Factors associated with receiving CF care and use of telehealth in 2020 among persons with Cystic Fibrosis in the United States.

BACKGROUND: The COVID-19 pandemic resulted in the use of telehealth to deliver the cystic fibrosis (CF) care model, which recommends routine follow-up for monitoring of nutritional status, bacterial culture surveillance, pulmonary function testing, and screening for CF-related complications such as diabetes or osteoporosis. METHODS: The objective of this study was to use Cystic Fibrosis Foundation Patient Registry (CFFPR) data to quantify the extent to which persons with CF received the recommended components of the care model in 2019 versus 2020. A risk factor analysis was implemented to identify patient characteristics associated with attaining the recommended CF care and use of any telehealth using multivariable logistic regression. RESULTS: A total of 28,132 CFFPR participants were included in the study. The proportion of individuals meeting the recommendations for CF care was lower in 2020 for every indicator, and lower in adults compared to children. In adults, demographic, socioeconomic and CF-related disease covariates were significantly associated with both achieving an aggregate level of care and use of telehealth. In the pediatric population, minority race/ethnicity and markers of lower socioeconomic status were associated with a lower odds of telehealth use. In all analyses, having received the recommended level of care in 2019 was associated with a higher odds of both reported telehealth use and achieving the recommended elements of the CF care model in 2020. CONCLUSION: Fewer participants met recommendations for care in 2020 despite widespread use of telehealth, and use of telehealth did not equate to adherence to all aspects of CF care.

Antipseudomonal treatment decisions during CF exacerbation management.

BACKGROUND: Cystic fibrosis (CF) pulmonary exacerbation (PEx) treatment guidelines suggest that Pseudomonas aeruginosa (Pa) airway infection be treated with two antipseudomonal agents. METHODS: We retrospectively studied treatment responses for STOP2 PEx treatment trial (NCT02781610) participants with a history of Pa infection. Mean lung function and symptom changes from intravenous (IV) antimicrobial treatment start to Visit 2 (7 to 10 days later) were compared between those receiving one, two, and three+ antipseudomonal classes before Visit 2 by ANCOVA. Odds of PEx retreatment with IV antimicrobials within 30 days and future IV-treated PEx hazard were modeled by logistic and Cox proportional hazards regression, respectively. Sensitivity analyses limited to the most common one-, two-, and three-class regimens, to only IV/oral antipseudomonal treatments, and with more stringent Pa infection definitions were conducted. RESULTS: Among 751 participants, 50 (6.7%) were treated with one antipseudomonal class before Visit 2, while 552 (73.5%) and 149 (19.8%) were treated with two and with three+ classes, respectively. Females and participants with a negative Pa culture in the prior month were more likely to be treated with a single class. The most common single, double, and triple class regimens were beta-lactam (BL; n = 42), BL/aminoglycoside (AG; n = 459), and BL/AG/fluoroquinolone (FQ; n = 73). No lung function or symptom response, odds of retreatment, or future PEx hazard differences were observed by number of antipseudomonal classes administered in primary or sensitivity analyses. CONCLUSIONS: We were unable to identify additional benefit when multiple antipseudomonal classes are used to treat PEx in people with CF and Pa.

C-reactive protein (CRP) as a biomarker of pulmonary exacerbation presentation and treatment response.

BACKGROUND: C-reactive protein (CRP) has been proposed as a biomarker for pulmonary exacerbation (PEx) diagnosis and treatment response. CRP >75mg/L has been associated with increased risk of PEx treatment failure. We have analyzed CRP measures as biomarkers for clinical response during the STOP2 PEx study (NCT02781610). METHODS: CRP measures were collected at antimicrobial treatment start (V1), seven to 10 days later (V2), and two weeks after treatment end (V3). V1 log10CRP concentrations and log10CRP change from V1 to V3 correlations with clinical responses (changes in lung function and symptom score) were assessed by least squares regression. Odds of intravenous (IV) antimicrobial retreatment within 30 days and future PEx hazard associated with V1 and V3 CRP concentrations and V1 CRP >75 mg/L were studied by adjusted logistic regression and proportional hazards modeling, respectively. RESULTS: In all, 951 of 982 STOP2 subjects (92.7%) had CRP measures at V1. V1 log10CRP varied significantly by V1 lung function subgroup, symptom score quartile, and sex, but not by age subgroup. V1 log10CRP correlated moderately with log10CRP change at V3 (r2=0.255) but less so with lung function (r2=0.016) or symptom (r2=0.031) changes at V3. Higher V1 CRP was associated with greater response. CRP changes from V1 to V3 only weakly correlated with lung function (r2=0.061) and symptom (r2=0.066) changes. However, V3 log10CRP was associated with increased odds of retreatment (P = .0081) and future PEx hazard (P = .0114). DISCUSSION: Despite consistent trends, log10CRP change was highly variable with only limited utility as a biomarker of PEx treatment response.

Association of site of treatment with clinical outcomes following intravenous antimicrobial treatment of a pulmonary exacerbation.

BACKGROUND: In the STOP2 (Standardized Treatment of Pulmonary Exacerbations-2) study, intravenous (IV) antimicrobial treatment duration for adults with cystic fibrosis (CF) experiencing pulmonary exacerbations (PEx) was determined based on initial treatment response. The impact of home vs hospital care remains an important clinical question in CF. Our hypothesis was that STOP2 participants treated at home would have less improvement in lung function compared to those treated in the hospital. METHODS: Treating clinicians determined PEx treatment location, which was a stratification factor for STOP2 randomization. Lung function, weight, and symptom recovery were evaluated by treatment location. Propensity scores and inverse probability treatment weighting were used to test for differences in clinical response by treatment location. RESULTS: In all, 33% of STOP2 participants received IV antimicrobials in the hospital only, 46% both in the hospital and at home, and 21% at home only. Mean (95% CI) ppFEV1 improvement was significantly (p < 0.05) lower for those treated at home only, 5.0 (3.5, 6.5), compared with at home and in the hospital, 7.0 (5.9, 8.1), and in the hospital only, 8.0 (6.7, 9.4). Mean weight (p < 0.001) and symptom (p < 0.05) changes were significantly smaller for those treated at home only compared to those treated in the hospital only. CONCLUSIONS: Compared to PEx treatment at home only, treatment in the hospital was associated with greater mean lung function, respiratory symptom, and weight improvements. The limitations of home IV therapy should be addressed in order to optimize outcomes for adults with CF treated at home.

Changes in symptom scores as a potential clinical endpoint for studies of cystic fibrosis pulmonary exacerbation treatment.

INTRODUCTION: Symptom improvement was assessed as changes in the Chronic Respiratory Infection Symptom Score (CRISS) during intravenous antimicrobial exacerbation treatments among subjects from study NCT02109822. METHODS: Median daily CRISS reduction (i.e., improvement) and covariates associated with CRISS reduction by Day 14 were assessed by logistic regression. RESULTS: Among 173 subjects, median baseline CRISS was 49 [IQR 41, 56]; 93.6% had a CRISS reduction of ≥11 (minimal clinically important difference); median time to -11 reduction was 2 days [95% CI 2, 3]. The greatest median CRISS difference from baseline, on Day 17, was -26 [-29, -23]. Odds of -26 CRISS change by Day 14 were greater in subjects with higher baseline CRISS (P=.006) and younger ages (P=.041). CONCLUSIONS: CRISS response has good dynamic range and may be a useful efficacy endpoint for PEx interventional trials. The optimal use of CRISS change as an endpoint remains uncharacterized.

Building global development strategies for cf therapeutics during a transitional cftr modulator era.

As CFTR modulator therapy transforms the landscape of cystic fibrosis (CF) care, its lack of uniform access across the globe combined with the shift towards a new standard of care creates unique challenges for the development of future CF therapies. The advancement of a full and promising CF therapeutics pipeline remains a necessary priority to ensure maximal clinical benefits for all people with CF. It is through collaboration across the global CF community that we can optimize the evaluation and approval process of new therapies. To this end, we must identify areas for which harmonization is lacking and for which efficiencies can be gained to promote ethical, feasible, and credible study designs amidst the changing CF care landscape. This article summarizes the counsel from core advisors across multiple international regions and clinical trial networks, developed during a one-day workshop in October 2019. The goal of the workshop was to identify, in consideration of the highly transitional era of CFTR modulator availability, the drug development areas for which global alignment is currently uncertain, and paths forward that will enable advancement of CF therapeutic development.

Rationalizing endpoints for prospective studies of pulmonary exacerbation treatment response in cystic fibrosis.

BACKGROUND: Given the variability in pulmonary exacerbation (PEx) management within and between Cystic Fibrosis (CF) Care Centers, it is possible that some approaches may be superior to others. A challenge with comparing different PEx management approaches is lack of a community consensus with respect to treatment-response metrics. In this analysis, we assess the feasibility of using different response metrics in prospective randomized studies comparing PEx treatment protocols. METHODS: Response parameters were compiled from the recent STOP (Standardized Treatment of PEx) feasibility study. Pulmonary function responses (recovery of best prior 6-month and 12-month FEV1% predicted and absolute and relative FEV1% predicted improvement from treatment initiation) and sign and symptom recovery from treatment initiation (measured by the Chronic Respiratory Infection Symptom Score [CRISS]) were studied as categorical and continuous variables. The proportion of patients retreated within 30days after the end of initial treatment was studied as a categorical variable. Sample sizes required to adequately power prospective 1:1 randomized superiority and non-inferiority studies employing candidate endpoints were explored. RESULTS: The most sensitive endpoint was mean change in CRISS from treatment initiation, followed by mean absolute FEV1% predicted change from initiation, with the two responses only modestly correlated (R2=.157; P<0.0001). Recovery of previous best FEV1 was a problematic endpoint due to missing data and a substantial proportion of patients beginning PEx treatment with FEV1 exceeding their previous best measures (12.1% >12-month best, 19.6% >6-month best). Although mean outcome measures deteriorated approximately 2-weeks post-treatment follow-up, the effect was non-uniform: 62.7% of patients experienced an FEV1 worsening versus 49.0% who experienced a CRISS worsening. CONCLUSIONS: Results from randomized prospective superiority and non-inferiority studies employing mean CRISS and FEV1 change from treatment initiation should prove compelling to the community. They will need to be large, but appear feasible.

Probability of IV antibiotic retreatment within thirty days is associated with duration and location of IV antibiotic treatment for pulmonary exacerbation in cystic fibrosis.

BACKGROUND: There are few objective data to guide management of cystic fibrosis (CF) pulmonary exacerbations. We studied intravenous (IV) antibiotic treatment failure as defined by a need to retreat patients with IV antibiotics within 30days of completion of a prior IV antibiotic treatment for pulmonary exacerbation. METHODS: The first IV-treated exacerbation on or after Jan. 1, 2010 among US CF Foundation Patient Registry patients was studied, combining treatments separated by <7days into single treatments. IV treatment duration categories were: 1-4, 5-8, 9-12, 13-16, 17-22, and ≥23days (inclusive). Logistic regressions for IV retreatment in ≤30days were adjusted with 12 categorical covariates, including age, sex, lung function, prior-year exacerbations, CF complications, CF Care Program, and ever/never treated in hospital. RESULTS: 777 of 13,579 patients (5.7%) were retreated within 30days, with incidence varying by treatment duration: 1-4days, 8.7%; 5-8days; 6.6%; 9-12days, 3.2%; 13-16days, 4.5%; 17-22days, 6.2%; ≥23days, 10.3% and hospitalization: ever, 5.0%; never 8.5%. Adjusted odds ratios (OR) for retreatment (compared to 13-16days treatment) were: 1-4days, 1.94 [95%CI 1.49, 2.54] P<.001; 5-8days, 1.55 [1.18, 2.04] P=.002; 9-12days, 0.78 [0.58, 1.04] P=.09; 17-22days, 1.12 [0.88, 1.42] P=.37; ≥23days, 1.46 [1.12, 1.91] P=.005. Adjusted retreatment OR for never/ever hospitalized was 1.57 [1.29, 1.90] P<.001. Prior-year exacerbation number, oxygen therapy, non-invasive ventilation, and female sex were significantly associated with retreatment. Modeling hazard rate time-dependence showed that treatment duration and location-associated hazard rates attenuated within a few months after treatment. CONCLUSION: After adjustment for covariates known to be associated with increased risk of IV treatment for exacerbation, IV antibiotic treatments of <9 and ≥23days and those without hospitalization were significant risk factors for IV retreatment within 30days of completion of an exacerbation treatment.

Risk of hemoptysis in cystic fibrosis clinical trials: A retrospective cohort study.

BACKGROUND: Cystic fibrosis (CF) is characterized by airway infection and inflammation resulting in respiratory complications including hemoptysis. The objectives of this study were to characterize the risk of hemoptysis attributable to underlying disease and in the presence of standard of care therapy. METHODS: This retrospective cohort study estimated hemoptysis rates overall and by relevant risk factors utilizing adverse event data from longitudinal prospective CF clinical trials. RESULTS: Of the 1008 participants, 73% were ≤18 years old; of 929 with available spirometry, 27% had an FEV1<70% predicted. During the average 8.2 months of follow-up, 8% experienced ≥1 hemoptysis events (95% CI: 6%, 10%). Of the 125 events, 76% were mild in severity and only 9% were serious. Hemoptysis rates were greater among adults than children, those with FEV1<70% predicted, and participants infected with P. aeruginosa but not with S. aureus. CONCLUSIONS: Hemoptysis is a common adverse event among CF clinical trial participants, and particularly in adults with more severe lung disease. These results can be used to predict event occurrence in future clinical trials.

Prerenal azotemia from excessive sweating in an adult with a cystic fibrosis gene mutation.

We present the case of a 58-year-old male with chronic kidney disease who was admitted to the hospital multiple times with extracellular fluid volume depletion and prerenal azotemia. Some episodes were associated with gastrointestinal fluid losses and others with profuse diaphoresis in the absence of gastrointestinal fluid losses. At the age of 57 years, a common cystic fibrosis transmembrane conductance regulator protein mutation and a family history of cystic fibrosis were documented. We hypothesize that the abnormal cystic fibrosis transmembrane conductance regulator resulted in repeated bouts of excessive sweating, extracellular fluid volume depletion, and acute renal failure. This case is unique because of the prolonged period of time over which multiple documented episodes of prerenal acute renal failure occurred and because of the onset of the episodes in adulthood.

Hepatopulmonary syndrome occurring after orthotopic liver transplantation.

Hepatopulmonary syndrome (HPS) is an infrequent complication of liver cirrhosis. Orthotopic liver transplantation (OLT) has gained increasing acceptance as a treatment modality for HPS, although there have been reports of HPS developing after OLT with documented recurrence of cirrhosis. We describe the case of a 9-year-old boy who underwent OLT at 7 months of age because of biliary atresia. He subsequently developed HPS in the setting of chronic rejection without cirrhosis or evidence of portal hypertension. Re-OLT resulted in resolution of HPS and a good clinical outcome.

Transition programs in cystic fibrosis centers: perceptions of pediatric and adult program directors.

There is a growing population of adults with cystic fibrosis (CF) and a need for development of adult CF programs. Recommendations for transfer of patients to an adult program include a transition program. Our goal was to assess the current status of transition programs in US CF centers. In addition, we sought to determine the problems related to the transfer of patients to adult programs as perceived by CF center program directors. A survey was sent in 1998 to 110 pediatric and 44 adult program directors at CF centers approved by the Cystic Fibrosis Foundation (CFF), with a response rate of 65.5% and 72.7%, respectively: 22.2% of pediatric centers reported having a non-CFF-approved adult program, and 38.9% had no specific adult program. About one fifth of pediatric centers cited lack of an adult CF physician as an impediment to establishing an adult program. Age (82% of programs; mean, 18.5 years), but not marriage (17.1%) or pregnancy (24.8%), was used as a criterion for transfer. Criteria precluding transfer included patient/family resistance (51.4%), disease severity (50.5%), and developmental delay (46.7%). The concept of transfer is introduced to the patient and family at the time of diagnosis in a minority (14%) of programs. Over one half of the patients did not meet the adult team until the time of transfer. Pediatricians reported higher perceived parent, patient, pediatric staff, and adult staff concerns about transition issues than did adult program directors. We conclude that there is a lack of standardized programs for transfer of CF patients from a pediatric to an adult care setting, and that there are differences between pediatric and adult program directors' perceptions of concerns that CF patients, their families, and the medical teams have about transfer. These differences may impede the successful transition of patients into an adult program.

Psychological functioning of adults with cystic fibrosis.

STUDY OBJECTIVES: The purpose of this study is to assess the psychological profiles of adult patients with cystic fibrosis (CF) and to investigate predictors of patients' psychological status. PATIENTS AND METHODS: Thirty-four adults with CF completed a battery of psychological testing including the Minnesota Multiphasic Personality Inventory-2, Beck Depression Inventory, and State-Trait Anxiety inventory. These were compared to health status data, including pulmonary function testing and nutritional status measures. RESULTS: As a group, adults with CF did not demonstrate significant levels of depression, anxiety, or other psychopathology. Results were not affected by age, sex, or severity of disease. Male gender predicted higher scores for depression and anxiety, and better lung functioning predicted less anxiety. Having a higher level of psychosocial support emerged as a strong predictor of better psychological functioning. CONCLUSIONS: Overall, adults with CF report relatively healthy psychological functioning. Better lung function and a strong social support system predicted better psychological functioning, which may have implications for clinical intervention.

Effect of pulmonary rehabilitation on quality of life in patients with COPD: the use of SF-36 summary scores as outcomes measures.

PURPOSE: Pulmonary rehabilitation (PR) is an accepted therapy for patients with chronic obstructive pulmonary disease (COPD), improving both exercise capacity and quality of life (QOL). Generic measures of QOL have been criticized as being insensitive to detecting the improvement in QOL after PR in contrast to disease-specific instruments. The authors looked at the Medical Outcomes Survey Short Form 36-item questionnaire (SF-36), a generic QOL measure, to detect changes in QOL in COPD patients after completion of PR. METHODS: Patients with COPD who participated in a PR program completed the QOL questionnaire before and after completion of PR. Exercise tolerance was assessed by the 6-minute walking test. Quality of life was assessed by the SF-36; the authors calculated its eight dimensions as well as mental (MCS) and physical (PCS) component summary scores. RESULTS: The patients realized a significant improvement in exercise tolerance; 6-minute walking test distance increased from 470 +/- 104 m (mean +/- standard deviation) to 536 +/- 133 m (P = 0.0006) after PR. Quality of life also improved in nearly all dimensions and in both summary scores; PCS improved from 26.1 +/- 8.0 before PR to 30.5 +/- 9.0 after PR (P = 0.008) and MCS improved from 27.9 +/- 7.0 before PR to 34.1 +/- 5.0 after PR (P = 0.0002). CONCLUSION: The SF-36 and its summary scores are sensitive instruments to detect improvement in QOL in COPD patients after PR.

A pilot study of the efficacy of constant-infusion ceftazidime in the treatment of endobronchial infections in adults with cystic fibrosis.

STUDY OBJECTIVE: To compare the efficacy of constant-infusion ceftazidime (CTZ) with that of traditional intermittent dosing in a pilot trial. DESIGN: Prospective, crossover trial. SUBJECTS: Five adults with cystic fibrosis requiring intravenous antibiotic therapy for pulmonary exacerbations of the disease. INTERVENTIONS: Patients were initially treated with standard CTZ 2 g 3 times/day for 10 days. At the next hospitalization patients were crossed over and CTZ was administered as a constant infusion at a rate determined to achieve a serum concentration 6.6 times the minimum inhibitory concentration (MIC) of the least susceptible Pseudomonas aeruginosa isolate. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of CTZ were determined, as were MICs for all P. aeruginosa isolates. Outcome parameters of interest were changes with therapy in white blood cell count, P aeruginosa density in sputum, and pulmonary function test results. Differences in these parameters for the two forms of administration were not significant. With the exception of one patient who received 6 g/day with both regimens, the average reduction in dosage with the constant infusion was 50%. CONCLUSION: These preliminary data suggest that constant-infusion CTZ may be as safe and efficacious as intermittent dosing.