Abstracts
OBJECTIVE:
To describe the clinical impact of the first year treatment with dornase alfa, according to age groups, in a cohort of Brazilian Cystic Fibrosis (CF) patients.
METHODS:
The data on 152 eligible patients, from 16 CF reference centers, that answered the medical questionnaires and performed laboratory tests at baseline (T0), and at six (T2) and 12 (T4) months after dornase alfa initiation, were analyzed. Three age groups were assessed: six to 11, 12 to 13, and >14 years. Pulmonary tests, airway microbiology, emergency room visits, hospitalizations, emergency and routine treatments were evaluated. Student's t-test, chi-square test and analysis of variance were used when appropriated.
RESULTS:
Routine treatments were based on respiratory physical therapy, regular exercises, pancreatic enzymes, vitamins, bronchodilators, corticosteroids, and antibiotics. In the six months prior the study (T0 phase), hospitalizations for pulmonary exacerbations occurred in 38.0, 10.0 and 61.4% in the three age groups, respectively. After one year of intervention, there was a significant reduction in the number of emergency room visits in the six to 11 years group. There were no significant changes in forced expiratory volume in one second (VEF1), in forced vital capacity (FVC), in oxygen saturation (SpO2), and in Tiffenau index for all age groups. A significant improvement in Shwachman-Kulczychi score was observed in the older group. In the last six months of therapy, chronic or intermittent colonization by P. aeruginosa was detected in 75.0, 71.4 and 62.5% of the studied groups, respectively, while S. aureus colonization was identified in 68.6, 66.6 and 41.9% of the cases.
CONCLUSIONS:
The treatment with dornase alfa promoted the maintenance of pulmonary function parameters and was associated with a significant reduction of emergency room visits due to pulmonary exacerbations in the six to 11 years age group, with better clinical scores in the >14 age group, one year after the intervention.
cystic fibrosis; dornase alfa; therapeutics; clinical evolution; pulmonary microbiology
OBJETIVO:
Relatar el impacto clínico del primer año de tratamiento con dornasa alfa conforme a la franja de edad, en una cohorte de pacientes brasileños con fibrosis quística (FC).
MÉTODOS:
El presente estudio analizó datos de 152 pacientes elegibles, de 16 centros de referencia para FC, los que contestaron a los cuestionarios clínicos y realizaron pruebas laboratoriales, al inicio del tratamiento con la dornasa alfa (T0) y después de 6 (T2) y 12 (T4) meses de la intervención. Se analizaron 3 grupos etarios: 6-11, 12-13 e >14 años de edad. Se evaluaron las pruebas pulmonares, la microbiología de vías aéreas, las atenciones de emergencia, hospitalizaciones y tratamientos emergenciales y de rutina. Las estadísticas descriptivas, pruebas t y chi-cuadrado y ANOVA fueron usadas cuando pertinentes.
RESULTADOS:
El tratamiento regular se basó en la fisioterapia respiratoria, ejercicios regulares, encimas pancreáticas, vitaminas, broncodilatadores, corticosteroides y antibióticos. En los 6 meses anteriores al estudio (fase T0), las hospitalizaciones por exacerbación pulmonar ocurrieron en 38, 10 y 61,4%, respectivamente, para las tres franjas de edad analizadas. En el grupo 6-11 años, hubo reducción significativa de atenciones de emergencia después de 1 año de tratamiento. No hubo modificaciones significativas de volumen espiratorio forzado en el 1er segundo (VEF1), capacidad vital forzada (CVF), saturación de oxígeno (SpO)2 e índice de Tiffeneau, en todos grupos. El escore de Schwachman-Kulczychi mejoró significativamente en el grupo de más edad. Los últimos 6 meses de tratamiento, la colonización crónica o intermitente por P. aeruginosa fue detectada en el 75, 71,4 y 62,5%, respectivamente, mientras que por S. aureus ocurrió en 68,6, 66,6 y 41,9% de los casos en cada grupo de edad.
CONCLUSIONES:
La intervención con dornasa alfa resultó en mantenimiento de los parámetros pulmonares y fue asociada a la reducción significativa de visitas a la emergencia por exacerbación pulmonar en el grupo de 6 a 11 años de edad, con mejora del escore clínico en el grupo >14 años de edad, al final de un año de estudio.
fibrosis quística; dornasa alfa; tratamiento; evolución clínica; microbiología pulmonar
OBJETIVO:
Relatar o impacto clínico do primeiro ano de tratamento com dornase alfa de acordo com a faixa etária, numa coorte de pacientes brasileiros com fibrose cística (FC).
MÉTODOS:
O presente estudo analisou dados de 152 pacientes elegíveis, de 16 centros de referência para FC, os quais responderam aos questionários clínicos e realizaram testes laboratoriais, ao início do tratamento com dornase alfa (T0) e após seis (T2) e 12 (T4) meses da intervenção. Analisaram-se três grupos etários: seis a 11, 12 a 13 e >14 anos de idade. Avaliaram-se os testes pulmonares, a microbiologia de vias aéreas, os atendimentos de emergência, as hospitalizações e os tratamentos emergenciais e rotineiros. O teste t de Student, o qui-quadrado e a análise de variância foram usados quando pertinentes.
RESULTADOS:
O tratamento baseou-se em fisioterapia respiratória, exercícios regulares, enzimas pancreáticas, vitaminas, broncodilatadores, corticosteroides e antibióticos. Nos seis meses anteriores ao estudo (fase T0), as hospitalizações por exacerbação pulmonar ocorreram em 38,0, 10,0 e 61,4%, respectivamente para as três faixas etárias analisadas. No grupo de seis a 11 anos, houve redução significativa de atendimentos de emergência após um ano de tratamento. Não houve modificações significativas de volume expiratório forçado no primeiro segundo (VEF1), capacidade vital forçada (CVF), saturação de oxigênio (SpO)2 e índice de Tiffeneau em todos os grupos. O escore de Shwachman-Kulczychi melhorou significativamente no grupo de mais idade. Nos últimos seis meses de tratamento, a colonização crônica ou intermitente por P.aeruginosa foi detectada em 75,0, 71,4 e 62,5%, respectivamente, enquanto a colonização por S.aureus ocorreu em 68,6, 66,6 e 41,9% dos casos em cada grupo etário.
CONCLUSÕES:
A intervenção com dornase alfa resultou em manutenção dos parâmetros pulmonares e associou-se à redução significativa de visitas à emergência por exacerbação pulmonar no grupo de seis a 11 anos de idade, com melhora do escore clínico no grupo >14 anos de idade ao final de um ano de estudo.
fibrose cística; dornase alfa; terapêutica; evolução clínica; microbiologia pulmonar
Introduction
Cystic fibrosis (CF) is the most common life-threatening autosomal recessive disorder
among Caucasians(
11. Cystic Fibrosis Foundation [homepage on the Internet]. Patient
Registry 2009: annual report [cited 2011 Sep 20]. Available from:
http://www.cff.org/UploadedFiles/research/ClinicalResearch/Patient-Registry-Report-2009.pdf
Available from:
http://www.cff.or...
,
22. Flume PA. Pulmonary complications of cystic fibrosis. Respir Care
2009;54:618-27.
). Caused by a mutation in the cystic fibrosis transmembrane
conductance regulator (CFTR) gene, this disease is characterized by
progressive lung destruction, with accumulation of viscous secretions and impairment
of mucociliary clearance in airways(
33. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z
et al. Identification of the cystic fibrosis gene: cloning and characterization
of complementary DNA. Science 1989;245:1066-73.
,
44. Padman R, Passi V. Cystic fibrosis overview and update on infant
care. OJPed 2012;2:187-96.
) Chronic pulmonary infection and increased inflammatory response are
hallmarks of CF lung disease, with a major impact on patients' morbidity and the
mortality(
44. Padman R, Passi V. Cystic fibrosis overview and update on infant
care. OJPed 2012;2:187-96.
5. Flume PA, O'Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr,
Willey-Courand DB et al. Cystic fibrosis pulmonary guidelines: chronic
medications for maintenance of lung health. Am J Respir Crit Care Med
2007;176:957-69.
-
66. Armstrong DS, Grimwood K, Carzino R, Carlin JB, Olinsky A, Phelan
PD. Lower respiratory infection and inflammation in infants with newly diagnosed
cystic fibrosis. BMJ 1995;310:1571-2.
).
Long-term accumulation of thickened mucus leads to chronic suppurative lung disease, with persistent infection or colonization by microorganisms such as Pseudomonas aeruginosa, Staphylococcus aureus, and Burkholderia cepacia, and evolution to bronchiectasis, pneumothorax, cor pulmonale, and respiratory failure, at the final stage of disease( 77. Farrell PM, Rosenstein BJ, White TB, Accurso FJ, Castellani C, Cutting GR et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr 2008;153:S4-14. ). Gastrointestinal and reproductive systems are also affected with pancreatic insufficiency with maldigestion and malabsorption of nutrients, distal intestinal obstruction, and hepatic disease. In addition, salt loss syndromes, diabetes mellitus, and genitourinary abnormalities are other clinical complications of CF( 22. Flume PA. Pulmonary complications of cystic fibrosis. Respir Care 2009;54:618-27. , 88. Orenstein DM, Winnie GB, Altman H. Cystic fibrosis: a 2002 update. J Pediatr 2002;140:156-64. ).
Improvements in CF diagnosis and treatment strategies led to an increase in life expectancy, raising the median age of survival to 36 years in the United States1 and around 18 years in Brazil( 99. Alvarez AE, Ribeiro AF, Hessel G, Bertuzzo CS, Ribeiro JD. Cystic fibrosis at a Brazilian center of excellence: clinical and laboratory characteristics of 104 patients and their association with genotype and disease severity. J Pediatr (Rio J) 2004;80:371-9. ). Although no cure exists, several therapeutic strategies are available for clinical use and current standard treatments for CF include antibiotics, respiratory physical therapy and mucolytic agents (dornase alfa, hypertonic saline solutions), bronchodilators, pancreatic enzymes, and daily supplementation with vitamins( 55. Flume PA, O'Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr, Willey-Courand DB et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2007;176:957-69. , 88. Orenstein DM, Winnie GB, Altman H. Cystic fibrosis: a 2002 update. J Pediatr 2002;140:156-64. , 1010. Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP, Marks GB et al. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med 2006;354:229-40. ).
Clinical use of dornase alfa, a recombinant human deoxyribonuclease I that reduces the viscosity of CF sputum through the hydrolization of DNA accumulated in secretions( 1111. Shak S, Capon DJ, Hellmiss R, Marsters SA, Baker CL. Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum. Proc Natl Acad Sci U S A 1990;87:9188-92. ), has demonstrated significant efficacy in CF, as it reduces respiratory exacerbations and improves lung function, regardless of patients age or disease stage( 55. Flume PA, O'Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr, Willey-Courand DB et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2007;176:957-69. , 1212. Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey BW et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group. N Engl J Med 1994;331:637-42. , 1313. Konstan MW, Wagener JS, Pasta DJ, Millar SJ, Jacobs JR, Yegin A et al. Clinical use of dornase alpha is associated with a slower rate of VEF1 decline in cystic fibrosis. Pediatr Pulmonol 2011;46:545-53. ).
Health-related quality of life (HRQoL) has gained importance lately as an endpoint for clinical trials, so we have conducted a multicenter prospective study to investigate the impact of dornase alfa introduction on patients' QoL. In our previous publication( 1414. Rozov T, de Oliveira VZ, Santana MA, Adde FV, Mendes RH, Paschoal IA et al. Dornase alfa improves the health-related quality of life among Brazilian patients with cystic fibrosis - a one-year prospective study. Pediatr Pulmonol 2010;45:874-82. ) we used modified, Portuguese-translated, validated CF QoL questionnaires CFQ-R (Cystic Fibrosis Questionnaire-Revised)( 1515. Rozov T, Cunha MT, Nascimento O, Quittner AL, Jardim JR. Linguistic validation of cystic fibrosis quality of life questionnaires. J Pediatr (Rio J) 2006;82:151-6. ), with dornase alfa promoting significant improvements in various CFQ-R domains. The aim of this publication is to present additional information about the clinical profile of CF Brazilian patients after starting dornase alfa chronic use and to analyze their clinical parameters and patterns of care.
Method
This paper shows complementary data of the 152 CF patients from the Brazilian Cystic Fibrosis Quality of Life Trial( 1414. Rozov T, de Oliveira VZ, Santana MA, Adde FV, Mendes RH, Paschoal IA et al. Dornase alfa improves the health-related quality of life among Brazilian patients with cystic fibrosis - a one-year prospective study. Pediatr Pulmonol 2010;45:874-82. ). Study design, simple size, patient eligibility criteria, and part of patients' demographic and clinical characteristics have been described previously( 1414. Rozov T, de Oliveira VZ, Santana MA, Adde FV, Mendes RH, Paschoal IA et al. Dornase alfa improves the health-related quality of life among Brazilian patients with cystic fibrosis - a one-year prospective study. Pediatr Pulmonol 2010;45:874-82. ). Free informed consent form was signed by patients or their guardians and this project was approved by human research ethics committees of all Centers( 1414. Rozov T, de Oliveira VZ, Santana MA, Adde FV, Mendes RH, Paschoal IA et al. Dornase alfa improves the health-related quality of life among Brazilian patients with cystic fibrosis - a one-year prospective study. Pediatr Pulmonol 2010;45:874-82. ).
Patients were followed in five outpatient visits: previous to dornase alfa initiation (T0), and then every 3 months until one year of follow up - 3 (T1), 6 (T2), 9 (T3) and 12 (T4) months, respectively. In all visits, disease-specific questionnaires, CFQ-R translated and validated, were used in patients aged from 6 to 11, 12 to 13 and 14 years or more, and in parents of patients aged 6 to 13 years( 1515. Rozov T, Cunha MT, Nascimento O, Quittner AL, Jardim JR. Linguistic validation of cystic fibrosis quality of life questionnaires. J Pediatr (Rio J) 2006;82:151-6. , 1616. Henry B, Aussage P, Grosskopf C, Goehrs JM, Launois R; the French CFQOL Study Group. Cystic fibrosis questionnaire (CFQ); Cystic Fibrosis Questionnaire Revised (CFQ-R). English version 2.0 [CD-ROM]. Miami: University of Miami; 2004. ). The responsible physician evaluated patient's medical record forms covering the last six months, prior to study entry (T0), and at 6 months (T2) and 12 months (T4) of dornase alfa. For each patient, these three forms and the following parameters were collected: method of CF diagnosis; reason, number and duration of hospitalizations; reason and number of visits to the emergency room; concomitant interventions routinely used; pulmonary function parameters forced expiratory volume in 1 second (FEV1, forced vital capacity [FVC], oxygen saturation of hemoglobin [SpO2] and Tiffeneau index); Shwachman-Kulczychi score; treatments for pulmonary exacerbations; use of antibiotics and airways microbiology. Patient condition/evolution and reason for follow-up interruption were obtained after 6 and 12 months. In addition, a clinical stability questionnaire was used to evaluate the clinical conditions in the previous month( 1414. Rozov T, de Oliveira VZ, Santana MA, Adde FV, Mendes RH, Paschoal IA et al. Dornase alfa improves the health-related quality of life among Brazilian patients with cystic fibrosis - a one-year prospective study. Pediatr Pulmonol 2010;45:874-82. ).
Genetic studies were performed by specific polymerase chain reaction. At each visit, physical examination, laboratory measures, and a spirometry were performed. Sputum cultures were collected routinely and considered positive when the following microorganisms were presented in at least one sample: S. aureus; P. aeruginosa; B. cepacia or Stenotrophomonas maltophilia. The colonization was defined as chronic when 3 positive samples were obtained, in previous 6 months.
The following variables were analyzed: age, gender, symptoms, diagnosis, medication use, pulmonary function parameters, concomitant treatments, and airway microbiology. Clinical outcomes and data on concomitant treatments, medication use, and routine therapies were based on data recorded.
Patients were analyzed according to the age-groups( 1414. Rozov T, de Oliveira VZ, Santana MA, Adde FV, Mendes RH, Paschoal IA et al. Dornase alfa improves the health-related quality of life among Brazilian patients with cystic fibrosis - a one-year prospective study. Pediatr Pulmonol 2010;45:874-82. , 1616. Henry B, Aussage P, Grosskopf C, Goehrs JM, Launois R; the French CFQOL Study Group. Cystic fibrosis questionnaire (CFQ); Cystic Fibrosis Questionnaire Revised (CFQ-R). English version 2.0 [CD-ROM]. Miami: University of Miami; 2004. ). Data were summarized using descriptive statistics suitable for each variable. Frequency and percentages were used for categorical variables and for ordinal numerical variables. Number of valid observations, range, mean, standard deviation (SD), median, and interquartile range were used to describe continuous numerical variables, including FEV1, FVC, SpO2, Tiffeneau index, and Shwachamn-Kulczychi score. Values for percentage of predicted FEV1 and FVC were calculated. Parametric data were compared between two groups using t-test for paired samples, when appropriated. Comparison between three or more means was performed using the analysis of variance. Changes in FEV1, FVC, SpO2, Tiffeneau index and Shwachman-Kulczychi score were assessed using the analysis of variance for repeated measures and multiple comparisons. The number of visits to the emergency room due to acute pulmonary exacerbations was compared over time using the McNemar test for dependent samples, and using Chi-square test for independent samples. Statistical analyses were performed using the SAS software (SAS Institute Inc). Two-sided p<0.05 were considered statistically significant.
Sample size calculation was performed as previously described and based on the primary endpoint of the study which was the quality of life( 1414. Rozov T, de Oliveira VZ, Santana MA, Adde FV, Mendes RH, Paschoal IA et al. Dornase alfa improves the health-related quality of life among Brazilian patients with cystic fibrosis - a one-year prospective study. Pediatr Pulmonol 2010;45:874-82. ). Briefly, based on the variance analysis of the CFQ-R punctuation found in a previous study( 1515. Rozov T, Cunha MT, Nascimento O, Quittner AL, Jardim JR. Linguistic validation of cystic fibrosis quality of life questionnaires. J Pediatr (Rio J) 2006;82:151-6. ) it was estimated that the inclusion of 64 patients per age group would give the study a power of 80% to detect a variation of 6.5% in the Respiratory Symptoms domain of the Cystic Fibrosis Questionnaire-Revised (CFQ-R) based on a two-sided type I error <5%.
Results
Of the 156 initial patients, four were excluded for not meeting the inclusion criteria. Among the 152 eligible patients, 79 were in age group 6 -11, 14 were in age group 12-13, and 59 were in age group >14 years, from 16 CF referral centers. Overall and per age group descriptive analysis of gender, age, age at diagnosis, and clinical manifestations were previously described( 1414. Rozov T, de Oliveira VZ, Santana MA, Adde FV, Mendes RH, Paschoal IA et al. Dornase alfa improves the health-related quality of life among Brazilian patients with cystic fibrosis - a one-year prospective study. Pediatr Pulmonol 2010;45:874-82. ). During the follow-up, 14 patients were lost for the following reasons: withdrawal from the treatment (4), death (3), frequently missed visits (1), transference to another city/state (1), pregnancy (1), lack of medication at the distribution site (1), drug intolerance (1), low adherence (1) and adverse reaction n(1).
The main method of CF diagnosis was based on two sweat tests associated or not to genetic studies. In the younger group, ΔF508 in homozygotic state was the most frequent mutation (42.9%), followed by ΔF508 in heterozygosis (32.1%) and unknown mutations (14.3%). In patients aged >14 years, the most common mutations were ΔF508 in heterozygosis (31.3%), ΔF508 in homozygosis (18.8%) and unknown mutations (37.5%). Other mutations, E542X/B10665, G542X/N1303K, R1162X/R1162, W1282X/N, and ΔF508/R553X, were detected.
Pulmonary function parameters and data related to hospitalization are presented in Tables 1 to 3.
Data on patients aged from 6 to 11 years are summarized in Table1. During the study, patients in this group required hospitalizations; most cases lasted from 11 to 20 days and were predominantly due to pulmonary infections. There was a significant reduction in the number of emergency room visits due to acute exacerbations when T4 was compared to T0. This age group showed no significant changes in FEV1, FVC, SpO2, Tiffeneau index and Shwachman-Kulczychi score after 6 and 12 months of dornase alfa.
Regarding the age group 12-13 years, pulmonary function parameters are summarized in Table 2. Due to sample size limitations, no statistical comparisons were made for this group regarding outcomes over time.
For the group aged >14 years, 16 patients were hospitalized due to pulmonary infections, with a length of stay that varied from 10 to 20 days. There were many visits to emergency rooms. When time points T0-T4 were compared, no significant differences were observed regarding the number of visits due to acute exacerbations. In addition, treatment with dornase alfa for 6 and 12 months was not associated with significant changes in pulmonary function parameters, with the exception of Shwachman-Kulczychi score that showed a significant improvement after 6 months of dornase alfa (Table 3).
Analysis of airways microbiology is shown in Table 4. In all age groups, P. aeruginosa and S. aureus were the most frequent pathogens found in chronic and intermittent colonization. During the first six months of dornase alfa, chronic P. aeruginosa was detected in 37.9%, 37.5% and 47.4% of the patients in age groups 6-11, 12-13 and >14 years, respectively, while chronic S. aureus was identified in 20.0%, 44.4% and 22.5% of the patients. When chronic and intermittent colonization were grouped, P. aeruginosa was found in more than 60% of the sample during treatment with dornase alfa, while S. aureus colonization showed a prevalence higher than 40-60%, for all age groups.
The routine concomitant treatments during the study follow-up are shown in Table 5.
The missing data has many reasons as incompletely fulfilled documents, patients' faults to clinics, physician misunderstanding of proposed questions, and CF younger patients lack of cooperation during pulmonary tests.
Discussion
We described the clinical characteristics and outcomes of the 152 patients included
in the Brazilian Cystic Fibrosis Quality of Life Trial(
1414. Rozov T, de Oliveira VZ, Santana MA, Adde FV, Mendes RH,
Paschoal IA et al. Dornase alfa improves the health-related quality of life
among Brazilian patients with cystic fibrosis - a one-year prospective study.
Pediatr Pulmonol 2010;45:874-82.
). The selection of CF patients in the 16 referral centers was based on
the physicians' decision to initiate chronic treatment with dornase alfa, following
the recommendations of current consensus(
11. Cystic Fibrosis Foundation [homepage on the Internet]. Patient
Registry 2009: annual report [cited 2011 Sep 20]. Available from:
http://www.cff.org/UploadedFiles/research/ClinicalResearch/Patient-Registry-Report-2009.pdf
Available from:
http://www.cff.or...
,
55. Flume PA, O'Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr,
Willey-Courand DB et al. Cystic fibrosis pulmonary guidelines: chronic
medications for maintenance of lung health. Am J Respir Crit Care Med
2007;176:957-69.
), with no additional costs to the routine treatment, as this medication
is regularly dispensed by our government. According to the international guidelines,
the chronic use of dornase alfa, aiming at improving lung function and reducing
exacerbations in children with 6 years of age and older in moderate to severe lung
disease, is a strong recommendation, grade A, with good level of evidence and
substantial benefit(
55. Flume PA, O'Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr,
Willey-Courand DB et al. Cystic fibrosis pulmonary guidelines: chronic
medications for maintenance of lung health. Am J Respir Crit Care Med
2007;176:957-69.
). It was also recommended for CF patients with mild lung disease by the
European Consensus(
1717. Heijerman H, Westerman E, Conway S, Touw D, Döring G; Consensus
Working Group. Inhaled medication and inhalation devices for lung disease in
patients with cystic fibrosis: a European consensus. J Cyst Fibros
2009;8:295-315.
). Our aim was to investigate whether the improvements observed in
patients' QoL(
1414. Rozov T, de Oliveira VZ, Santana MA, Adde FV, Mendes RH,
Paschoal IA et al. Dornase alfa improves the health-related quality of life
among Brazilian patients with cystic fibrosis - a one-year prospective study.
Pediatr Pulmonol 2010;45:874-82.
) would also reflect benefits in clinical status.
In the previous studies( 1414. Rozov T, de Oliveira VZ, Santana MA, Adde FV, Mendes RH, Paschoal IA et al. Dornase alfa improves the health-related quality of life among Brazilian patients with cystic fibrosis - a one-year prospective study. Pediatr Pulmonol 2010;45:874-82. , 1515. Rozov T, Cunha MT, Nascimento O, Quittner AL, Jardim JR. Linguistic validation of cystic fibrosis quality of life questionnaires. J Pediatr (Rio J) 2006;82:151-6. ), CF patients were divided into three age groups according to the original protocol of the CFQ-R( 1616. Henry B, Aussage P, Grosskopf C, Goehrs JM, Launois R; the French CFQOL Study Group. Cystic fibrosis questionnaire (CFQ); Cystic Fibrosis Questionnaire Revised (CFQ-R). English version 2.0 [CD-ROM]. Miami: University of Miami; 2004. ). The formal inclusion of CFQ-R questionnaires as a clinical outcome was essential, as it detected the impact of dornase alfa treatment over QoL, from the perspective of patients and their families. It allowed the identification of baseline reference values for QoL in the different age groups, and the progression of the QoL domains scores over the time (14,15,18). The present paper was an attempt to rescue the outcomes of distinct age groups. Thus, it would be possible to make comparisons between these groups, to evaluate individual patients in relation to the baseline characteristics of their respective age groups, and to plan future strategies.
Patients aged 6 to 11 years were those who most benefited from the use of dornase alfa. A significant reduction in the number of emergency room visits due to acute exacerbations was coincident with improvement in the QoL Respiratory Domain of previous paper( 1414. Rozov T, de Oliveira VZ, Santana MA, Adde FV, Mendes RH, Paschoal IA et al. Dornase alfa improves the health-related quality of life among Brazilian patients with cystic fibrosis - a one-year prospective study. Pediatr Pulmonol 2010;45:874-82. ). The significant improvement in the Shwachman-Kulczychi score observed in the older group can also be pointed as a positive outcome of the therapy, and when considered together with the favorable results in CFQ-R other domains( 1414. Rozov T, de Oliveira VZ, Santana MA, Adde FV, Mendes RH, Paschoal IA et al. Dornase alfa improves the health-related quality of life among Brazilian patients with cystic fibrosis - a one-year prospective study. Pediatr Pulmonol 2010;45:874-82. ), it allows the conclusion that dornase alfa is an additional therapeutic option for CF. Recently, dornase alfa was included in the recommendations of the Ministerial Order SAS/MS, n° 224, emended in 2010( 1919. Brasil - Ministério da Saúde - Secretaria de Atenção à Saúde. Portaria SAS/MS nº 224, de 10 de maio de 2010. Protocolos clínicos e diretrizes terapêuticas na fibrose cística - manifestações pulmonares. Ministério da Saúde; 2010. ). Evidently the cost-benefit relationship of this therapeutics was carefully revised by ANVISA (National Agency of Sanitary Surveillance) before its implementation in routine usage( 1919. Brasil - Ministério da Saúde - Secretaria de Atenção à Saúde. Portaria SAS/MS nº 224, de 10 de maio de 2010. Protocolos clínicos e diretrizes terapêuticas na fibrose cística - manifestações pulmonares. Ministério da Saúde; 2010. ).
Regarding patients' characteristics, mean age at diagnosis was 9.3 years, ranging
from <1 to 56 years, and the main clinical manifestations were pulmonary
infections, malnutrition and pancreatic insufficiency, as in other studies. The CF
diagnosis occurred late in all age groups (median age at diagnosis, 4.0 and 15.0
years); as already known, the late diagnosis results in worse prognosis of CF lung
disease. Fortunately, improvements in age at diagnosis has been observed in recent
Brazilian research(
2020. Grupo Brasileiro de Estudos de Fibrose Cística [homepage on the
Internet]. Registro Brasileiro de Fibrose Cística: primeiro relatório anual -
ano 2009 [cited 2013 Feb 21]. Available from:
http://www.gbefc.org.br/gbefc/estudo_gbefc_2009.pdf
Available from:
http://www.gbefc....
).
In our study, ΔF508 was the most frequent mutation detected in agreement with
genotype distribution study of Brazilian patients from five different states
(overall frequency of 48%)(
2020. Grupo Brasileiro de Estudos de Fibrose Cística [homepage on the
Internet]. Registro Brasileiro de Fibrose Cística: primeiro relatório anual -
ano 2009 [cited 2013 Feb 21]. Available from:
http://www.gbefc.org.br/gbefc/estudo_gbefc_2009.pdf
Available from:
http://www.gbefc....
,
2121. Raskin S, Pereira-Ferrari L, Reis FC, Abreu F, Marostica P,
Rozov T et al. Incidence of cystic fibrosis in five different states of Brazil
as determined by screening of p.F508del, mutation at the CFTR gene in newborns
and patients. J Cyst Fibros 2008;7:15-22.
). According to the Cystic Fibrosis Foundation's Patient Report 2009,
almost 91% of the CF patients have their mutations identified, and the ΔF508
mutation is present in near 90% of cases(
11. Cystic Fibrosis Foundation [homepage on the Internet]. Patient
Registry 2009: annual report [cited 2011 Sep 20]. Available from:
http://www.cff.org/UploadedFiles/research/ClinicalResearch/Patient-Registry-Report-2009.pdf
Available from:
http://www.cff.or...
). Mutations found in our study are among the most common mutations
detected in CF(
11. Cystic Fibrosis Foundation [homepage on the Internet]. Patient
Registry 2009: annual report [cited 2011 Sep 20]. Available from:
http://www.cff.org/UploadedFiles/research/ClinicalResearch/Patient-Registry-Report-2009.pdf
Available from:
http://www.cff.or...
,
2020. Grupo Brasileiro de Estudos de Fibrose Cística [homepage on the
Internet]. Registro Brasileiro de Fibrose Cística: primeiro relatório anual -
ano 2009 [cited 2013 Feb 21]. Available from:
http://www.gbefc.org.br/gbefc/estudo_gbefc_2009.pdf
Available from:
http://www.gbefc....
).
Persistent airway colonization has a devastating impact on patient's life spam and
contributes to local inflammatory response and to progressive deterioration of lung
function with age(
22. Flume PA. Pulmonary complications of cystic fibrosis. Respir Care
2009;54:618-27.
)
P. aeruginosa and S. aureus are of primary
importance in chronic infections. Gangell et al. suggested that
pulmonary inflammatory response may vary according to the infecting organism, and
P. aeruginosa was associated with greater levels of
inflammation(
2222. Gangell C, Gard S, Douglas T, Park J, de Klerk N, Keil T et al.
Inflammatory responses to individual microorganisms in the lungs of children
with cystic fibrosis. Clin Infect Dis 2011;53:425-32.
). S aureus, P.aeruginosa and B
cepacia complex are the most important bacteria in CF lung infections;
however, other agents are emerging as S. maltophilia, A. xylosoxidans,
methicillin-resistant Staphylococcus aureus (MRSA) and
nontuberculosis mycobacteria(
2020. Grupo Brasileiro de Estudos de Fibrose Cística [homepage on the
Internet]. Registro Brasileiro de Fibrose Cística: primeiro relatório anual -
ano 2009 [cited 2013 Feb 21]. Available from:
http://www.gbefc.org.br/gbefc/estudo_gbefc_2009.pdf
Available from:
http://www.gbefc....
,
2323. Rajan S, Saiman L. Pulmonary infections in patients with cystic
fibrosis. Semin Respir Infect 2002;17:47-56.
,
2424. Steinkamp G, Wiedemann B, Rietschel E, Krahl A, Gielen J,
Bärmeier H et al. Prospective evaluation of emerging bacteria in cystic
fibrosis. J Cyst Fibros 2005;4:41-8.
). In our study population, a similar pattern of microbiology
distribution was observed, with prevalence of infections by P. aeruginosa
and S. aureus, and the emergence of isolate cases of
oxacilin-resistant S. aureus, Aspergillus spp,
K. pneumonia, and other gram-negative bacteria, predominantly
in the older age group of patients. Findings for the age group 6 to 11 are
especially worrying as 64% of patients were already intermittently or chronically
colonized by P. aeruginosa at the initiation of the therapy (T0),
and this rate increased to 75% until the end of the follow-up period. In agreement
with Bonestroo et al
(
2525. Bonestroo HJ, Slieker MG, Arets HG. No positive effect of
rhdnase on the pulmonary colonization in children with cystic fibrosis. Monaldi
Arch Chest Dis 2010;73:12-7.
), we have not observed a positive effect of dornase alfa in reducing
pulmonary colonization. However, our finding contrasts with results of a randomized
study by Frederiksen et al
(
2626. Frederiksen B, Pressler T, Hansen A, Koch C, Høiby N. Effect of
aerosolized rhDNase (Pulmozyme) on pulmonary colonization in patients with
cystic fibrosis. Acta Paediatr 2006;95:1070-4.
), who demonstrated a significant reduction of airway colonization by
gram-negative or gram-positive bacteria with dornase alfa, with the exception of
P. aeruginosa. In this respect, we may speculate that our
colonization results are not consistent with the clinical outcomes observed: during
dornase alfa treatment there was a significant reduction in the number of
hospitalizations, and emergency visits due to acute exacerbations in the younger
group, in agreement to other studies(
2727. Quan JM, Tiddens HA, Sy JP, McKenzie SG, Montgomery MD, Robinson
PJ 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;139:813-20.
).
Treatment strategies for CF are known to be demanding and have a complex scheme. Analysis of procedures performed in the daily routine, several times per day, including respiratory physical therapy, regular exercises, bronchodilators, oral and inhaled antibiotics, corticosteroids, dornase alfa, pancreatic enzymes and vitamins supplements, besides home oxygen and insulin in selected cases, showed that patients and their families are constantly occupied in performing time-consuming routines and complex treatment schedules imposed by the disease, and therefore, have limited time for leisure and a poor quality of life( 2828. Sawicki GS, Rasouliyan L, McMullen AH, Wagener JS, McColley SA, Pasta DJ et al. Longitudinal assessment of health-related quality of life in an observational cohort of patients with cystic fibrosis. Pediatr Pulmonol 2011;46:36-44. ) .
A systematic review addressed the impact of dornase alfa compared to placebo or other
mucolytics on morbidity and mortality, and found that the use of dornase alfa for a
period over one month until two years was associated with an improvement in lung
function(
2929. Jones AP, Wallis C. Dornase alfa for cystic fibrosis. Cochrane
Database Syst Rev [serial on the Internet]. 2010(3):CD001127 [cited 2013 Feb
20]. Available from:
http://www.ncbi.nlm.nih.gov/pubmed/20238314
Available from:
http://www.ncbi.n...
). In our study, treatment with dornase alfa did not promote significant
changes in a mean FEV1 after one year of use, as compared to baseline, in
all age groups. It is known that an important aspect of CF evolution and prognosis
is the rate of lung function decline, and slowing this rate is crucial for long-term
survival(
1313. Konstan MW, Wagener JS, Pasta DJ, Millar SJ, Jacobs JR, Yegin A
et al. Clinical use of dornase alpha is associated with a slower rate of VEF1
decline in cystic fibrosis. Pediatr Pulmonol 2011;46:545-53.
). Recently, an association between the use of dornase alfa for a period
of two years and the reduction in the rate of FEV1 decline was observed
in a large prospective observational study(
1313. Konstan MW, Wagener JS, Pasta DJ, Millar SJ, Jacobs JR, Yegin A
et al. Clinical use of dornase alpha is associated with a slower rate of VEF1
decline in cystic fibrosis. Pediatr Pulmonol 2011;46:545-53.
). In a placebo controlled trial investigating the effects of long-term
treatment with dornase alfa, it was shown that in young patients with CF, dornase
alfa maintains lung function and reduces respiratory tract exacerbations.
Considering that the progressive decline in lung function is a hallmark of CF,
maintenance of lung function should be highlighted as an important achievement of
the treatment(
2727. Quan JM, Tiddens HA, Sy JP, McKenzie SG, Montgomery MD, Robinson
PJ 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;139:813-20.
). Similarly, our findings show a stabilization of lung function
parameters at 6 and 12 months of dornase alfa, with no reductions in FEV1
over the one year period as it would be expected(
3030. Sanders DB, Bittner RC, Rosenfeld M, Redding GJ, Goss CH.
Pulmonary exacerbations are associated with subsequent FEV1 decline in both
adults and children with cystic fibrosis. Pediatr Pulmonol
2011;46:393-400.
).Although not statistically significant, the absolute increase of 3% in
the final mean of VEF1 in the younger group may be considered as a
progress from a clinical perspective. This improvement or maintenance of
VEF1 values confirms other findings showing the advantages of early
introduction of dornase alfa for patients with mild disease (VEF1>80%)
in the reduction of lung function decline rate(
2727. Quan JM, Tiddens HA, Sy JP, McKenzie SG, Montgomery MD, Robinson
PJ 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;139:813-20.
). Delaying the decline in organ functions is one of the main goals of
current treatments for CF, and initiation of dornase alfa early in the life is one
of the identified factors associated with slower rate of decline in lung
function(
3131. McPhail GL, Acton JD, Fenchel MC, Amin RS, Seid M. Improvements
in lung function outcomes in children with cystic fibrosis are associated with
better nutrition, fewer chronic pseudomonas aeruginosa infections, and dornase
alfa use. J Pediatr 2008;153:752-7.
).
The importance of this publication resides on the fact that it was mostly prospective, following a standardized documentation used in all 16 CF centers, with a significant number of patients. Although information collected at T0 was based on retrospective data, it was important to obtain the standard patterns of care and clinical characteristics of this population before treatment. Obtaining baseline data of a population to allow future comparisons is one of the elements that contribute to the good quality of research( 1818. Abbott J, Hart A. Measuring and reporting quality of life outcomes in clinical trials in cystic fibrosis: a critical review. Health Qual Life Outcomes 2005;3:19. , 3232. Clarke SA, Eiser C. The measurement of health-related quality of life (QOL) in paediatric clinical trials: a systematic review. Health Qual Life Outcomes 2004;2:66. ). However, an extended duration of the study, a wide spread of CF Centers across Brazil and CF patient personal problems had contributed to less than ideal register of collecting data, with missing data in all age groups, that was considered a limitation of the study.
The lack of a control group not treated with dornase alfa and the heterogeneity of some clinical procedures adopted in the participating centers are also limitations of this study. The lack of a comparison group, not treated with dornase alfa, is a limitation that impairs a complete investigation about the benefits of the drug in CF patients. In view of the current recommendations regarding the use of dornase alfa, it was decided not to have a control group, as the use of placebo or another mucolytic drug would be ethically questionable( 55. Flume PA, O'Sullivan BP, Robinson KA, Goss CH, Mogayzel PJ Jr, Willey-Courand DB et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2007;176:957-69. , 3333. Shah PL, Conway S, Scott SF, Rainisio M, Wildman M, Stableforth D et al. A case-controlled study with dornase alfa to evaluate impact on disease progression over a 4-year period. Respiration 2001;68:160-4. ). Nevertheless, in our study, subjects served as their own controls as clinical information of the last 6 months prior to the study entry were rescued for each patient. Regarding variations in clinical management of the various centers, regular updating and contact between researchers have minimized differences in basic care approaches and monitoring of patients. Further multicenter research will be welcomed to clarify many clinical aspects and outcomes of CF patients without the limitations imposed by this study.
In summary, we have observed that CF patients have significant disease morbidity despite all routine therapies that they receive in CF centers. Dornase alfa promotes stabilization of lung function parameters, including FEV1, in patients aged 6-11 and ³14 years, and exerts a favorable impact on the clinical profile of CF patients irrespective of the age.
Acknowlegments
This study received technical support and medical advises from Dr. José Roberto Jardim PhD, and an educational grant from Roche, Brazil.
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-
25Bonestroo HJ, Slieker MG, Arets HG. No positive effect of rhdnase on the pulmonary colonization in children with cystic fibrosis. Monaldi Arch Chest Dis 2010;73:12-7.
-
26Frederiksen B, Pressler T, Hansen A, Koch C, Høiby N. Effect of aerosolized rhDNase (Pulmozyme) on pulmonary colonization in patients with cystic fibrosis. Acta Paediatr 2006;95:1070-4.
-
27Quan JM, Tiddens HA, Sy JP, McKenzie SG, Montgomery MD, Robinson PJ 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;139:813-20.
-
28Sawicki GS, Rasouliyan L, McMullen AH, Wagener JS, McColley SA, Pasta DJ et al. Longitudinal assessment of health-related quality of life in an observational cohort of patients with cystic fibrosis. Pediatr Pulmonol 2011;46:36-44.
-
29Jones AP, Wallis C. Dornase alfa for cystic fibrosis. Cochrane Database Syst Rev [serial on the Internet]. 2010(3):CD001127 [cited 2013 Feb 20]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20238314
» Available from: http://www.ncbi.nlm.nih.gov/pubmed/20238314 -
30Sanders DB, Bittner RC, Rosenfeld M, Redding GJ, Goss CH. Pulmonary exacerbations are associated with subsequent FEV1 decline in both adults and children with cystic fibrosis. Pediatr Pulmonol 2011;46:393-400.
-
31McPhail GL, Acton JD, Fenchel MC, Amin RS, Seid M. Improvements in lung function outcomes in children with cystic fibrosis are associated with better nutrition, fewer chronic pseudomonas aeruginosa infections, and dornase alfa use. J Pediatr 2008;153:752-7.
-
32Clarke SA, Eiser C. The measurement of health-related quality of life (QOL) in paediatric clinical trials: a systematic review. Health Qual Life Outcomes 2004;2:66.
-
33Shah PL, Conway S, Scott SF, Rainisio M, Wildman M, Stableforth D et al. A case-controlled study with dornase alfa to evaluate impact on disease progression over a 4-year period. Respiration 2001;68:160-4.
Brazilian Cystic Fibrosis Multicenter Study Group
-
Instituição: Escola Paulista de Medicina da Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
-
Fonte financiadora: Produtos Roche do Brasil. A indústria, ao fim do estudo, doou equipamentos médicos e/ou computadores a cada Centro de Fibrose Cística. O monitoramento dos Centros, quando necessário, foi feito pela pesquisadora principal e por uma monitora, com facilidades de transporte e eventuais gastos durante as viagens custeados pela Produtos Roche. O custo da análise estatística, realizada por firma independente, foi arcado pela indústria.
Publication Dates
-
Publication in this collection
Dec 2013
History
-
Received
22 Nov 2012 -
Accepted
15 May 2013