A comparison of aminoglycoside antibiotic serum concentrations collected by peripheral veins and peripherally inserted central catheters in adults with cystic fibrosis.

BACKGROUND: People with cystic fibrosis (PwCF) are frequently hospitalized for treatment of pulmonary exacerbation. The Cystic Fibrosis Foundation Pulmonary Guidelines support the use of intravenous aminoglycosides with therapeutic drug monitoring for the treatment of pulmonary exacerbation due to Pseudomonas aeruginosa. Serum intravenous tobramycin concentrations are commonly collected by peripheral venipuncture (PV). Discomfort associated with collection of samples by PV prompts collection via PICC, but the accuracy of intravenous tobramycin serum levels collected by PICC has not been documented in adult PwCF. The primary study objective was to evaluate the difference between intravenous tobramycin serum levels collected by PV and PICC in adult PwCF. METHODS: The authors conducted a prospective case-control study of adult PwCF admitted to University of Utah Health for a pulmonary exacerbation receiving tobramycin by a single lumen PICC. The authors compared tobramycin peak and random serum levels collected by PV and PICC using a detailed flush and waste protocol. RESULTS: The authors analyzed a total of 19 patients with peripheral and PICC samples. The mean tobramycin peak collected by PV (27.2 mcg/mL) was similar to the mean peak collected by PICC (26.9 mcg/mL) (paired samples Wilcoxon signed-rank test, p = .94). The correlation coefficient was 0.88 (95% CI = 0.85-0.91, p < .001). CONCLUSION: Tobramycin serum samples collected by PICC appear to be similar in value to PV collections. Collecting aminoglycoside levels by PICC rather than PV may reduce patient discomfort and improve quality of life. Additional multicenter studies are needed to confirm these results.

Airway inflammation accelerates pulmonary exacerbations in cystic fibrosis.

Airway inflammation underlies cystic fibrosis (CF) pulmonary exacerbations. In a prospective multicenter study of randomly selected, clinically stable adolescents and adults, we assessed relationships between 24 inflammation-associated molecules and the future occurrence of CF pulmonary exacerbation using proportional hazards models. We explored relationships for potential confounding or mediation by clinical factors and assessed sensitivities to treatments including CF transmembrane regulator (CFTR) protein synthesis modulators. Results from 114 participants, including seven on ivacaftor or lumacaftor-ivacaftor, representative of the US CF population during the study period, identified 10 biomarkers associated with future exacerbations mediated by percent predicted forced expiratory volume in 1 s. The findings were not sensitive to anti-inflammatory, antibiotic, and CFTR modulator treatments. The analyses suggest that combination treatments addressing RAGE-axis inflammation, protease-mediated injury, and oxidative stress might prevent pulmonary exacerbations. Our work may apply to other airway inflammatory diseases such as bronchiectasis and the acute respiratory distress syndrome.

SARS-CoV-2 innate effector associations and viral load in early nasopharyngeal infection.

COVID-19 causes severe disease with poor outcomes. We tested the hypothesis that early SARS-CoV-2 viral infection disrupts innate immune responses. These changes may be important for understanding subsequent clinical outcomes. We obtained residual nasopharyngeal swab samples from individuals who requested COVID-19 testing for symptoms at drive-through COVID-19 clinical testing sites operated by the University of Utah. We applied multiplex immunoassays, real-time polymerase chain reaction assays and quantitative proteomics to 20 virus-positive and 20 virus-negative samples. ACE-2 transcripts increased with infection (OR =17.4, 95% CI [CI] =4.78-63.8) and increasing viral N1 protein transcript load (OR =1.16, CI =1.10-1.23). Transcripts for two interferons (IFN) were elevated, IFN-λ1 (OR =71, CI =7.07-713) and IFN-λ2 (OR =40.2, CI =3.86-419), and closely associated with viral N1 transcripts (OR =1.35, CI =1.23-1.49 and OR =1.33 CI =1.20-1.47, respectively). Only transcripts for IP-10 were increased among systemic inflammatory cytokines that we examined (OR =131, CI =1.01-2620). We found widespread discrepancies between transcription and translation. IFN proteins were unchanged or decreased in infected samples (IFN-γ OR =0.90 CI =0.33-0.79, IFN-λ2,3 OR =0.60 CI =0.48-0.74) suggesting viral-induced shut-off of host antiviral protein responses. However, proteins for IP-10 (OR =3.74 CI =2.07-6.77) and several interferon-stimulated genes (ISG) increased with viral load (BST-1 OR =25.1, CI =3.33-188; IFIT1 OR =19.5, CI =4.25-89.2; IFIT3 OR =245, CI =15-4020; MX-1 OR =3.33, CI =1.44-7.70). Older age was associated with substantial modifications of some effects. Ambulatory symptomatic patients had an innate immune response with SARS-CoV-2 infection characterized by elevated IFN, proinflammatory cytokine and ISG transcripts, but there is evidence of a viral-induced host shut-off of antiviral responses. Our findings may characterize the disrupted immune landscape common in patients with early disease.

SARS-CoV-2 Innate Effector Associations and Viral Load in Early Nasopharyngeal Infection.

To examine innate immune responses in early SARS-CoV-2 infection that may change clinical outcomes, we compared nasopharyngeal swab data from 20 virus-positive and 20 virus-negative individuals. Multiple innate immune-related and ACE-2 transcripts increased with infection and were strongly associated with increasing viral load. We found widespread discrepancies between transcription and translation. Interferon proteins were unchanged or decreased in infected samples suggesting virally-induced shut-off of host anti-viral protein responses. However, IP-10 and several interferon-stimulated gene proteins increased with viral load. Older age was associated with modifications of some effects. Our findings may characterize the disrupted immune landscape of early disease.

Prospective multicenter randomized patient recruitment and sample collection to enable future measurements of sputum biomarkers of inflammation in an observational study of cystic fibrosis.

BACKGROUND: Biomarkers of inflammation predictive of cystic fibrosis (CF) disease outcomes would increase the power of clinical trials and contribute to better personalization of clinical assessments. A representative patient cohort would improve searching for believable, generalizable, reproducible and accurate biomarkers. METHODS: We recruited patients from Mountain West CF Consortium (MWCFC) care centers for prospective observational study of sputum biomarkers of inflammation. After informed consent, centers enrolled randomly selected patients with CF who were clinically stable sputum producers, 12 years of age and older, without previous organ transplantation. RESULTS: From December 8, 2014 through January 16, 2016, we enrolled 114 patients (53 male) with CF with continuing data collection. Baseline characteristics included mean age 27 years (SD = 12), 80% predicted forced expiratory volume in 1 s (SD = 23%), 1.0 prior year pulmonary exacerbations (SD = 1.2), home elevation 328 m (SD = 112) above sea level. Compared with other patients in the US CF Foundation Patient Registry (CFFPR) in 2014, MWCFC patients had similar distribution of sex, age, lung function, weight and rates of exacerbations, diabetes, pancreatic insufficiency, CF-related arthropathy and airway infections including methicillin-sensitive or -resistant Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, fungal and non-tuberculous Mycobacteria infections. They received CF-specific treatments at similar frequencies. CONCLUSIONS: Randomly-selected, sputum-producing patients within the MWCFC represent sputum-producing patients in the CFFPR. They have similar characteristics, lung function and frequencies of pulmonary exacerbations, microbial infections and use of CF-specific treatments. These findings will plausibly make future interpretations of quantitative measurements of inflammatory biomarkers generalizable to sputum-producing patients in the CFFPR.

Sleep Phase Delay in Cystic Fibrosis: A Potential New Manifestation of Cystic Fibrosis Transmembrane Regulator Dysfunction.

BACKGROUND: Cystic fibrosis (CF) transmembrane regulator (CFTR) protein dysfunction causes CF. Improving survival allows detection of increasingly subtle disease manifestations. CFTR dysfunction in the central nervous system (CNS) may disturb circadian rhythm and thus sleep phase. We studied sleep in adults to better understand potential CNS CFTR dysfunction. METHODS: We recruited participants from April 2012 through April 2015 and administered the Munich Chronotype Questionnaire (MCTQ). We compared free-day sleep measurements between CF and non-CF participants and investigated associations with CF survival predictors. RESULTS: We recruited 23 female and 22 male adults with CF aged 18 to 46 years and 26 female and 22 male volunteers aged 18 to 45 years. Compared with volunteers without CF, patients with CF had delayed sleep onset (0.612 h; P = .015), midsleep (1.11 h; P < .001), and wake (1.15 h; P < .001) times and prolonged sleep latency (7.21 min; P = .05) and duration (0.489 h; P = .05). Every hour delay in sleep onset was associated with shorter sleep duration by 0.29 h in patients with CF and 0.75 h in subjects without CF (P = .007) and longer sleep latency by 7.51 min in patients with CF and 1.6 min in volunteers without CF (P = .035). Among patients with CF, FEV1 % predicted, prior acute pulmonary exacerbations, and weight were independent of all free-day sleep measurements. CONCLUSIONS: CF in adults is associated with marked delays in sleep phase consistent with circadian rhythm phase delays. Independence from disease characteristics predictive of survival suggests that sleep phase delay is a primary manifestation of CFTR dysfunction in the CNS.

Improving performance in the detection and management of cystic fibrosis-related diabetes in the Mountain West Cystic Fibrosis Consortium.

OBJECTIVE: Cystic fibrosis (CF)-related diabetes (CFRD) is associated with increased morbidity and mortality. Improved detection and management may improve outcomes; however, actual practice falls short of published guidelines. We studied efforts to improve CFRD screening and management in the Mountain West CF Consortium (MWCFC). RESEARCH DESIGN AND METHODS: This is a prospective observational cohort study evaluating quality improvement by accredited CF centers in Arizona, Colorado, New Mexico, and Utah performed between 2002 and 2008. After Institutional Review Board (IRB) approval, centers evaluated adherence with CF Foundation guidelines for CFRD. Each center developed and implemented quality improvement plans to improve both screening and management. Centers were reassessed 1 year later. RESULTS: Initially, each CF center had low adherence with screening recommendations (26.5% of eligible patients) that did not improve during the study. However, patients with confirmed CFRD markedly increased (141 (12% of MWCFC patients) to 224 (17%), p<0.001), and with improved adherence to management guidelines, patients with CFRD had increased weight (56.8-58.9 kg, p<0.001), body mass index (21.1-21.4, p=0.003), and weight-for-age z-score (-1.42 to -0.84, p<0.001). Quality improvement methods were specific to the practice settings of each center but shared the common goal of adhering to CFRD care guidelines. 1 year after implementation, no center significantly differed from any other in level of adherence to guidelines. CONCLUSIONS: Improving adherence with CFRD care guidelines requires substantial effort and may be incompletely successful, particularly for CFRD screening, but the effort may significantly improve patient monitoring and clinically relevant outcomes such as weight.

Sputum biomarkers and the prediction of clinical outcomes in patients with cystic fibrosis.

Lung function, acute pulmonary exacerbations (APE), and weight are the best clinical predictors of survival in cystic fibrosis (CF); however, underlying mechanisms are incompletely understood. Biomarkers of current disease state predictive of future outcomes might identify mechanisms and provide treatment targets, trial endpoints and objective clinical monitoring tools. Such CF-specific biomarkers have previously been elusive. Using observational and validation cohorts comprising 97 non-transplanted consecutively-recruited adult CF patients at the Intermountain Adult CF Center, University of Utah, we identified biomarkers informative of current disease and predictive of future clinical outcomes. Patients represented the majority of sputum producers. They were recruited March 2004-April 2007 and followed through May 2011. Sputum biomarker concentrations were measured and clinical outcomes meticulously recorded for a median 5.9 (interquartile range 5.0 to 6.6) years to study associations between biomarkers and future APE and time-to-lung transplantation or death. After multivariate modeling, only high mobility group box-1 protein (HMGB-1, mean=5.84 [log ng/ml], standard deviation [SD] =1.75) predicted time-to-first APE (hazard ratio [HR] per log-unit HMGB-1=1.56, p-value=0.005), number of future APE within 5 years (0.338 APE per log-unit HMGB-1, p<0.001 by quasi-Poisson regression) and time-to-lung transplantation or death (HR=1.59, p=0.02). At APE onset, sputum granulocyte macrophage colony stimulating factor (GM-CSF, mean 4.8 [log pg/ml], SD=1.26) was significantly associated with APE-associated declines in lung function (-10.8 FEV(1)% points per log-unit GM-CSF, p<0.001 by linear regression). Evaluation of validation cohorts produced similar results that passed tests of mutual consistency. In CF sputum, high HMGB-1 predicts incidence and recurrence of APE and survival, plausibly because it mediates long-term airway inflammation. High APE-associated GM-CSF identifies patients with large acute declines in FEV(1)%, possibly providing a laboratory-based objective decision-support tool for determination of an APE diagnosis. These biomarkers are potential CF reporting tools and treatment targets for slowing long-term progression and reducing short-term severity.