Pulmonary exacerbation inflammatory phenotypes in adults with cystic fibrosis.

BACKGROUND: Adults with cystic fibrosis (CF) develop exuberant inflammatory responses during pulmonary exacerbations (PEx) but whether distinct systemic inflammatory profiles can be identified and whether these associate with disparate treatment outcomes are unclear. We conducted a pilot study to address this question and hypothesized that CF adults with a pauci-inflammatory phenotype might derive less clinical benefit from intravenous (IV) antibiotic treatment than patients with other systemic inflammatory phenotypes. METHODS: Six proteins reflective of systemic inflammation were examined in 37 PEx from 28 unique CF subjects. We applied exploratory factor analysis and cluster analysis to identify biological clusters. Levels of blood proteins at PEx and clinical outcomes following IV antibiotic treatment were compared between clusters. RESULTS: Three clusters of PEx were identified. The pauci-inflammatory phenotype was characterized by lower levels of interleukin (IL)-1ß, IL-6, IL-10, tumor necrosis factor (TNF)-α, calprotectin, and C-reactive protein (CRP) (p < 0.05). Higher levels of IL-6 and IL-1ß were observed in the other 2 inflammatory clusters, but one of them was associated with higher calprotectin levels (p = 0.001) (neutrophil-predominant phenotype); whereas the other was associated with increased TNF-α and IL-10 levels (p < 0.001) (pro-inflammatory phenotype). A greater proportion of events from the neutrophil-predominant phenotype presented with acute respiratory symptoms and a larger decrease in ppFEV1 from baseline to hospital admission than the other two inflammatory phenotypes (p = 0.03). CONCLUSIONS: Three distinct inflammatory phenotypes were identified at PEx admission and each presented with unique clinical characteristics.

Whole blood RNA-seq demonstrates an increased host immune response in individuals with cystic fibrosis who develop nontuberculous mycobacterial pulmonary disease.

BACKGROUND: Individuals with cystic fibrosis have an elevated lifetime risk of colonization, infection, and disease caused by nontuberculous mycobacteria. A prior study involving non-cystic fibrosis individuals reported a gene expression signature associated with susceptibility to nontuberculous mycobacteria pulmonary disease (NTM-PD). In this study, we determined whether people living with cystic fibrosis who progress to NTM-PD have a gene expression pattern similar to the one seen in the non-cystic fibrosis population. METHODS: We evaluated whole blood transcriptomics using bulk RNA-seq in a cohort of cystic fibrosis patients with samples collected closest in timing to the first isolation of nontuberculous mycobacteria. The study population included patients who did (n = 12) and did not (n = 30) develop NTM-PD following the first mycobacterial growth. Progression to NTM-PD was defined by a consensus of two expert clinicians based on reviewing clinical, microbiological, and radiological information. Differential gene expression was determined by DESeq2. RESULTS: No differences in demographics or composition of white blood cell populations between groups were identified at baseline. Out of 213 genes associated with NTM-PD in the non-CF population, only two were significantly different in our cystic fibrosis NTM-PD cohort. Gene set enrichment analysis of the differential expression results showed that CF individuals who developed NTM-PD had higher expression levels of genes involved in the interferon (α and γ), tumor necrosis factor, and IL6-STAT3-JAK pathways. CONCLUSION: In contrast to the non-cystic fibrosis population, the gene expression signature of patients with cystic fibrosis who develop NTM-PD is characterized by increased innate immune responses.

IL-8 correlates with reduced baseline femoral neck bone mineral density in adults with cystic fibrosis: a single center retrospective study.

Cystic fibrosis (CF) is a multi-system disease that is characterized by lung disease due to recurrent airway infection and inflammation. Endocrine complications, such as CF bone disease (CFBD), are increasingly identified as patients are living longer. The cause of CFBD is multifactorial with chronic systemic inflammation theorized to be a contributing factor. Thus, we attempted to identify inflammatory biomarkers that are associated with CFBD. We conducted a retrospective observational study of 56 adult patients with CF with an average percentage predictive forced expiratory volume in one second (ppFEV1) of 73.7% (standard deviation: 30.0) who underwent baseline serum analysis for osteoprotegerin (OPG) and pro-inflammatory biomarkers (IL-1ß, IL-6, IL-8 and TNF-α), and had repeated dual-energy x-ray absorptiometry (DXA) scans separated by at least 2 years to examine correlations between serum biomarkers and bone mineral density (BMD) measurements. Univariate linear regression model analysis demonstrated that serum IL-1ß and IL-8, but not other pro-inflammatory markers, were negatively correlated with baseline BMD results. However, after accounting for confounding variables, only the relationship between IL-8 and left femoral neck BMD remained statistically significant. Additionally, IL-8 level was associated with BMD decline over time. These results suggest that IL-8 might play a unique role in the pathophysiology of CFBD relative to other pro-inflammatory cytokines but further study is warranted before firm conclusions can be made.

Circulating CRP and calprotectin to diagnose CF pulmonary exacerbations.

Cystic fibrosis (CF) pulmonary exacerbations (PEx) remain underdiagnosed by CF clinicians. Serum C-reactive protein (CRP) and calprotectin are inflammatory biomarkers that have the potential to aid in the diagnosis of PEx. 19 subjects (56 stable, 46 PEx visits) from a longitudinal study were included and the diagnostic performance of absolute and fold-change CRP and calprotectin cut-offs to discriminate stable and PEx visits was assessed. Based on Youden's index, optimal absolute and fold-change thresholds to identify PEx were 9.5 mg/L (Sn 76%, Sp 73%; AUC 0.76) and 2.2-fold (Sn 50%, Sp 96%; AUC 0.78) for CRP and 8.1 mg/L (Sn 61%, Sp 79%; AUC 0.72) and 1.3-fold (Sn 57%, Sp 88%; AUC 0.74) for calprotectin. A step-wise algorithm was able to improve diagnostic performance (Sn 80%; Sp 88%). CRP and calprotectin could discriminate stable vs. PEx visits with good performance and appear promising as diagnostic biomarkers but further validation studies are required prior to implementing these diagnostic thresholds.

Duplex Ultrasound for Diagnosis of Failing Stents Placed for Lower Extremity Arterial Occlusive Disease.

BACKGROUND: Noninvasive diagnostic testing may be beneficial to identify stenotic (failing) stents placed for occlusive lower extremity peripheral arterial disease (LEPAD), especially if subsequent intervention proves useful in maintaining prolonged stent patency. We previously documented the benefit of surveillance duplex ultrasound (DU) for peripheral covered stents (stent grafts). The purpose of this study was to evaluate whether DU can reliably diagnose failing bare metal stents placed in iliac, femoral, and popliteal arteries for LEPAD. METHODS: Between January 1, 2013, and December 31, 2016, 172 stents were placed for LEPAD in 119 arterial segments (1.4 stents/stenotic artery) in 110 patients who underwent one or more DU surveillance study documenting stent patency. Poststent DU surveillance was performed in our Intersocietal Accreditation Commission accredited noninvasive vascular lab at 1 week and then every 6 months. DU measured peak systolic velocities (PSVs) and ratio of adjacent PSVs (Vr) every 2.0 cm within the stent(s) and adjacent arteries. We retrospectively classified the following factors as "abnormal DU findings": focal PSVs >300 cm/s, uniform PSVs <45 cm/s, and Vr > 3.0. RESULTS: During average follow-up of 22 months (range, 1 week-48 months), all three of these DU criteria were "normal" in 62 (52%) of the 119 stented segments. Of the other 57 (48%) stented arterial segments that had one or more abnormal DU findings, 40 underwent prophylactic intervention, 12 patients did not undergo intervention and subsequently occluded (5 patient refusal, 4 surgeon-decision, 3 shortened surveillance interval), and 5 remained patent after mean follow-up of 7.2 months. Of the 12 arterial segments that occluded, 6 patients chose not to have further intervention, 4 failed additional endovascular intervention and required an arterial bypass, and 2 required amputation. Therefore, of the 17 stented arterial segments with one or more abnormal DU findings that did not undergo intervention, 12 (70%) went on to occlude versus 2 of 62 (3%) with normal DU findings demonstrating an odds ratio of 72.0 (95% CI 12.5-415.6, P < 0.0001). Of these 12 stented arterial segments with abnormal DU findings that occluded, 7 had uniform low PSVs alone, 3 had both abnormal PSV and Vr's, and 2 had abnormal Vr's alone. CONCLUSIONS: DU surveillance can predict LEPAD stent occlusion. While PSV >300 cm/sec alone is not a statistically significant predictor of stent failure, Vr > 3.0, and most importantly, uniform PSVs <45 cm/s throughout the stent were statistically reliable markers for predicting stent thrombosis, while the absence of any of these abnormalities strongly predicted stent patency.

Antiretroviral adherence and the nature of HIV-associated verbal memory impairment.

The authors investigated the relationship between antiretroviral adherence and HIV-associated verbal memory impairment. HIV-positive participants demonstrated poorer verbal memory than HIV-negative participants. Both good (≥90%) and poor (<90%) adherers displayed encoding deficits as compared with controls, but only poor adherers exhibited retrieval deficits. Encoding deficits primarily accounted for reduced delayed recall in good adherers, but both encoding and retrieval deficits accounted for reduced delayed recall in poor adherers. The retrieval difference between the adherence groups might be explained by a neuroprotective effect of good antiretroviral adherence or preexisting HIV-related retrieval deficits that result in poorer adherence.