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233 Early eradication therapy against P. aeruginosa using short-term tobramycin inhalation solution (TIS) in children with cystic fibrosis (CF)
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Poster Sessions / Journal of Cystic Fibrosis 16S1 (2017) S63–S174
Pulmonary disease in CF patients begins early in life and progresses in the absence of clinical symptoms. Lung function decline is associated to chronic infections, impaired nutritional status, gender and others factors. Objective: To determine individual factors associated to low pulmonary function (LPF) in a cohort of CF patients. Methods: A cross sectional study of a cohort of pediatric CF patients was designed. Medical records of 2016 were reviewed and the best FEV1 was recorded. Age, gender, p.F508del, BMI Zscore, chronic lung colonization with P. aeruginosa (Pa), methicillin resistant Staphylococcus aureus (MRSA), Burkholderia cepacia complex (BCC), Achromobacter spp and Small Colony Variant Staphylococcus aureus (SCV Sa); Cystic Fibrosis Related Diabetes (CFRD) and intravenous antibiotics requirement were registered. Univariate and multivariate linear regression analysis using FEV1 as dependent variable was carried out. Associations between FEV1 and the analyzed variables were expressed as odds ratio (OR) and their respective 95% confidence intervals (95% CI). Results: 97 patients (60% male) were included. Mean age: 11.7 years (SD 4.4), f508del: 73.2%, Mean BMI Zscore: −0.14 (SD 1.06), chronic colonization with SCV Sa: 9.2%, Pa: 27.8%, Achromobacter spp: 6.2% and MRSA: 26.8%; CFRD: 11.3% and intravenous antibiotics use: 34%, were significantly associated to LPF in the univariate analysis. The multivariate analysis, including those variables shown to be relevant in the univariate analysis, confirmed that BMI Zscore (OR 6.95 CI95% 3.7 to 10.1, p < 0.001), SCV Sa colonization (OR −33 CI95% −45 to 22.2, p < 0.001), MRSA Colonization (OR −10.2, CI95% −18.9 to 1.5 p = 0.02) and Pa Colonization (OR −10.5 (CI95% −18.9 to 2, p = 0.01) were statistically significantly associated variables to LPF. Conclusions: Poor nutritional status, chronic colonization with SCV Sa, Pa and MRSA were associated to LPF in this cohort. These results will be confirmed in a prospective study. 232 Lumacaftor/Ivacaftor is associated with a significant improvement in walk test and reduction in sweat chloride in a cohort of homozygous F508del CF patients with severe disease – a single centre experience N.J. Ronan1,2, Y. McCarthy1,2, K. James3, P. Arooj1,2, E.B. Hunt1,2, C. Shortt1, C. Fleming1, M. McCarthy1, C. Howlett1, C. Hickey1, E. Flanagan2, M. Daly1,2, J.A. Eustace2, M.M. Maher3, B.J. Plant1,2. 1Cork Adult CF Centre, University College Cork/Cork University Hospital, Cork, Ireland; 2HRB Clinical Research Facility, University College Cork, Cork, Ireland; 3Cork University Hospital, Department of Radiology, Cork, Ireland Objectives: Lumacaftor/Ivacaftor produces significant benefit in patients with CF who are homozygous for the F508del mutation. Less is known about utility in patients with a pre-treatment FEV1 < 40%. Methods: Seven patients (homozygous F508del) with severe CF (median FEV1 30%) commenced Lumacaftor/Ivacaftor. Spirometry, BMI, sweat test, modified shuttle walk test, quality of life (CFQ-R), low dose chest CT and blood cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α) were assessed before Lumacaftor/Ivacaftor and three monthly after treatment for a median follow up of 9 months. Chest CT scans were Bhalla scored. Number of pulmonary exacerbations requiring intravenous (IV) antibiotics were recorded post treatment and for a matched period pre-treatment. Results: There was no significant change in FEV1 (median change 0.67%, p = 0.2), BMI ( p = 0.24), number of IV antibiotics (total 12 IV’s pre v 8 IV’s post, p = 0.08), chest CT total Bhalla score after treatment ( p > 0.05) or in IL1β, IL-6, IL-8, IL-10 or TNF-α after treatment ( p > 0.05). There was no significant change in CFQ-R respiratory (median change 0, p = 0.6), physical (median change 9.36, p = 0.08) or vitality (median change 8.37, p = 0.17) domains post-treatment. A significant reduction in sweat chloride (median change −24 mmol/L, p = 0.046) and significant increase in walk distance (median change 75 metres, p = 0.043) were observed after treatment. Conclusion: In a severe cohort determining clinical response to CFTR modulatory therapy is challenging. That said a functional improvement of 75 meters and a trend towards a reduction in intravenous antibiotic usage with an associated clinically meaningful improvement in CFQ-R vitality and physical domains support the role of this therapy in severe disease. There is a need for a multi-centre collaboration to address this important issue in severe disease.
233 Early eradication therapy against P. aeruginosa using short-term tobramycin inhalation solution (TIS) in children with cystic fibrosis (CF) S. Esref1, E. Gunes Yalcin1, M. Gharibzadeh Hizal1, G.D. Tugcu1, N. Emiralioglu2, D. Dogru Ersoz1, U. Ozcelik1, B. Sener3, N. Kiper1. 1Hacettepe University Ihsan Dogramaci Children Hospital, Pediatric Pulmonology, Ankara, Turkey; 2Gaziantep Cengiz Gokcek Children Hospital, Pediatric Pulmonology, Gaziantep, Turkey; 3Hacettepe University Ihsan Dogramaci Children Hospital, Clinical Microbiology, Ankara, Turkey Methods: This study retrospectively evaluated the results of eradication treatment regimens of 28 days TIS or 28 days TIS + 14 days po ciprofloxacin for children with CF who had first Pa infection from respiratory tract cultures between January 2015 and November 2016. Results: Twenty-eight children (16 girls/12 boys) with a mean age of 91 months (20–288 months) were included in this study. At least one allele of 19 patients (67%) had a mutation causing CF, the most common was F508del. Antibiotic resistance was detected in 5 patients (17%) of the first Pa growth. Two of these patients (2/28) were accompanied by S. aureus and H. influenzae, and in 17/28 patients only S. aureus was present. Nineteen patients had no symptoms while 9 patients had symptoms of mild acute pulmonary exacerbation. Among the patients who were able to perform pulmonary function tests (n: 11), the mean FEV1 was 96%. For Pa eradication 9/28 children (mean age 75 months) with no symptoms at the time of first growth received only 28 days TIS 2 × 300 mg (Group I); 9/28 children (mean age 101 months) received TIS 28 days and po ciprofloxacin 14 days treatment regimens (Group II) because of the presence of mild pulmonary exacerbation symptoms at the time of first growth. The total follow-up period of all patients after treatment regimen was 8.1 months (1–16 months). 10/28 patients was completed 12 months period after eradication therapy and Pa regrowth was not detected (n = 7 in Group I, n = 3 in Group II). In 18/28 patients, the treatment success rates were not evaluated because the follow-up period of 12 months was not completed after the eradication regimen. Among patients who were able to perform pulmonary function tests after treatment regimen (n: 11), the mean FEV1 after treatment was 101%. Conclusion: The use of short-term TIS in the treatment of Pa eradication in patients with CF is an effective and reliable treatment method that can be used in children of all age groups. 235 Association of the first phase xenobiotic biotransformation system genes with the risk of undesirable side effects and efficacy of antibiotic therapy in Russian CF children O.G. Novoselova1, N.V. Petrova1, E.I. Kondratyeva1, V.D. Sherman1, R.A. Bikanov1, R.A. Zinchenko1,2. 1Federal State Budgetary Institution «Research Centre for Medical Genetics», Moscow, Russian Federation; 2Pirogov Russian National Research Medical University, Moscow, Russian Federation Objectives: Study the association of the first phase xenobiotic biotransformation system genes with the risk of adverse reactions and effectiveness of intravenous antimicrobial therapy in children with cystic fibrosis (CF). Methods: 118 CF children, 70 healthy individuals were examined for six polymorphisms of four genes – CYP2C9, CYP2C19, CYP2D6, CYP3A4 by RFLP-analysis. The survey was performed by comparing the following groups: CF patients/healthy individuals; patients with a high frequency of bronchopulmonary exacerbations/without; patients with chronic highly pathogenic respiratory tract infection/without; patients had adverse reactions to antibiotics/no. Results: There were no significant differences in the frequencies of alleles and genotypes of studied polymorphisms between CF patients and healthy controls, except the higher frequency of CYP2D6*4 allele in CF patients ( p = 0.023). The association of CYP3A4*1B allele and CYP3A4*1B/*1A genotype with the development of adverse reactions to antibiotics was found ( p = 0.023 and p = 0.025). Heterozygous genotype CYP3A4*1B/*1A and a combination of al alleles CYP3A4*1B/*1A × CYP2D6*1/*1 can be considered as markers of increased risk of adverse reactions to intravenous antibiotic therapy for CF patients (OR = 8,50 (95% CI 1.64–44.04) and OR = 35.00 (95% CI 3.29–372.14)). The frequency of CYP2C9*3 allele and CYP2C9*3/CYP2C9*1 genotype in CF children having not
Poster Sessions / Journal of Cystic Fibrosis 16S1 (2017) S63–S174
Pulmonary disease in CF patients begins early in life and progresses in the absence of clinical symptoms. Lung function decline is associated to chronic infections, impaired nutritional status, gender and others factors. Objective: To determine individual factors associated to low pulmonary function (LPF) in a cohort of CF patients. Methods: A cross sectional study of a cohort of pediatric CF patients was designed. Medical records of 2016 were reviewed and the best FEV1 was recorded. Age, gender, p.F508del, BMI Zscore, chronic lung colonization with P. aeruginosa (Pa), methicillin resistant Staphylococcus aureus (MRSA), Burkholderia cepacia complex (BCC), Achromobacter spp and Small Colony Variant Staphylococcus aureus (SCV Sa); Cystic Fibrosis Related Diabetes (CFRD) and intravenous antibiotics requirement were registered. Univariate and multivariate linear regression analysis using FEV1 as dependent variable was carried out. Associations between FEV1 and the analyzed variables were expressed as odds ratio (OR) and their respective 95% confidence intervals (95% CI). Results: 97 patients (60% male) were included. Mean age: 11.7 years (SD 4.4), f508del: 73.2%, Mean BMI Zscore: −0.14 (SD 1.06), chronic colonization with SCV Sa: 9.2%, Pa: 27.8%, Achromobacter spp: 6.2% and MRSA: 26.8%; CFRD: 11.3% and intravenous antibiotics use: 34%, were significantly associated to LPF in the univariate analysis. The multivariate analysis, including those variables shown to be relevant in the univariate analysis, confirmed that BMI Zscore (OR 6.95 CI95% 3.7 to 10.1, p < 0.001), SCV Sa colonization (OR −33 CI95% −45 to 22.2, p < 0.001), MRSA Colonization (OR −10.2, CI95% −18.9 to 1.5 p = 0.02) and Pa Colonization (OR −10.5 (CI95% −18.9 to 2, p = 0.01) were statistically significantly associated variables to LPF. Conclusions: Poor nutritional status, chronic colonization with SCV Sa, Pa and MRSA were associated to LPF in this cohort. These results will be confirmed in a prospective study. 232 Lumacaftor/Ivacaftor is associated with a significant improvement in walk test and reduction in sweat chloride in a cohort of homozygous F508del CF patients with severe disease – a single centre experience N.J. Ronan1,2, Y. McCarthy1,2, K. James3, P. Arooj1,2, E.B. Hunt1,2, C. Shortt1, C. Fleming1, M. McCarthy1, C. Howlett1, C. Hickey1, E. Flanagan2, M. Daly1,2, J.A. Eustace2, M.M. Maher3, B.J. Plant1,2. 1Cork Adult CF Centre, University College Cork/Cork University Hospital, Cork, Ireland; 2HRB Clinical Research Facility, University College Cork, Cork, Ireland; 3Cork University Hospital, Department of Radiology, Cork, Ireland Objectives: Lumacaftor/Ivacaftor produces significant benefit in patients with CF who are homozygous for the F508del mutation. Less is known about utility in patients with a pre-treatment FEV1 < 40%. Methods: Seven patients (homozygous F508del) with severe CF (median FEV1 30%) commenced Lumacaftor/Ivacaftor. Spirometry, BMI, sweat test, modified shuttle walk test, quality of life (CFQ-R), low dose chest CT and blood cytokines (IL-1β, IL-6, IL-8, IL-10, TNF-α) were assessed before Lumacaftor/Ivacaftor and three monthly after treatment for a median follow up of 9 months. Chest CT scans were Bhalla scored. Number of pulmonary exacerbations requiring intravenous (IV) antibiotics were recorded post treatment and for a matched period pre-treatment. Results: There was no significant change in FEV1 (median change 0.67%, p = 0.2), BMI ( p = 0.24), number of IV antibiotics (total 12 IV’s pre v 8 IV’s post, p = 0.08), chest CT total Bhalla score after treatment ( p > 0.05) or in IL1β, IL-6, IL-8, IL-10 or TNF-α after treatment ( p > 0.05). There was no significant change in CFQ-R respiratory (median change 0, p = 0.6), physical (median change 9.36, p = 0.08) or vitality (median change 8.37, p = 0.17) domains post-treatment. A significant reduction in sweat chloride (median change −24 mmol/L, p = 0.046) and significant increase in walk distance (median change 75 metres, p = 0.043) were observed after treatment. Conclusion: In a severe cohort determining clinical response to CFTR modulatory therapy is challenging. That said a functional improvement of 75 meters and a trend towards a reduction in intravenous antibiotic usage with an associated clinically meaningful improvement in CFQ-R vitality and physical domains support the role of this therapy in severe disease. There is a need for a multi-centre collaboration to address this important issue in severe disease.
233 Early eradication therapy against P. aeruginosa using short-term tobramycin inhalation solution (TIS) in children with cystic fibrosis (CF) S. Esref1, E. Gunes Yalcin1, M. Gharibzadeh Hizal1, G.D. Tugcu1, N. Emiralioglu2, D. Dogru Ersoz1, U. Ozcelik1, B. Sener3, N. Kiper1. 1Hacettepe University Ihsan Dogramaci Children Hospital, Pediatric Pulmonology, Ankara, Turkey; 2Gaziantep Cengiz Gokcek Children Hospital, Pediatric Pulmonology, Gaziantep, Turkey; 3Hacettepe University Ihsan Dogramaci Children Hospital, Clinical Microbiology, Ankara, Turkey Methods: This study retrospectively evaluated the results of eradication treatment regimens of 28 days TIS or 28 days TIS + 14 days po ciprofloxacin for children with CF who had first Pa infection from respiratory tract cultures between January 2015 and November 2016. Results: Twenty-eight children (16 girls/12 boys) with a mean age of 91 months (20–288 months) were included in this study. At least one allele of 19 patients (67%) had a mutation causing CF, the most common was F508del. Antibiotic resistance was detected in 5 patients (17%) of the first Pa growth. Two of these patients (2/28) were accompanied by S. aureus and H. influenzae, and in 17/28 patients only S. aureus was present. Nineteen patients had no symptoms while 9 patients had symptoms of mild acute pulmonary exacerbation. Among the patients who were able to perform pulmonary function tests (n: 11), the mean FEV1 was 96%. For Pa eradication 9/28 children (mean age 75 months) with no symptoms at the time of first growth received only 28 days TIS 2 × 300 mg (Group I); 9/28 children (mean age 101 months) received TIS 28 days and po ciprofloxacin 14 days treatment regimens (Group II) because of the presence of mild pulmonary exacerbation symptoms at the time of first growth. The total follow-up period of all patients after treatment regimen was 8.1 months (1–16 months). 10/28 patients was completed 12 months period after eradication therapy and Pa regrowth was not detected (n = 7 in Group I, n = 3 in Group II). In 18/28 patients, the treatment success rates were not evaluated because the follow-up period of 12 months was not completed after the eradication regimen. Among patients who were able to perform pulmonary function tests after treatment regimen (n: 11), the mean FEV1 after treatment was 101%. Conclusion: The use of short-term TIS in the treatment of Pa eradication in patients with CF is an effective and reliable treatment method that can be used in children of all age groups. 235 Association of the first phase xenobiotic biotransformation system genes with the risk of undesirable side effects and efficacy of antibiotic therapy in Russian CF children O.G. Novoselova1, N.V. Petrova1, E.I. Kondratyeva1, V.D. Sherman1, R.A. Bikanov1, R.A. Zinchenko1,2. 1Federal State Budgetary Institution «Research Centre for Medical Genetics», Moscow, Russian Federation; 2Pirogov Russian National Research Medical University, Moscow, Russian Federation Objectives: Study the association of the first phase xenobiotic biotransformation system genes with the risk of adverse reactions and effectiveness of intravenous antimicrobial therapy in children with cystic fibrosis (CF). Methods: 118 CF children, 70 healthy individuals were examined for six polymorphisms of four genes – CYP2C9, CYP2C19, CYP2D6, CYP3A4 by RFLP-analysis. The survey was performed by comparing the following groups: CF patients/healthy individuals; patients with a high frequency of bronchopulmonary exacerbations/without; patients with chronic highly pathogenic respiratory tract infection/without; patients had adverse reactions to antibiotics/no. Results: There were no significant differences in the frequencies of alleles and genotypes of studied polymorphisms between CF patients and healthy controls, except the higher frequency of CYP2D6*4 allele in CF patients ( p = 0.023). The association of CYP3A4*1B allele and CYP3A4*1B/*1A genotype with the development of adverse reactions to antibiotics was found ( p = 0.023 and p = 0.025). Heterozygous genotype CYP3A4*1B/*1A and a combination of al alleles CYP3A4*1B/*1A × CYP2D6*1/*1 can be considered as markers of increased risk of adverse reactions to intravenous antibiotic therapy for CF patients (OR = 8,50 (95% CI 1.64–44.04) and OR = 35.00 (95% CI 3.29–372.14)). The frequency of CYP2C9*3 allele and CYP2C9*3/CYP2C9*1 genotype in CF children having not