical practice. Wang D, Freedman SD. Laboratory tests for the diagnosis of cystic fibrosis. Am J Clin Pathol . 2002;117:S109-S115.
- Prevalence of F508 Mutation Varies in Ethnic Groups The mutation detection rate varies across ethnic groups depending on the frequencies of the common mutations used in the mutational analysis screen. This slide shows the prevalence of the F508 mutation across different ethnic groups in the US. F508 is most prevalent among Caucasians, comprising 70% of the CF mutations in this group. The prevalence rate drops to 48% for African Americans and to 46% for Hispanics. The mutation is least prevalent among Asian Americans and Ashkenazi Jews, where it constitutes only 30% of the CF mutations. Delayed CF diagnosis has been reported in children of ethnic minorities. Customizing mutation analysis screens might improve genotyping sensitivity in different ethnic backgrounds, although this is not yet routine clinical practice. Wang D, Freedman SD. Laboratory tests for the diagnosis of cystic fibrosis. Am J Clin Pathol . 2002;117:S109-S115.
- Prevalence of F508 Mutation Varies in Ethnic Groups The mutation detection rate varies across ethnic groups depending on the frequencies of the common mutations used in the mutational analysis screen. This slide shows the prevalence of the F508 mutation across different ethnic groups in the US. F508 is most prevalent among Caucasians, comprising 70% of the CF mutations in this group. The prevalence rate drops to 48% for African Americans and to 46% for Hispanics. The mutation is least prevalent among Asian Americans and Ashkenazi Jews, where it constitutes only 30% of the CF mutations. Delayed CF diagnosis has been reported in children of ethnic minorities. Customizing mutation analysis screens might improve genotyping sensitivity in different ethnic backgrounds, although this is not yet routine clinical practice. Wang D, Freedman SD. Laboratory tests for the diagnosis of cystic fibrosis. Am J Clin Pathol . 2002;117:S109-S115.
- Prevalence of F508 Mutation Varies in Ethnic Groups The mutation detection rate varies across ethnic groups depending on the frequencies of the common mutations used in the mutational analysis screen. This slide shows the prevalence of the F508 mutation across different ethnic groups in the US. F508 is most prevalent among Caucasians, comprising 70% of the CF mutations in this group. The prevalence rate drops to 48% for African Americans and to 46% for Hispanics. The mutation is least prevalent among Asian Americans and Ashkenazi Jews, where it constitutes only 30% of the CF mutations. Delayed CF diagnosis has been reported in children of ethnic minorities. Customizing mutation analysis screens might improve genotyping sensitivity in different ethnic backgrounds, although this is not yet routine clinical practice. Wang D, Freedman SD. Laboratory tests for the diagnosis of cystic fibrosis. Am J Clin Pathol . 2002;117:S109-S115.
- Prevalence of F508 Mutation Varies in Ethnic Groups The mutation detection rate varies across ethnic groups depending on the frequencies of the common mutations used in the mutational analysis screen. This slide shows the prevalence of the F508 mutation across different ethnic groups in the US. F508 is most prevalent among Caucasians, comprising 70% of the CF mutations in this group. The prevalence rate drops to 48% for African Americans and to 46% for Hispanics. The mutation is least prevalent among Asian Americans and Ashkenazi Jews, where it constitutes only 30% of the CF mutations. Delayed CF diagnosis has been reported in children of ethnic minorities. Customizing mutation analysis screens might improve genotyping sensitivity in different ethnic backgrounds, although this is not yet routine clinical practice. Wang D, Freedman SD. Laboratory tests for the diagnosis of cystic fibrosis. Am J Clin Pathol . 2002;117:S109-S115.
- Prevalence of F508 Mutation Varies in Ethnic Groups The mutation detection rate varies across ethnic groups depending on the frequencies of the common mutations used in the mutational analysis screen. This slide shows the prevalence of the F508 mutation across different ethnic groups in the US. F508 is most prevalent among Caucasians, comprising 70% of the CF mutations in this group. The prevalence rate drops to 48% for African Americans and to 46% for Hispanics. The mutation is least prevalent among Asian Americans and Ashkenazi Jews, where it constitutes only 30% of the CF mutations. Delayed CF diagnosis has been reported in children of ethnic minorities. Customizing mutation analysis screens might improve genotyping sensitivity in different ethnic backgrounds, although this is not yet routine clinical practice. Wang D, Freedman SD. Laboratory tests for the diagnosis of cystic fibrosis. Am J Clin Pathol . 2002;117:S109-S115.
- Prevalence of F508 Mutation Varies in Ethnic Groups The mutation detection rate varies across ethnic groups depending on the frequencies of the common mutations used in the mutational analysis screen. This slide shows the prevalence of the F508 mutation across different ethnic groups in the US. F508 is most prevalent among Caucasians, comprising 70% of the CF mutations in this group. The prevalence rate drops to 48% for African Americans and to 46% for Hispanics. The mutation is least prevalent among Asian Americans and Ashkenazi Jews, where it constitutes only 30% of the CF mutations. Delayed CF diagnosis has been reported in children of ethnic minorities. Customizing mutation analysis screens might improve genotyping sensitivity in different ethnic backgrounds, although this is not yet routine clinical practice. Wang D, Freedman SD. Laboratory tests for the diagnosis of cystic fibrosis. Am J Clin Pathol . 2002;117:S109-S115.
- Early Diagnosis by NBS May Improve Survival In a separate study, Lai and colleagues evaluated the relationship between method of diagnosis (meconium ileus [MI], prenatal or newborn screening, positive family history [FH], or symptoms other than MI) and survival in 27,703 patients enrolled in the Cystic Fibrosis Foundation Patient Registry from 1986 to 2000. This figure shows the probability of survival as a function of age for each of the diagnostic groups. Compared to the early diagnosis (screening) group, the MI and symptom groups each had a 1.8-fold higher risk for shortened survival ( P = 0.001). The FH group had only a slightly higher risk compared with the screened group ( P = 0.046). These results indicate that early diagnosis (through newborn screening) is associated with improved survival as compared with other modes of diagnosis. Lai HJ, Cheng Y, Cho H, Kosorok MR, Farrell PM. Association between initial disease presentation, lung disease outcomes, and survival in patients with cystic fibrosis. Am J Epidemiol . 2004;159(6):537-546.