Standardized Treatment of Pulmonary Exacerbations (STOP) study: Physician treatment practices and outcomes for individuals with cystic fibrosis with pulmonary Exacerbations.
ABSTRACT: BACKGROUND:Pulmonary Exacerbations (PEx) are associated with increased morbidity and mortality in individuals with CF. PEx management practices vary widely, and optimization through interventional trials could potentially improve outcomes. The object of this analysis was to evaluate current physician treatment practices and patient outcomes for PEx. METHODS:The Standardized Treatment of Pulmonary Exacerbations (STOP) observational study enrolled 220 participants ?12years old admitted to the hospital for PEx at 11 U.S. CF centers. Spirometry and daily symptom scores were collected during the study. Physicians were surveyed on treatment goals and their management practices were observed. Treatment outcomes were compared to stated goals. RESULTS:The mean (SD) duration of IV antibiotic treatment was 15.9 (6.0) days. Those individuals with more severe lung disease (<50% FEV1) were treated nearly two days longer than those with >50% FEV1. Physician-reported FEV1 improvement goals were 10% (95% CI: 5%, 14%) lower for patients with 6-month baseline FEV1 ?50% predicted compared with those with 6-month baseline FEV1 >50% predicted. There were clinically and statistically significant improvements in symptoms from the start of IV antibiotic treatment to the end of IV antibiotic treatment and 28days after the start of treatment. The mean absolute increase in FEV1 from admission was 9% predicted at end of IV antibiotic treatment, and 7% predicted at day 28. Only 39% fully recovered lost lung function, and only 65% recovered at least 90% of lost lung function. Treatment was deemed successful by 84% of clinicians, although 6-month baseline FEV1 was only recovered in 39% of PEx. CONCLUSIONS:In this prospective observational study of PEx, treatment regimens and durations showed substantial variation. A significant proportion of patients did not reach physician's treatment goals, yet treatment was deemed successful.
Project description:BACKGROUND:The Standardized Treatment of Pulmonary Exacerbations (STOP) program has the intent of defining best practices in the treatment of pulmonary exacerbations (PEx) in patients with cystic fibrosis (CF). The objective of this analysis was to describe the clinical presentations of patients admitted for intravenous (IV) antibiotics and enrolled in a prospective observational PEx study as well as to understand physician treatment goals at the start of the intervention. METHODS:We enrolled adolescents and adults admitted to the hospital for a PEx treated with IV antibiotics. We recorded patient and PEx characteristics at the time of enrollment. We surveyed treating physicians on treatment goals as well as their willingness to enroll patients in various study designs. Additional demographic and clinical data were obtained from the CF Foundation Patient Registry. RESULTS:Of 220 patients enrolled, 56% were female, 19% were adolescents, and 71% were infected with P. aeruginosa. The mean (SD) FEV1 at enrollment was 51.1 (21.6)% predicted. Most patients (85%) experienced symptoms for ?7days before admission, 43% had received IV antibiotics within the previous 6months, and 48% received oral and/or inhaled antibiotics prior to IV antibiotic initiation. Forty percent had ?10% FEV1 decrease from their best value recorded in the previous 6months, but for 20% of patients, their enrollment FEV1 was their best FEV1 recorded within the previous 6months. Physicians reported that their primary treatment objectives were lung function recovery (53%) and improvement of symptoms (47%) of PEx. Most physicians stated they would enroll patients in studies involving 10-day (72%) or 14-day (87%), but not 7-day (29%), treatment regimens. CONCLUSIONS:Based on the results of this study, prospective studies are feasible and physician willingness for interventional studies of PEx exists. Results of this observational study will help design future PEx trials.
Project description:BACKGROUND:Pulmonary exacerbations (PEx) in cystic fibrosis (CF) are common and contribute to morbidity and mortality. Duration of IV antibiotic therapy to treat PEx varies widely in the US, and there are few data to guide treatment decisions. METHODS:We combined a survey of CF stakeholders with retrospective analyses of a recent observational study of CF PEx to design a multicenter, randomized, prospective study comparing the efficacy and safety of different durations of IV antibiotics for PEx to meet the needs of people with CF and their caregivers. RESULTS:IV antibiotic duration was cited as the most important PEx research question by responding CF physicians and top concern among surveyed CF patients/caregivers. During PEx, forced expiratory volume in 1s (FEV1% predicted) and symptom responses at 7-10days of IV antibiotics identified two distinct groups: early robust responders (ERR) who subsequently experienced greater FEV1 improvements compared to non-ERR (NERR). In addition to greater FEV1 and symptom responses, only 14% of ERR patients were treated with IV antibiotics for >15days, compared with 45% of NERR patients. CONCLUSIONS:A divergent trial design that evaluates subjects' interim improvement in FEV1 and symptoms to tailor randomization to IV treatment duration (10 vs. 14days for ERR, 14 vs. 21days for NERR) may alleviate physician and patient concerns about excess or inadequate treatment. Such a study has the potential to provide evidence necessary to standardize IV antibiotic duration in CF PEx care -a first step to conducting PEx research of other treatment features.
Project description:Patients with cystic fibrosis (CF) experience frequent pulmonary exacerbations (PExs). Clinicians manage these episodes of worsening signs and symptoms in a variety of ways.To characterize the antibiotic management and associated change in lung function following PExs.We used 2003-2005 data from the Epidemiologic Study of Cystic Fibrosis to examine antibiotic treatment and the immediate and long-term lung function change associated with clinician reported PExs.A total of 45,374 PExs were reported in 13,194 unique patients. Most PExs (73%) were treated with oral antibiotics, while 39% were treated IV and 24% were treated with inhaled antibiotics. The likelihood of non-IV versus IV antibiotic treatment was associated with the patient's age, stage of lung disease, and magnitude of lung function drop prior to the PEx. Following treatment, the average improvement in the FEV1 was 3.4 ± 12.2% predicted with a greater (5.1 ± 12.7% predicted) improvement following IV antibiotic treatment than with non-IV treatment (2.0 ± 11.6% predicted). When the best FEV1 from the year before was compared with 180 days following the PEx there was an average fall of 3.8 ± 10.5% predicted with little difference observed between antibiotic treatment routes. Patients with only one exacerbation during the 3-year study had a similar loss of lung function to patients with no reported exacerbations.Clinicians treat the majority of PExs with oral antibiotics, particularly in younger, healthier patients. Pulmonary function improves with antibiotic therapy, however, PExs are associated with lung function deterioration over time.
Project description:BACKGROUND:Pulmonary exacerbations (PEx) in children with cystic fibrosis (CF) are frequently treated in the outpatient setting with oral antibiotics. However, little is known about the characteristics of PEx managed on an outpatient basis and the effectiveness of oral antibiotic therapy. We sought to prospectively evaluate clinical and laboratory changes associated with oral antibiotic treatment for PEx. METHODS:Children with CF between 8 and 18?years of age prescribed two weeks of oral antibiotics for a PEx were eligible to enroll. The study consisted of a visit within 48?h of starting antibiotics and a second visit within one week of antibiotic completion. Twenty-eight participants were evaluated by exacerbation score, quality of life measurements, lung function, sputum microbiology and inflammation. RESULTS:Oral antibiotic treatment was associated with a significant improvement in exacerbation score and quality of life measured by the CF Questionnaire-Revised (CFQ-R) respiratory domain. Following treatment, forced expiratory volume in 1?s (FEV1) % predicted increased [median (range)] 9% (-8%, 31%), and 22 (81%) subjects returned to 90% or higher of baseline FEV1. Bacterial density of the primary organism identified on sputum culture decreased significantly with a median (range) decrease of 0.8 log10 cfu/mL (-8 log10, 2 log10, p?=?0.03). Sputum neutrophil elastase [-37??g/mL (-464, 272), p?=?0.02] and IL-1? [-2.8?×?103?g/mL (-6.9?×?104, 3.3?×?104), p?=?0.03] decreased significantly following treatment in this cohort. CONCLUSIONS:Treatment of PEx with oral antibiotics was associated with measurable improvements in patient reported outcomes, lung function, bacterial density and sputum inflammatory markers.
Project description:BACKGROUND:Patients with CF treated for pulmonary exacerbations (PEx) may experience faster subsequent declines in FEV1. Additionally, incomplete recovery to baseline FEV1 occurs frequently following PEx treatment. Whether accelerated declines in FEV1 are preceded by poor PEx recovery has not been studied. METHODS:Using 2004 to 2011 CF Foundation Patient Registry data, we randomly selected one PEx among patients ?6years of age with no organ transplantations, ?12months of data before and after the PEx, and ?1 FEV1 recorded within the 6months before and 3months after the PEx. We defined poor PEx recovery as the best FEV1 in the 3months after the PEx <90% of the best FEV1 in the 6months before the PEx. We calculated mean (95% CI) hazard ratios (HR) of having >5% predicted/year FEV1 decline and poor PEx recovery using multi-state Markov models. RESULTS:From 13,954 PEx, FEV1 declines of >5% predicted/year were more likely to precede poor spirometric recovery, HR 1.17 (1.08, 1.26), in Markov models adjusted for age and sex. Non-Responders were less likely to have a subsequent fast FEV1 decline, HR 0.41 (0.37, 0.46), than patients who recovered to >90% of baseline FEV1 following PEx treatment. CONCLUSIONS:Accelerated declines in FEV1 are more likely to precede a PEx with poor recovery than to occur in the following year. Preventing or halting declines in FEV1 may also have the benefit of preventing PEx episodes.
Project description:RATIONALE:C-reactive protein (CRP) is a systemic marker of inflammation that correlates with disease status in cystic fibrosis (CF). The clinical utility of CRP measurement to guide pulmonary exacerbation (PEx) treatment decisions remains uncertain. OBJECTIVES:To determine whether monitoring CRP during PEx treatment can be used to predict treatment response. We hypothesized that early changes in CRP can be used to predict treatment response. METHODS:We reviewed all PEx events requiring hospitalization for intravenous (IV) antibiotics over 2 years at our institution. 83 PEx events met our eligibility criteria. CRP levels from admission to day 5 were evaluated to predict treatment non-response, using a modified version of a prior published composite definition. CRP was also evaluated to predict time until next exacerbation (TUNE). MEASUREMENTS AND MAIN RESULTS:53% of 83 PEx events were classified as treatment non-response. Paradoxically, 24% of PEx events were characterized by a ? 50% increase in CRP levels within the first five days of treatment. Absolute change in CRP from admission to day 5 was not associated with treatment non-response (p = 0.58). Adjusted for FEV1% predicted, admission log10 CRP was associated with treatment non-response (OR: 2.39; 95% CI: 1.14 to 5.91; p = 0.03) and shorter TUNE (HR: 1.60; 95% CI: 1.13 to 2.27; p = 0.008). The area under the receiver operating characteristics (ROC) curve of admission CRP to predict treatment non-response was 0.72 (95% CI 0.61-0.83; p<0.001). 23% of PEx events were characterized by an admission CRP of > 75 mg/L with a specificity of 90% for treatment non-response. CONCLUSIONS:Admission CRP predicts treatment non-response and time until next exacerbation. A very elevated admission CRP (>75mg/L) is highly specific for treatment non-response and might be used to target high-risk patients for future interventional studies aimed at improving exacerbation outcomes.
Project description:RATIONALE:People with CF treated with IV antibiotics for a pulmonary exacerbation (PEx) frequently fail to recover to baseline FEV1 . The long-term impact of these events has not been studied. OBJECTIVES:To determine if a patient's spirometric recovery after a PEx is associated with time to next PEx within 1 year, the spirometric recovery after the next PEx, and/or the number of PEx episodes in the next 3 years. METHODS:We used data from the CF Foundation Patient Registry from 2004 to 2011. We randomly selected one PEx per patient that met inclusion/exclusion criteria. Patients were defined as Non-Responders if their best FEV1 (in liters) recorded in the 3 months after the PEx was <90% of the best FEV1 (in liters) in the 6 months before the PEx. We compared Responders and Non-Responders using multivariable regression models. RESULTS:We randomly chose 13?954 PEx episodes that met inclusion/exclusion criteria. A total of 2?762 (19.8%) patients were classified as Non-Responders. Non-Responders had a shorter median time to the next PEx, 235 (95%CI 218, 252) days, versus >365 days for Responders. Thirty-four percent of Non-Responders at the initial PEx were also Non-Reponders at the next PEx, versus 20% of Responders at the initial PEx. Non-Responders had more PEx episodes over the next 3 years, 4.99 (95%CI 4.84, 5.13), than Responders, 3.46 (95%CI 3.41, 3.51). CONCLUSIONS:Poor recovery after a PEx is associated with a shorter time to the next PEx, increased risk of poor recovery at a second PEx, and more frequent subsequent PEx treatments.
Project description:Pulmonary exacerbations (PEx) are clinically impactful events for individuals with CF. Unfortunately, many CF individuals with PEx fail to regain their baseline lung function despite treatment. The objective of this study was to use unbiased proteomic technology to identify novel blood protein biomarkers that change following intravenous (IV) antibiotic treatment and to explore if changes correlate with clinical response by the end of treatment. Blood samples from 25 PEx events derived from 22 unique CF adults were collected within 24?hours of hospital admission, day 5, day 10, and IV antibiotic completion. Three-hundred and forty-six blood proteins were evaluated with label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) quantitative proteomics and immunoassays. Forty-seven plasma proteins changed significantly following 5 days of IV antibiotic treatment (q-value???0.10). Early change in IGF2R from hospital admission to day 5 correlated with overall change in symptom score (CFRSD-CRISS) by the end of treatment (r?=?-0.48, p-value?=?0.04). Several plasma proteins identified and quantified by label-free LC-MS/MS changed early following treatment with IV antibiotics and many of these proteins are involved in complement activation and inflammatory/immune-related pathways. Early change in IGF2R correlated with symptom response following IV antibiotic treatment and requires further validation as a predictive biomarker of symptom response.
Project description:Pulmonary exacerbations (PEx) are clinically impactful events for individuals with CF. Unfortunately, many CF individuals with PEx fail to regain their baseline lung function despite treatment. The objective of this study was to use unbiased proteomic technology (LC-MS/MS) to identify novel blood protein biomarkers that change following intravenous (IV) antibiotic treatment and to explore if changes correlate with clinical response by the end of treatment. Blood samples from 25 PEx events derived from 22 unique CF adults were collected within 24 hours of hospital admission, day 5, day 10, and IV antibiotic completion. Three-hundred and forty-six blood proteins were evaluated with label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) quantitative proteomics and immunoassays. Forty-seven plasma proteins changed significantly following 5 days of IV antibiotic treatment (q-value ≤ 0.10). Early change in IGF2R from hospital admission to day 5 correlated with overall change in symptom score (CFRSD-CRISS) by the end of treatment (r = -0.48, p-value = 0.04). Several plasma proteins identified and quantified by label-free LC-MS/MS changed early following treatment with IV antibiotics and many of these proteins are involved in complement activation and inflammatory/immune-related pathways. Early change in IGF2R correlated with symptom response following IV antibiotic treatment and requires further validation as a predictive biomarker of symptom response.
Project description:Pulmonary exacerbations (PEx) in Cystic Fibrosis (CF) are associated with an increased morbidity and even mortality. We investigated whether early detection of PEx in children with CF is possible by electronic home monitoring of symptoms and lung function. During this one-year prospective multi-centre study, 49 children with CF were asked to use a home monitor three times a week. Measurements consisted of a respiratory symptom questionnaire and assessment of Forced Expiratory Volume in one second (FEV1). Linear mixed-effects and multiple logistic regression analyses were used. In the 2 weeks before a PEx, the Respiratory Symptom Score (RSS) of the home monitor increased (p?=?0.051). The FEV1 as percentage of predicted (FEV1%pred) did not deteriorate in the 4 weeks before a PEx. Nevertheless, the FEV1%pred at the start of exacerbation was significantly lower than the FEV1%pred in the non-exacerbation group (mean difference 16.3%, p?=?0.012). The combination of FEV1%pred and RSS had a sensitivity to predict an exacerbation of 92.9% (CI 75.0-98.8%) and a specificity of 88.9% (CI 50.7-99.4%). The combination of home monitor FEV1%pred and RSS can be helpful to predict a PEx in children with CF at an early stage.