Analysis of tissue lipidomics and computed tomography pulmonary fat attenuation volume (CTPFAV ) in idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: There is increasing interest in the role of lipids in processes that modulate lung fibrosis with evidence of lipid deposition in idiopathic pulmonary fibrosis (IPF) histological specimens. The aim of this study was to identify measurable markers of pulmonary lipid that may have utility as IPF biomarkers. STUDY DESIGN AND METHODS: IPF and control lung biopsy specimens were analysed using a unbiased lipidomic approach. Pulmonary fat attenuation volume (PFAV) was assessed on chest CT images (CTPFAV ) with 3D semi-automated lung density software. Aerated lung was semi-automatically segmented and CTPFAV calculated using a Hounsfield-unit (-40 to -200HU) threshold range expressed as a percentage of total lung volume. CTPFAV was compared to pulmonary function, serum lipids and qualitative CT fibrosis scores. RESULTS: There was a significant increase in total lipid content on histological analysis of IPF lung tissue (23.16 nmol/mg) compared to controls (18.66 mol/mg, p = 0.0317). The median CTPFAV in IPF was higher than controls (1.34% vs. 0.72%, p < 0.001) and CTPFAV correlated significantly with DLCO% predicted (R2 = 0.356, p < 0.0001) and FVC% predicted (R2 = 0.407, p < 0.0001) in patients with IPF. CTPFAV correlated with CT features of fibrosis; higher CTPFAV was associated with >10% reticulation (1.6% vs. 0.94%, p = 0.0017) and >10% honeycombing (1.87% vs. 1.12%, p = 0.0003). CTPFAV showed no correlation with serum lipids. CONCLUSION: CTPFAV is an easily quantifiable non-invasive measure of pulmonary lipids. In this pilot study, CTPFAV correlates with pulmonary function and radiological features of IPF and could function as a potential biomarker for IPF disease severity assessment.

Alpha-1 antitrypsin deficiency: clarifying the role of the putative protective threshold.

Alpha-1 antitrypsin deficiency (AATD) is the only readily identifiable monogenic cause of COPD. To date the only condition-specific treatment for AATD-associated COPD is weekly administration of intravenous plasma-purified human alpha-1 antitrypsin (IV-AAT). Uncertainties regarding which AATD genotypes should benefit from IV-AAT persist. IV-AAT is costly and involves weekly administration of a plasma product. Much of the risk stratification has been centred around the long-accepted hypothesis of a "putative protective threshold" of 11 µM (0.57 g·L-1) AAT in serum. This hypothesis has become central to the paradigm of AATD care, although its derivation and accuracy for defining risk of disease remain unclear.We reviewed the literature and examined the association between the 11 µM threshold and clinical outcomes to provide context and insight into the issues surrounding this topic.We found no data demonstrating an increased risk of COPD dependent on the 11 µM threshold. Moreover, an abundance of recent clinical data examining this threshold refutes the hypothesis. Conversely, the use of 11 µM as a treatment target in appropriate ZZ individuals is supported by clinical evidence, although more refined dosing regimens are being explored.Continued use of the 11 µM threshold as a determinant of clinical risk is questionable, perpetuates inappropriate AAT-augmentation practices, may drive increased healthcare expenditure and should not be used as an indicator for commencing treatment.Genotype represents a more proven indicator of risk, with ZZ and rare ZZ-equivalent genotypes independently associated with COPD. New and better risk assessment models are needed to provide individuals diagnosed with AATD with reliable risk estimation and optimised treatment goals.

Alpha-1 antitrypsin deficiency-associated panniculitis.

BACKGROUND: Panniculitis represents a rare and potentially lethal manifestation of alpha-1 antitrypsin deficiency (AATD). Evidence regarding management is limited to case reports and small case series. We sought to clarify typical features and investigation of AATD-associated panniculitis and assess the evidence regarding therapeutic options. SEARCH METHODOLOGY: Articles and abstracts published between 1970 and 2020 were identified by searches of MEDLINE, PubMed, and secondary searches of references from relevant articles using the search terms "panniculitis," "alpha-1," "antitrypsin," "deficiency," and "Weber-Christian." FINDINGS: We identified 117 cases of AATD-associated panniculitis. In 1 series, AATD was present in 15% of all cases of biopsy-proven panniculitis. Failure to achieve clinical response was seen in all instances of systemic steroid use. Dapsone, although effective and accessible, is frequently associated with failure to achieve remission. In these instances, intravenous AAT augmentation therapy generally resulted in response. CONCLUSIONS: AATD may be more prevalent among patients presenting with panniculitis than previously thought. Patients presenting with panniculitis and systemic illness show high mortality risk. Although most cases are associated with the severe ZZ-genotype, moderate genotypes may also predispose to panniculitis. Dapsone remains the most cost-effective therapeutic option, whereas intravenous AAT augmentation remains the most efficacious. Finally, glucocorticoids appear ineffective in this setting.

SZ alpha-1 antitrypsin deficiency and pulmonary disease: more like MZ, not like ZZ.

The ZZ genotype of alpha-1 antitrypsin deficiency (AATD) is associated with COPD regardless of smoking. Heterozygous MZ-AATD is recognised as a moderate deficiency state, increasing the risk of COPD only among smokers. The risk attributable to SZ-AATD remains debated. We compared 486 AATD-registry participants, to determine whether SZ-AATD was associated with pulmonary outcomes more comparable to MZ-AATD or ZZ-AATD. We found no significant differences between MZ and SZ individuals regardless of never-smoking/ever-smoking (p>0.05 for all). ZZ-AATD was associated with lower FEV1pp than SZ, regardless of never-smoking/ever-smoking, as well as an increased OR of lung-index status and visually defined emphysema on CT (p≤0.002 for all). In our registry cohort SZ-AATD is associated with a risk of lung disease comparable to MZ, not ZZ-AATD.

Clarifying the Risk of Lung Disease in SZ Alpha-1 Antitrypsin Deficiency.

Rationale: The ZZ genotype of alpha-1 antitrypsin deficiency (AATD) is associated with chronic obstructive pulmonary disease (COPD), even among never-smokers. The SZ genotype is also considered severe; yet, its effect on lung health remains unclear.Objectives: To determine the effect of SZ-AATD on spirometry compared with a normal-risk population and to determine the effect of smoking cessation in this genotype.Methods: We prospectively enrolled 166 related individuals, removing lung index cases to reduce bias, and compared spirometry between 70 SZ and 46 MM/MS individuals (control subjects). The effect of AAT concentrations on outcomes was assessed in 82 SZ individuals (including lung index cases). Subsequently, we analyzed retrospective SZ registry data to determine the effect of smoking cessation on spirometry decline (n = 60) and plasma anti-neutrophil elastase capacity (n = 20).Measurements and Main Results: No difference between SZ and control never-smokers was seen. Ever smoking was associated with a lower FEV1% predicted (-14.3%; P = 0.0092) and a lower FEV1/FVC ratio (-0.075; P = 0.0041) in SZ-AATD. No association was found between AAT concentration and outcomes for SZ-AATD. Longitudinal analysis of 60 SZ individuals demonstrated that COPD at baseline, but not former smoking or AAT concentrations, predicted greater spirometry decline. Finally, anti-neutrophil elastase capacity did not differ between former smokers and never-smokers (P = 0.67).Conclusions: SZ never-smokers demonstrated no increased risk of COPD, regardless of AAT concentration. Smoking interacts with SZ-AATD to significantly increase airflow obstruction. Former smoking alone is not associated with greater spirometry decline in SZ-AATD, suggesting that cessation attenuates the obstructive process. We found no evidence that the putative protective threshold or AAT concentrations predict risk within the SZ genotype, raising further doubts over the need for intravenous AAT augmentation in this cohort.

Alpha-1 Antitrypsin Deficiency and Tobacco Smoking: Exploring Risk Factors and Smoking Cessation in a Registry Population.

The ZZ genotype of alpha-1 antitrypsin deficiency (AATD) is strongly associated with COPD, even in never-smokers. Moderate AATD genotypes (MZ and SZ) have been shown to increase the severity of COPD in smokers. In this comparative study, we examine the association between AATD, genotypes, and smoking cessation. Two hundred and ninety-three Irish people with AATD [MZ (n = 91), SZ (n = 72), and ZZ/rare (n = 130)] completed a custom questionnaire assessing their social and smoking histories. The primary outcomes analyzed were the predictors of ever-smoking and effect of genotype on awareness of AATD and maintained smoking cessation, using logistic regression analyses. Parental smoking exposure was associated with ever-smoking status (OR 1.84 vs. no parental smoking, p = 0.018), higher cumulative tobacco consumption (23.47 vs. 14.87 pack-years, p = 0.005) and more quit attempts required to achieve cessation among former-smokers (2.97 vs. 5.60, p = 0.007). Awareness of genotype was 67.7% versus 56.3% versus 33% for ZZ, SZ, and MZ, respectively (p < 0.001). Among ever-smokers, current-smoking was uncommon (2.5% vs. 17% vs. 16% for ZZ, SZ, and MZ, respectively, p = 0.009) with ZZs significantly less likely to be current-smokers (OR 0.15 relative to MZ, p = 0.025). These results suggest that the genetic risk of COPD in AATD families is compounded by transmission of social risk factors (via parental smoking). Increasing severity of genotype is associated with lower current-smoking rates among ever-smokers. Whether this is attributable to greater awareness of risk is an area of interest. Achieving a change in smoking habits may also result in positive health behavior in subsequent generations.

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.

Management of comorbidities in difficult and severe asthma.

Difficult-to-treat and severe asthma are challenging clinical entities. In the face of suboptimal asthma control, the temptation for clinicians is to reflexively escalate asthma-directed therapy, including increasing exposure to corticosteroids and commencement of costly but potent biologic therapies. However, asthma control is objectively and subjectively assessed based on measurable parameters (such as exacerbations or variability in pulmonary physiology), symptoms and patient histories. Crucially, these features can be confounded by common untreated comorbidities, affecting clinicians' assessment of asthma treatment efficacy.

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.

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.

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.

Nanoparticle Biomolecular Corona-Based Enrichment of Plasma Glycoproteins for N-Glycan Profiling and Application in Biomarker Discovery.

Biomolecular corona formation has emerged as a recurring and important phenomenon in nanomedicine that has been investigated for potential applications in disease diagnosis. In this study, we have combined the "personalized protein corona" with the N-glycosylation profiling that has recently gained considerable interest in human plasma biomarker discovery as a powerful early warning diagnostic and patient stratification tool. We envisioned that the protein corona formation could be exploited as an enrichment step that is critically important in both proteomic and proteoglycomic workflows. By using silica nanoparticles, plasma fibrinogen was enriched to a level in which its proteomic and glycomic "fingerprints" could be traced with confidence. Despite being a more simplified glycan profile compared to full plasma, the corona glycan profile revealed a fibrinogen-derived glycan peak that was found to potentially distinguish lung cancer patients from controls in a pilot study.

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.