Fatigue and symptom-based clusters in post COVID-19 patients: a multicentre, prospective, observational cohort study.

BACKGROUND: In the Netherlands, the prevalence of post COVID-19 condition is estimated at 12.7% at 90-150 days after SARS-CoV-2 infection. This study aimed to determine the occurrence of fatigue and other symptoms, to assess how many patients meet the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) criteria, to identify symptom-based clusters within the P4O2 COVID-19 cohort and to compare these clusters with clusters in a ME/CFS cohort. METHODS: In this multicentre, prospective, observational cohort in the Netherlands, 95 post COVID-19 patients aged 40-65 years were included. Data collection at 3-6 months after infection included demographics, medical history, questionnaires, and a medical examination. Follow-up assessments occurred 9-12 months later, where the same data were collected. Fatigue was determined with the Fatigue Severity Scale (FSS), a score of ≥ 4 means moderate to high fatigue. The frequency and severity of other symptoms and the percentage of patients that meet the ME/CFS criteria were assessed using the DePaul Symptom Questionnaire-2 (DSQ-2). A self-organizing map was used to visualize the clustering of patients based on severity and frequency of 79 symptoms. In a previous study, 337 Dutch ME/CFS patients were clustered based on their symptom scores. The symptom scores of post COVID-19 patients were applied to these clusters to examine whether the same or different clusters were found. RESULTS: According to the FSS, fatigue was reported by 75.9% of the patients at 3-6 months after infection and by 57.1% of the patients 9-12 months later. Post-exertional malaise, sleep disturbances, pain, and neurocognitive symptoms were also frequently reported, according to the DSQ-2. Over half of the patients (52.7%) met the Fukuda criteria for ME/CFS, while fewer patients met other ME/CFS definitions. Clustering revealed specific symptom patterns and showed that post COVID-19 patients occurred in 11 of the clusters that have been observed in the ME/CFS cohort, where 2 clusters had > 10 patients. CONCLUSIONS: This study shows persistent fatigue and diverse symptomatology in post COVID-19 patients, up to 12-18 months after SARS-CoV-2 infection. Clustering showed that post COVID-19 patients occurred in 11 of the clusters that have been observed in the ME/CFS cohort.

Associations between spirometric impairments and microvascular complications in type 2 diabetes: a cross-sectional study.

OBJECTIVE: Evidence shows that the conventional cardiometabolic risk factors do not fully explain the burden of microvascular complications in type 2 diabetes (T2D). One potential factor is the impact of pulmonary dysfunction on systemic microvascular injury. We assessed the associations between spirometric impairments and systemic microvascular complications in T2D. DESIGN: Cross-sectional study. SETTING: National Diabetes Management and Research Centre in Ghana. PARTICIPANTS: The study included 464 Ghanaians aged ≥35 years with established diagnosis of T2D without primary myocardial disease or previous/current heart failure. Participants were excluded if they had primary lung disease including asthma or chronic obstructive pulmonary disease. PRIMARY AND SECONDARY OUTCOME MEASURES: The associations of spirometric measures (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio) with microvascular complications (nephropathy (albumin-creatinine ratio ≥3 mg/g), neuropathy (vibration perception threshold ≥25 V and/or Diabetic Neuropathy Symptom score >1) and retinopathy (based on retinal photography)) were assessed using multivariable logistic regression models with adjustments for age, sex, diabetes duration, glycated haemoglobin concentration, suboptimal blood pressure control, smoking pack years and body mass index. RESULTS: In age and sex-adjusted models, lower Z-score FEV1 was associated with higher odds of nephropathy (OR 1.55, 95% CI 1.19-2.02, p=0.001) and neuropathy (1.27 (1.01-1.65), 0.038) but not retinopathy (1.22 (0.87-1.70), 0.246). Similar observations were made for the associations of lower Z-score FVC with nephropathy (1.54 (1.19-2.01), 0.001), neuropathy (1.25 (1.01-1.54), 0.037) and retinopathy (1.19 (0.85-1.68), 0.318). In the fully adjusted model, the associations remained significant for only lower Z-score FEV1 with nephropathy (1.43 (1.09-1.87), 0.011) and neuropathy (1.34 (1.04-1.73), 0.024) and for lower Z-score FVC with nephropathy (1.45 (1.11-1.91), 0.007) and neuropathy (1.32 (1.03-1.69), 0.029). Lower Z-score FEV1/FVC ratio was not significantly associated with microvascular complications in age and sex and fully adjusted models. CONCLUSION: Our study shows positive but varying strengths of associations between pulmonary dysfunction and microvascular complications in different circulations. Future studies could explore the mechanisms linking pulmonary dysfunction to microvascular complications in T2D.

Haemophilus influenzae and Moraxella catarrhalis in sputum of severe asthma with inflammasome and neutrophil activation.

BACKGROUND: Because of altered airway microbiome in asthma, we analysed the bacterial species in sputum of patients with severe asthma. METHODS: Whole genome sequencing was performed on induced sputum from non-smoking (SAn) and current or ex-smoker (SAs/ex) severe asthma patients, mild/moderate asthma (MMA) and healthy controls (HC). Data were analysed by asthma severity, inflammatory status and transcriptome-associated clusters (TACs). RESULTS: α-diversity at the species level was lower in SAn and SAs/ex, with an increase in Haemophilus influenzae and Moraxella catarrhalis, and Haemophilus influenzae and Tropheryma whipplei, respectively, compared to HC. In neutrophilic asthma, there was greater abundance of Haemophilus influenzae and Moraxella catarrhalis and in eosinophilic asthma, Tropheryma whipplei was increased. There was a reduction in α-diversity in TAC1 and TAC2 that expressed high levels of Haemophilus influenzae and Tropheryma whipplei, and Haemophilus influenzae and Moraxella catarrhalis, respectively, compared to HC. Sputum neutrophils correlated positively with Moraxella catarrhalis and negatively with Prevotella, Neisseria and Veillonella species and Haemophilus parainfluenzae. Sputum eosinophils correlated positively with Tropheryma whipplei which correlated with pack-years of smoking. α- and ß-diversities were stable at one year. CONCLUSIONS: Haemophilus influenzae and Moraxella catarrhalis were more abundant in severe neutrophilic asthma and TAC2 linked to inflammasome and neutrophil activation, while Haemophilus influenzae and Tropheryma whipplei were highest in SAs/ex and in TAC1 associated with highest expression of IL-13 type 2 and ILC2 signatures with the abundance of Tropheryma whipplei correlating positively with sputum eosinophils. Whether these bacterial species drive the inflammatory response in asthma needs evaluation.

Pharmacokinetics and pharmacodynamics of imatinib for optimal drug repurposing from cancer to COVID-19.

INTRODUCTION: In the randomized double-blind placebo-controlled CounterCOVID study, oral imatinib treatment conferred a positive clinical outcome and a signal for reduced mortality in COVID-19 patients. High concentrations of alpha-1 acid glycoprotein (AAG) were observed in these patients and were associated with increased total imatinib concentrations. AIMS: This post-hoc study aimed to compare the difference in exposure following oral imatinib administration in COVID-19 patients to cancer patients and assess assocations between pharmacokinetic (PK) parameters and pharmacodynamic (PD) outcomes of imatinib in COVID-19 patients. We hypothesize that a relatively higher drug exposure of imatinib in severe COVID-19 patients leads to improved pharmacodynamic outcome parameters. METHODS: 648 total concentration plasma samples obtained from 168 COVID-19 patients were compared to 475 samples of 105 cancer patients, using an AAG-binding model. Total trough concentration at steady state (Cttrough) and total average area under the concentration-time curve (AUCtave) were associated with ratio between partial oxygen pressure and fraction of inspired oxygen (P/F), WHO ordinal scale (WHO-score) and liberation of oxygen supplementation (O2lib). Linear regression, linear mixed effects models and time-to-event analysis were adjusted for possible confounders. RESULTS: AUCtave and Cttrough were respectively 2.21-fold (95%CI 2.07-2.37) and 1.53-fold (95%CI 1.44-1.63) lower for cancer compared to COVID-19 patients. Cttrough, not AUCtave, associated significantly with P/F (ß=-19,64; p-value=0.014) and O2lib (HR 0.78; p-value= 0.032), after adjusting for sex, age, neutrophil-lymphocyte ratio, dexamethasone concomitant treatment, AAG and baseline P/F-and WHO-score. Cttrough, but not AUCtave associated significantly with WHO-score. These results suggest an inverse relationship between PK-parameters, Cttrough and AUCtave, and PD outcomes. CONCLUSION: COVID-19 patients exhibit higher total imatinib exposure compared to cancer patients, attributed to differences in plasma protein concentrations. Higher imatinib exposure in COVID-19 patients did not associate with improved clinical outcomes. Cttrough and AUCtave inversely associated with some PD-outcomes, which may be biased by disease course, variability in metabolic rate and protein binding. Therefore, additional PKPD analyses into unbound imatinib and its main metabolite may better explain exposure-response.

Analysis of Volatile Organic Compounds in Exhaled Breath Following a COMEX-30 Treatment Table.

The COMEX-30 hyperbaric treatment table is used to manage decompression sickness in divers but may result in pulmonary oxygen toxicity (POT). Volatile organic compounds (VOCs) in exhaled breath are early markers of hyperoxic stress that may be linked to POT. The present study assessed whether VOCs following COMEX-30 treatment are early markers of hyperoxic stress and/or POT in ten healthy, nonsmoking volunteers. Because more oxygen is inhaled during COMEX-30 treatment than with other treatment tables, this study hypothesized that VOCs exhaled following COMEX-30 treatment are indicators of POT. Breath samples were collected before and 0.5, 2, and 4 h after COMEX-30 treatment. All subjects were followed-up for signs of POT or other symptoms. Nine compounds were identified, with four (nonanal, decanal, ethyl acetate, and tridecane) increasing 33-500% in intensity from before to after COMEX-30 treatment. Seven subjects reported pulmonary symptoms, five reported out-of-proportion tiredness and transient ear fullness, and four had signs of mild dehydration. All VOCs identified following COMEX-30 treatment have been associated with inflammatory responses or pulmonary diseases, such as asthma or lung cancer. Because most subjects reported transient pulmonary symptoms reflecting early-stage POT, the identified VOCs are likely markers of POT, not just hyperbaric hyperoxic exposure.

Cisplatin-induced nephrotoxicity in childhood cancer: comparison between two countries.

BACKGROUND: Various definitions used to describe cisplatin nephrotoxicity potentially lead to differences in determination of risk factors. This study evaluated incidence of kidney injury according to commonly used and alternative definitions in two cohorts of children who received cisplatin. METHODS: This retrospective cohort study included children from Vancouver, Canada (one center), and Mexico City, Mexico (two centers), treated with cisplatin for a variety of solid tumors. Serum creatinine-based definitions (KDIGO and Pediatric RIFLE (pRIFLE)), electrolyte abnormalities consisted of hypokalemia, hypophosphatemia and hypomagnesemia (based on NCI-CTCAE v5), and an alternative definition (Alt-AKI) were used to describe nephrotoxicity. Incidence with different definitions, definitional overlap, and inter-definition reliability was analyzed. RESULTS: In total, 173 children (100 from Vancouver, 73 from Mexico) were included. In the combined cohort, Alt-AKI criteria detected more patients with cisplatin nephrotoxicity compared to pRIFLE and KDIGO criteria (82.7 vs. 63.6 vs. 44.5%, respectively). Nephrotoxicity and all electrolyte abnormalities were significantly more common in Vancouver cohort than in Mexico City cohort except when using KDIGO definition. The most common electrolyte abnormalities were hypomagnesemia (88.9%, Vancouver) and hypophosphatemia (24.2%, Mexico City). The KDIGO definition provided highest overlap of cases in Vancouver (100%), Mexico (98.6%), and the combined cohort (99.4%). Moderate overall agreement was found among Alt-AKI, KDIGO, and pRIFLE definitions (κ = 0.18, 95% CI 0.1-0.27) in which KDIGO and pRIFLE showed moderate agreement (κ = 0.48, 95% CI 0.36-0.60). CONCLUSIONS: Compared to pRIFLE and KDIGO criteria, Alt-AKI criteria detected more patients with cisplatin nephrotoxicity. pRIFLE is more sensitive to detect not only actual kidney injury but also patients at risk of cisplatin nephrotoxicity, while KDIGO seems more useful to detect clinically significant kidney injury. A higher resolution version of the Graphical abstract is available as Supplementary information.

Real-life efficacy and safety of elexacaftor/tezacaftor/ivacaftor on severe cystic fibrosis lung disease patients.

Elexacaftor/tezacaftor/ivacaftor (ETI) is a cystic fibrosis (CF) transmembrane conductance regulator modulator, which has shown efficacy in CF patients (≥6 years) with ≥1 Phe508del mutation and a minimal function mutation. In October 2019, ETI became available on compassionate use basis for Dutch CF patients with severe lung disease. Our objective was to investigate safety and efficacy of ETI in this patient group in a real-life setting. A multicenter longitudinal observational study was conducted to examine changes in FEV1 , BMI, and adverse events at initiation and 1, 3, 6, and 12 months after starting ETI. The number of exacerbations was recorded in the 12 months before and the 12 months after ETI treatment. Patients eligible for compassionate use had a FEV1 <40% predicted. Wilcoxon signed-rank test analyzed changes over time. Twenty subjects were included and followed up for up to 12 months after starting ETI. Treatment was well tolerated with mild side effects reported, namely, rash (15%) and stomach ache (20%) with 80% resolving within 1 month. Mean absolute increase of FEV1 was 11.8/13.7% (p ≤ .001) and BMI was 0.49/1.87 kg/m2 (p < .001-0.02) after 1/12 months, respectively. In comparison to the number of exacerbations pretrial, there was a marked reduction in exacerbations after initiation. Our findings show long-term effects of treatment with ETI in patients with severe CF lung disease in a real-life setting. Treatment with ETI is associated with increased lung function and BMI, less exacerbations, and only mild side effects.

Comparison of microbial composition of cough swabs and sputum for pathogen detection in patients with cystic fibrosis.

BACKGROUND: With the continued advancement of CFTR modulator therapies there is likely to be a burgeoning population of adult cystic fibrosis (CF) patients unable to expectorate sputum. Consequently, the detection and surveillance of pulmonary colonisation, previously reliant on sputum culture, needs re-examining. We hypothesised that cough swabs analysed with culture-independent analysis of the 16S gene could serve as a surrogate for colonisation of the lower airways. METHODS: Cough swabs and sputum samples were prospectively collected from consecutive adults and children with CF across two sites at regular outpatient appointments. Conventional culture analysis and next generation sequencing were used to compare paired same day samples. RESULTS: Twenty-two adults and 8 paediatric patients provided 75 paired cough swabs and sputum samples. Alpha diversity measures showed increased bacterial richness in sputum, while evenness and Simpson's diveristy index were higher in cough swabs. Within each sampling technique, microbial composition showed greater similarity when considering intra-patient variation. Poor concordance was observed between culture independent cough swabs and culture dependent/independent sputum analysis for specific pathogens, with cough swabs unable to accurately identify commonly associated CF pathogens (AUROCC range: 0.51 to 0.64). CONCLUSION: Culture independent analysis of cough swabs provides an inaccurate diagnosis of lower respiratory tract colonisation and should not be used as a diagnostic test in patients with CF.

Targeted exhaled breath analysis for detection of Pseudomonas aeruginosa in cystic fibrosis patients.

BACKGROUND: Pseudomonas aeruginosa (PA) is an important respiratory pathogen for cystic fibrosis (CF) patients. Routine microbiology surveillance is time-consuming, and is best performed on expectorated sputum. As alternative, volatile organic compounds (VOCs) may be indicative of PA colonisation. In this study, we aimed to identify VOCs associated with PA in literature and perform targeted exhaled breath analysis to recognize PA positive CF patients non-invasively. METHODS: This study consisted of 1) a literature review to select VOCs of interest, and 2) a cross-sectional CF study. Definitions used: A) PA positive, PA culture at visit/chronically; B) PA free, no PA culture in ≥12 months. Exhaled VOCs were identified via quadrupole MS. The primary endpoint was the area under the receiver operating characteristics curve (AUROCC) of individual VOCs as well as combined VOCs against PA culture. RESULTS: 241 VOCs were identified in literature, of which 56 were further evaluated, and 13 could be detected in exhaled breath in our cohort. Exhaled breath of 25 pediatric and 28 adult CF patients, PA positive (n=16) and free (n=28) was available. 3/13 VOCs were significantly (p<0.05) different between PA groups in children; none were in adults. Notably, a composite model based on 5 or 1 VOC(s) showed an AUROCC of 0.86 (CI 0.71-1.0) and 0.87 (CI 0.72-1.0) for adults and children, respectively. CONCLUSIONS: Targeted VOC analysis appears to discriminate children and adults with and without PA positive cultures with clinically acceptable sensitivity values.

Associations of Serum Uric Acid Levels With Macrovascular and Renal Microvascular Dysfunction Among Individuals From Sub-Saharan Africa.

Importance: Serum uric acid (SUA) level is associated with vascular dysfunction in Eurasian populations, but little is known about this association in individuals from sub-Saharan Africa, who have a high prevalence of both relatively high SUA levels and vascular dysfunction. Objectives: To assess the associations of SUA levels with macrovascular and kidney microvascular dysfunction in individuals of sub-Saharan African ancestry and evaluate potential factors that could mediate these associations. Design, Setting, and Participants: Cross-sectional analyses of baseline data from the multicenter Research on Obesity and Diabetes Among African Migrants study, conducted from 2012 to 2015, were performed from January to March 2021. The population included Ghanaian individuals living in Ghana and Europe. Exposure: Abnormal SUA levels. Main Outcomes and Measures: Logistic regression was used to examine the associations of SUA level quartiles with microvascular (albuminuria) and macrovascular (peripheral artery disease and coronary artery disease) dysfunction, with adjustments for age, sex, estimated glomerular filtration rate, site of residence, socioeconomic status, alcohol, smoking, diabetes, hypertension, waist-hip ratio, and total cholesterol level. Mediation analysis was performed to assess whether the association was via elevated blood pressure, hemoglobin A1c, and high-sensitivity C-reactive protein levels or via weight-hip ratio. The research questions were formulated after data collection. Results: A total of 4919 Ghanaian individuals (3047 [61.9%] women) aged 25-75 years (mean [SD], 46.26 [11.08] years) were included. There was a significant positive association between SUA quartiles and albuminuria, but not coronary artery disease or peripheral artery disease, after adjustment for covariates. After full adjustment, individuals in the fourth SUA quartile had higher odds of albuminuria (adjusted odds ratio [aOR], 1.54; 95% CI, 1.07-2.21), but not peripheral artery disease (aOR, 1.35; 95% CI, 0.87-2.08) or coronary artery disease (aOR, 1.09; 95% CI, 0.77-1.55), compared with individuals in the first quartile. After full adjustment, systolic and diastolic blood pressure significantly mediated the association between SUA concentrations and albuminuria, accounting for 19.4% of the total association for systolic and 17.2% for diastolic blood pressure; hemoglobin A1c, high-sensitivity C-reactive protein, and waist-hip ratio did not mediate this association. Conclusions and Relevance: In this cross-sectional study among a sub-Saharan African population, elevated SUA levels were significantly associated with kidney microvascular dysfunction and mediated partly through elevated blood pressure. These findings suggest that individuals from sub-Saharan Africa with elevated SUA levels may benefit from periodic screening for kidney microvascular dysfunction to aid early detection or treatment.

Alterations to the urinary metabolome following semi-controlled short exposures to ultrafine particles at a major airport.

BACKGROUND: Inflammation, oxidative stress and reduced cardiopulmonary function following exposure to ultrafine particles (UFP) from airports has been reported but the biological pathways underlying these toxicological endpoints remain to be explored. Urinary metabolomics offers a robust method by which changes in cellular pathway activity can be characterised following environmental exposures. OBJECTIVE: We assessed the impact of short-term exposures to UFP from different sources at a major airport on the human urinary metabolome. METHODS: 21 healthy, non-smoking volunteers (aged 19-27 years) were repeatedly (2-5 visits) exposed for 5h to ambient air at Amsterdam Airport Schiphol, while performing intermittent, moderate exercise. Pre- to-post exposure changes in urinary metabolite concentrations were assessed via 1H NMR spectroscopy and related to total and source-specific particle number concentrations (PNC) using linear mixed effects models. RESULTS: Total PNC at the exposure site was on average, 53,500 particles/cm3 (range 10,500-173,200) and associated with significant reductions in urinary taurine (-0.262 AU, 95% CI: -0.507 to -0.020) and dimethylamine concentrations (-0.021 AU, 95% CI: -0.040 to -0.067). Aviation UFP exposure accounted for these changes, with the reductions in taurine and dimethylamine associating with UFP produced during both aircraft landing and take-off. Significant reductions in pyroglutamate concentration were also associated with aviation UFP specifically, (-0.005 AU, 95% CI: -0.010 - <0.000) again, with contributions from both landing and take-off UFP exposure. While non-aviation UFPs induced small changes to the urinary metabolome, their effects did not significantly impact the overall response to airport UFP exposure. DISCUSSION: Following short-term exposures at a major airport, aviation-related UFP caused the greatest changes to the urinary metabolome. These were consistent with a heightened antioxidant response and altered nitric oxide synthesis. Although some of these responses could be adaptive, they appeared after short-term exposures in healthy adults. Further study is required to determine whether long-term exposures induce injurious effects.

Inflammation and its associations with aortic stiffness, coronary artery disease and peripheral artery disease in different ethnic groups: The HELIUS Study.

BACKGROUND: evidence shows important ethnic differences in vascular dysfunction rates; however, the mechanisms driving these differences remain unclear. One potential factor is the ethnic differences in the role of inflammation in vascular injury. We tested the hypothesis that low-grade inflammation is unequally associated with vascular dysfunction in different ethnic groups. METHODS: we included 5698 participants (similar-sized Dutch, African Surinamese, South-Asian Surinamese, Ghanaians, Turkish, and Moroccans) of the HELIUS study (the Netherlands) conducted between 2011 and 2015. Logistic regression was used to examine the associations of Z-score inflammatory biomarker concentration (high sensitivity C-reactive protein [hs-CRP], fibrinogen, and d-dimer) with vascular dysfunction (aortic stiffness, coronary artery disease [CAD], and peripheral artery disease [PAD]), with adjustments for age, sex, smoking (pack-years), BMI, hypertension, HbA1c, total cholesterol, and statin use. FINDINGS: in the fully adjusted models, higher Z-score hs-CRP was positively associated with CAD in Dutch [OR 1·63, (95% CI 1·21-2·18)] and PAD in South Asians [1·25(1·03-1·53)], respectively. Higher Z-score fibrinogen was positively associated with CAD in African Surinamese [1·28(1·03-1·59)] while higher Z-score d-dimer was positively associated with PAD in Moroccans [1·39(1·01-1·93)]. Higher Z-score hs-CRP [0·71(0·54-0·94)] and fibrinogen [0·75(0·58-0·97)] concentrations were negatively associated with PAD in African Surinamese. INTERPRETATION: our study shows that inflammatory biomarkers are unequally associated with vascular dysfunction in different ethnic groups. These observations provide opportunities for future studies aimed at assessing the predictive roles of inflammation on vascular disease in different ethnic groups.

Lumacaftor/ivacaftor changes the lung microbiome and metabolome in cystic fibrosis patients.

RATIONALE: Targeted cystic fibrosis (CF) therapy with lumacaftor/ivacaftor partly restores chloride channel function and improves epithelial fluid transport in the airways. Consequently, changes may occur in the microbiome, which is adapted to CF lungs. OBJECTIVES: To investigate the effects of lumacaftor/ivacaftor on respiratory microbial composition and microbial metabolic activity by repeatedly sampling the lower respiratory tract. METHODS: This was a single-centre longitudinal observational cohort study in adult CF patients with a homozygous Phe508del mutation. Lung function measurements and microbial cultures of sputum were performed as part of routine care. An oral and nasal wash, and a breath sample, were collected before and every 3 months after starting therapy, for up to 12 months. RESULTS: Twenty patients were included in this study. Amplicon 16S RNA and metagenomics sequencing revealed that Pseudomonas aeruginosa was most abundant in sputum and seemed to decrease after 6 months of treatment, although this did not reach statistical significance after correction for multiple testing. Two types of untargeted metabolomics analyses in sputum showed a change in metabolic composition between 3 and 9 months that almost returned to baseline levels after 12 months of treatment. The volatile metabolic composition of breath was significantly different after 3 months and remained different from baseline until 12 months follow-up. CONCLUSIONS: After starting CF transmembrane conductance regulator (CFTR) modulating treatment in CF patients with a homozygous Phe508del mutation, a temporary and moderate change in the lung microbiome is observed, which is mainly characterised by a reduction in the relative abundance of Pseudomonas aeruginosa.

Genetic variants associated with methotrexate-induced mucositis in cancer treatment: A systematic review and meta-analysis.

Methotrexate (MTX), an important chemotherapeutic agent, is often accompanied with mucositis. The occurrence and severity are unpredictable and show large interindividual variability. In this study, we review and meta-analyze previously studied genetic variants in relation to MTX-induced mucositis. We conducted a systematic search in Medline and Embase. We included genetic association studies of MTX-induced mucositis in cancer patients. A meta-analysis was conducted for single nucleotide polymorphisms (SNPs) for which at least two studies found a statistically significant association. A total of 34 SNPs were associated with mucositis in at least one study of the 57 included studies. Two of the seven SNPs included in our meta-analysis were statistically significantly associated with mucositis: MTHFR c.677C > T (recessive, grade ≥3 vs grade 0-2, OR 2.53, 95 %CI [1.48-4.32], False Discovery Rate[FDR]-corrected p-value 0.011) and MTRR c.66A > G (overdominant, grade ≥1 vs grade 0, OR 2.08, 95 %CI [1.16-3.73], FDR-corrected p-value 0.042).

Treating severe asthma: Targeting the IL-5 pathway.

Severe asthma is a heterogeneous disease with different phenotypes based on clinical, functional or inflammatory parameters. In particular, the eosinophilic phenotype is associated with type 2 inflammation and increased levels of interleukin (IL)-4, IL-5 and IL-13). Monoclonal antibodies that target the eosinophilic inflammatory pathways (IL-5R and IL-5), namely mepolizumab, reslizumab, and benralizumab, are effective and safe for severe eosinophilic asthma. Eosinophils threshold represents the most indicative biomarker for response to treatment with all three monoclonal antibodies. Improvement in asthma symptoms scores, lung function, the number of exacerbations, history of late-onset asthma, chronic rhinosinusitis with nasal polyposis, low oral corticosteroids use and low body mass index represent predictive clinical markers of response. Novel Omics studies are emerging with proteomics data and exhaled breath analyses. These may prove useful as biomarkers of response and non-response biologics. Moreover, future biomarker studies need to be undertaken in paediatric patients affected by severe asthma. The choice of appropriate biologic therapy for severe asthma remains challenging. The importance of finding biomarkers that can predict response continuous an open issue that needs to be further explored. This review describes the clinical effects of targeting the IL-5 pathway in severe asthma in adult and paediatric patients, focusing on predictors of response and non-response.

The Influence of Smoking Status on Exhaled Breath Profiles in Asthma and COPD Patients.

Breath analysis using eNose technology can be used to discriminate between asthma and COPD patients, but it remains unclear whether results are influenced by smoking status. We aim to study whether eNose can discriminate between ever- vs. never-smokers and smoking <24 vs. >24 h before the exhaled breath, and if smoking can be considered a confounder that influences eNose results. We performed a cross-sectional analysis in adults with asthma or chronic obstructive pulmonary disease (COPD), and healthy controls. Ever-smokers were defined as patients with current or past smoking habits. eNose measurements were performed by using the SpiroNose. The principal component (PC) described the eNose signals, and linear discriminant analysis determined if PCs classified ever-smokers vs. never-smokers and smoking <24 vs. >24 h. The area under the receiver-operator characteristic curve (AUC) assessed the accuracy of the models. We selected 593 ever-smokers (167 smoked <24 h before measurement) and 303 never-smokers and measured the exhaled breath profiles of discriminated ever- and never-smokers (AUC: 0.74; 95% CI: 0.66-0.81), and no cigarette consumption <24h (AUC 0.54, 95% CI: 0.43-0.65). In healthy controls, the eNose did not discriminate between ever or never-smokers (AUC 0.54; 95% CI: 0.49-0.60) and recent cigarette consumption (AUC 0.60; 95% CI: 0.50-0.69). The eNose could distinguish between ever and never-smokers in asthma and COPD patients, but not recent smokers. Recent smoking is not a confounding factor of eNose breath profiles.

Associations between macrovascular and renal microvascular dysfunction in type 2 diabetes and non-diabetes: the HELIUS study.

BACKGROUND: Although the associations between measures of macrovascular and microvascular dysfunctions are well characterized in diabetes, there is limited data on these associations in individuals without diabetes. We compared the associations between macrovascular dysfunction and renal microvascular dysfunction in individuals with type 2 diabetes (T2D) and without diabetes. METHODS: Cross-sectional analyses of baseline data from the multiethnic Healthy Life in an Urban Setting (HELIUS) study (Amsterdam, the Netherlands), including 986 participants with T2D and 7680 participants without diabetes were done. Logistic regression analyses were used to examine the associations between macrovascular dysfunction [aortic stiffness, coronary artery disease (CAD), peripheral artery disease (PAD), and stroke] and renal microvascular dysfunction [albuminuria] with adjustments for age, sex, ethnicity, waist-to-hip ratio, systolic blood pressure, LDL-cholesterol, and smoking (and HbA1c and diabetes duration for the T2D group). RESULTS: In the fully adjusted models, aortic stiffness was associated with albuminuria in individuals with T2D [OR 2.55; 95% CI,1.30-4.98], but not without diabetes [0.96; 0.63-1.45]; stroke was associated with albuminuria in T2D [2.40;1.10-5.25], but not in non-diabetes [1.39;0.83-2.33]. In age-sex adjusted models, CAD was associated with albuminuria in T2D [1.65;1.09-2.50] and in non-diabetes [1.56;1.13-2.15]; the associations were no longer significant in the fully adjusted model. There were no associations between PAD and albuminuria in T2D and non-diabetes. CONCLUSIONS: Our study shows important differences in the associations between measures of macrovascular and renal microvascular dysfunction in T2D and non-diabetes. These findings provide opportunities for future research aimed at prevention and treatment strategies for individuals with vascular dysfunction.

Sputum microbiome profiles identify severe asthma phenotypes of relative stability at 12 to 18 months.

BACKGROUND: Asthma is a heterogeneous disease characterized by distinct phenotypes with associated microbial dysbiosis. OBJECTIVES: Our aim was to identify severe asthma phenotypes based on sputum microbiome profiles and assess their stability after 12 to 18 months. A further aim was to evaluate clusters' robustness after inclusion of an independent cohort of patients with mild-to-moderate asthma. METHODS: In this longitudinal multicenter cohort study, sputum samples were collected for microbiome profiling from a subset of the Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes adult patient cohort at baseline and after 12 to 18 months of follow-up. Unsupervised hierarchical clustering was performed by using the Bray-Curtis ß-diversity measure of microbial profiles. For internal validation, partitioning around medoids, consensus cluster distribution, bootstrapping, and topological data analysis were applied. Follow-up samples were studied to evaluate within-patient clustering stability in patients with severe asthma. Cluster robustness was evaluated by using an independent cohort of patients with mild-to-moderate asthma. RESULTS: Data were available for 100 subjects with severe asthma (median age 55 years; 42% males). Two microbiome-driven clusters were identified; they were characterized by differences in asthma onset, smoking status, residential locations, percentage of blood and/or sputum neutrophils and macrophages, lung spirometry results, and concurrent asthma medications (all P values < .05). The cluster 2 patients displayed a commensal-deficient bacterial profile that was associated with worse asthma outcomes than those of the cluster 1 patients. Longitudinal clusters revealed high relative stability after 12 to 18 months in those with severe asthma. Further inclusion of an independent cohort of 24 patients with mild-to-moderate asthma was consistent with the clustering assignments. CONCLUSION: Unbiased microbiome-driven clustering revealed 2 distinct robust phenotypes of severe asthma that exhibited relative overtime stability. This suggests that the sputum microbiome may serve as a biomarker for better characterizing asthma phenotypes.

Impact of a Gap Junction Protein Alpha 4 Variant on Clinical Disease Phenotype in F508del Homozygous Patients With Cystic Fibrosis.

BACKGROUND: Lung disease phenotype varies widely even in the F508del (homozygous) genotype. Leukocyte-driven inflammation is important for pulmonary disease pathogenesis in cystic fibrosis (CF). Blood cytokines correlate negatively with pulmonary function in F508del homozygous patients, and gap junction proteins (GJA) might be related to the influx of blood cells into the lung and influence disease course. We aimed to assess the relationship between GJA1/GJA4 genotypes and the clinical disease phenotype. METHODS: One-hundred-and-sixteen homozygous F508del patients (mean age 27 years, m/f 66/50) were recruited from the CF centers of Bonn, Frankfurt, and Amsterdam. Sequence analysis was performed for GJA1 and GJA4. The clinical disease course was assessed over 3 years using pulmonary function tests, body mass index, Pseudomonas aeruginosa colonization, diabetes mellitus, survival to end-stage lung disease, blood and sputum inflammatory markers. RESULTS: Sequence analysis revealed one clinically relevant single nucleotide polymorphism. In this GJA4 variant (rs41266431), homozygous G variant carriers (n = 84/116; 72.4%) had poorer pulmonary function (FVC% pred: mean 78/86, p < 0.040) and survival to end-stage lung disease was lower (p < 0.029). The frequency of P. aeruginosa colonization was not influenced by the genotype, but in those chronically colonized, those with the G/G genotype had reduced pulmonary function (FVC% pred: mean 67/80, p < 0.049). Serum interleukin-8 (median: 12.4/6.7 pg/ml, p < 0.052) and sputum leukocytes (2305/437.5 pg/ml, p < 0.025) were higher for the G/G genotype. CONCLUSIONS: In carriers of the A allele (27.6%) the GJA4 variant is associated with significantly better protection against end-stage lung disease and superior pulmonary function test results in F508del homozygous patients. This SNP has the potential of a modifier gene for phenotyping severity of CF lung disease, in addition to the CFTR genotype. CLINICAL TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov, number NCT04242420, retrospectively on January 24th, 2020.

Precision Medicine in Neonates: Future Perspectives for the Lung.

Bronchopulmonary dysplasia (BPD) is the most common complication of pre-term birth with long lasting sequelae. Since its first description more than 50 years ago, many large randomized controlled trials have been conducted, aiming to improve evidence-based knowledge on the optimal strategies to prevent and treat BPD. However, most of these intervention studies have been performed on a population level without regard for the variation in clinical and biological diversity (e.g., gestational age, ethnicity, gender, or disease progression) between patients that is driven by the complex interaction of genetic pre-disposition and environmental exposures. Nevertheless, clinicians provide daily care such as lung protective interventions on an individual basis every day despite the fact that research supporting individualized or precision medicine for monitoring or treating pre-term lungs is immature. This narrative review summarizes four potential developments in pulmonary research that might facilitate the process of individualizing lung protective interventions to prevent development of BPD. Electrical impedance tomography and electromyography of the diaphragm are bedside monitoring tools to assess regional changes in lung volume and ventilation and spontaneous breathing effort, respectively. These non-invasive tools allow a more individualized optimization of invasive and non-invasive respiratory support. Investigation of the genomic variation in caffeine metabolism in pre-term infants can be used to optimize and individualize caffeine dosing regimens. Finally, volatile organic compound analysis in exhaled breath might accurately predict BPD at an early stage of the disease, enabling clinicians to initiate preventive strategies for BPD on an individual basis. Before these suggested diagnostic or monitoring tools can be implemented in daily practice and improve individualized patient care, future research should address and overcome their technical difficulties, perform extensive external validation and show their additional value in preventing BPD.