Factors Affecting Prognosis and Prediction of Outcome in Cystic Fibrosis Lung Disease

Cystic fibrosis (CF) is a multisystem disorder with a significantly shortened life expectancy with the major cause of mortality related to lung disease. Inflammation is seen in the CF airways from a very early age and contributes significantly to symptoms and disease progression. As the condition worsens over time, lung function declines, usually measured by Forced Expiratory Volume in 1 second (FEV1)% predicted, and extra-pulmonary complications often manifest. While the life expectancy in CF is still short, the median age of death and predicted survival age are continually increasing. Therapeutic interventions for CF have improved significantly in the last 20 years and now there are targeted therapies towards specific elements in CF that may impact upon exacerbation frequency, symptoms, and eventually mortality due to lung disease

Nebulized levofloxacin for chronic Burkholderia cenocepacia pulmonary infection in cystic fibrosis: A case report

We present a patient with cystic fibrosis who used nebulized levofloxacin off-label to suppress chronic Burkholderia cenocepacia pulmonary infection. The patient was initially using tobramycin inhalation powder (TIP) off-label continuously for suppression of chronic B. cenocepacia; this was changed to alternating months of nebulized levofloxacin and TIP. Following initiation of nebulized levofloxacin, the patient had significant improvement in respiratory symptom burden and lung function (as measured by forced expiratory volume in 1 second [FEV1]), and a decrease in the frequency of pulmonary exacerbations. Further research is necessary to determine whether the benefits observed with nebulized levofloxacin in our patient translate to a larger population of patients with chronic Burkholderia spp. pulmonary infection

Rare Manifestations

AATD is usually diagnosed following pulmonary or hepatic manifestations; however, rarer presentations may alert clinicians to its presence. Of these, panniculitis and anti-neutrophilic cytoplasmic autoantibody (ANCA)-positive vasculitis are the most commonly reported. Panniculitis is a histopathological finding from skin biopsies attributable to many causes. However, lobular fat necrosis with dense neutrophil infiltration on biopsy may represent AAT-related disease, a subtype associated with significant morbidity and frequent relapses. Treatment with doxycycline, dapsone and AAT replacement therapy have all shown reliable effect, with the latter particularly effective in refractory disease. A significant body of work has been performed examining the role of AATD variants in ANCA vasculitis. The association between antibodies against both myeloperoxidase and proteinase (PR)3 (both neutrophil derived) and AATD has been shown to be significant, with clear evidence of over-representation of the AATD variants in ANCA vasculitis cohorts. While in vitro mechanistic evidence exists demonstrating a role for AAT replacement in anti-PR3 positive disease, there is little evidence for its use in vivo. In addition to these two conditions, AATD has also been associated with other systemic illness but the associations are as yet not fully proven.</p

Global burden of nontuberculous mycobacteria in the cystic fibrosis population: a systematic review and meta-analysis

Background People living with cystic fibrosis have an increased risk of lung infection with nontuberculous mycobacteria (NTM), the prevalence of which is reportedly increasing. We conducted a systematic review of the literature to estimate the burden (prevalence and incidence) of NTM in the cystic fibrosis population. Methods Electronic databases, registries and grey literature sources were searched for cohort and cross-sectional studies reporting epidemiological measures (incidence and prevalence) of NTM infection or NTM pulmonary disease in cystic fibrosis. The last search was conducted in September 2021; we included reports published since database creation and registry reports published since 2010. The methodological quality of studies was appraised with the Joanna Briggs Institute tool. A random effects meta-analysis was conducted to summarise the prevalence of NTM infection, and the remaining results are presented in a narrative synthesis. Results This review included 95 studies. All 95 studies reported on NTM infection, and 14 of these also reported on NTM pulmonary disease. The pooled estimate for the point prevalence of NTM infection was 7.9% (95% CI 5.1–12.0%). In meta-regression, sample size and geographical location of the study modified the estimate. Longitudinal analysis of registry reports showed an increasing trend in NTM infection prevalence between 2010 and 2019. Conclusions The overall prevalence of NTM infection in cystic fibrosis is 7.9% and is increasing over time based on international registry reports. Future studies should report screening frequency, microbial identification methods and incidence rates of progression from NTM infection to pulmonary disease

Hyperoxemia in postsurgical sepsis/septic shock patients is associated with reduced mortality

Medicine, Faculty ofCritical Care Medicine, Division ofMedicine, Department ofReviewedFacultyResearche

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

Diagnostic agreement among experts assessing adults presenting with possible cystic fibrosis: need for improvement and implications for patient care

Background Increasing awareness of milder presentations of cystic fibrosis (CF) and greater interest in non-CF bronchiectasis are likely to lead to more CF screening by respiratory clinicians. As a result, adults who may not strictly fulfil CF diagnostic criteria yet display evidence of abnormal CF transmembrane conductance regulator (CFTR) function are being identified. The degree of agreement on diagnosis and care needs in these cases between CF clinicians remains unknown, and has implications for patient care, including access to CFTR modulator therapies. Methods We surveyed adult CF physicians in Canada, the USA, the UK and Ireland, and presented them with anonymised vignettes of adult patients referred for assessment of possible CF. Diagnostic inter-rater agreement over diagnosis, ease of classifying cases and appropriate follow-up was assessed using Krippendorff's reliability coefficient (α). Results Agreement over diagnosis (α=0.282), ease of classification (α= −0.01) and recommended follow-up (α=0.054) was weak. Clinician experience (>10 and 5–10 years versus <5 years) and location (UK and Ireland versus Canada) were associated with higher odds of recommending further testing compared with selecting a formal diagnosis (respectively, OR 2.87; p=0.022, OR 3.74; p=0.013 and OR 3.16; p=0.007). A modified standard of care was recommended in 28.7% of cases labelled as CF. 70% of respondents agreed with the statement that “Accurate distinction between CF and CFTR-related disorder has become significantly more pertinent with the advent of highly effective CFTR modulators”. Conclusions Our results demonstrate low diagnostic concordance among CF specialists assessing cases of possible adult CF and highlight an area in need of improvement

Demographic and clinical characteristics of included patients at baseline, stratified by NTM-PD status.

Demographic and clinical characteristics of included patients at baseline, stratified by NTM-PD status.</p

Assignment of reads to genomic regions produced by Picard tools.

Coding: protein-coding region. UTR: untranscribed region. Intronic: intronic region. Intergenic: intergenic region. Ribosomal: mapping to ribosomal RNA or proteins. PF not aligned: bases that passed the quality filter and were not aligned. (TIF)</p

Gene set enrichment analysis of whole blood gene expression in those who did vs. did not develop NTM-PD.

Gene set enrichment analysis of whole blood gene expression in those who did vs. did not develop NTM-PD.</p