C FTR variants are associated with chronic bronchitis in smokers.

INTRODUCTION: Loss-of-function variants in both copies of the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF); however, there is evidence that reduction in CFTR function due to the presence of one deleterious variant can have clinical consequences. Here, we hypothesise that CFTR variants in individuals with a history of smoking are associated with chronic obstructive pulmonary disease (COPD) and related phenotypes. METHODS: Whole-genome sequencing was performed through the National Heart, Lung, and Blood Institute TOPMed (TransOmics in Precision Medicine) programme in 8597 subjects from the COPDGene (Genetic Epidemiology of COPD) study, an observational study of current and former smokers. We extracted clinically annotated CFTR variants and performed single-variant and variant-set testing for COPD and related phenotypes. Replication was performed in 2118 subjects from the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study. RESULTS: We identified 301 coding variants within the CFTR gene boundary: 147 of these have been reported in individuals with CF, including 36 CF-causing variants. We found that CF-causing variants were associated with chronic bronchitis in variant-set testing in COPDGene (one-sided p=0.0025; OR 1.53) and in meta-analysis of COPDGene and ECLIPSE (one-sided p=0.0060; OR 1.52). Single-variant testing revealed that the F508del variant was associated with chronic bronchitis in COPDGene (one-sided p=0.015; OR 1.47). In addition, we identified 32 subjects with two or more CFTR variants on separate alleles and these subjects were enriched for COPD cases (p=0.010). CONCLUSIONS: Cigarette smokers who carry one deleterious CFTR variant have higher rates of chronic bronchitis, while presence of two CFTR variants may be associated with COPD. These results indicate that genetically mediated reduction in CFTR function contributes to COPD related phenotypes, in particular chronic bronchitis.

Point prevalence survey of antibiotic use in hospitals in Latin American countries.

BACKGROUND: Point prevalence surveys (PPSs) on antibiotic use are useful for understanding different aspects related to prescription patterns in hospitals. METHODS: An adaptation of the WHO methodology for a PPS on antibiotic use was applied. Hospital wards were divided into medical (MED), surgical (SUR), ICUs, gynaecology and obstetrics (GO), high-risk (HR) and mixed wards (MIX). A web application (RedCap©) through a mobile device was used for data collection. RESULTS: Between December 2018 and August 2019, 5444 patients in 33 hospitals in five countries were included (10 hospitals in Cuba, 7 in Paraguay, 6 in El Salvador, 5 in Mexico and 5 in Peru). Of these patients, 54.6% received at least one antibiotic, with variations between and within hospitals and countries. Antibiotics were more frequently used in ICUs (67.2%), SUR (64.5%) and MED wards (54.2%), with 51.2% of antibiotics prescribed for community-acquired infections (CAIs), 22.9% for healthcare-associated infections (HAIs), 11.1% for surgical prophylaxis and 6.1% for unknown reasons. Adherence to guidelines was observed in 68.6% of cases (72.8% for CAIs, 72.4% for HAIs and 44.3% for prophylaxis). Third-generation cephalosporins were the class of antibiotics most frequently used (26.8%), followed by carbapenems (10.3%) and fluoroquinolones (8%). Targeted treatments were achieved in 17.3% of cases. CONCLUSIONS: Antibiotic use was generally higher than that published in other studies. There is an urgent need to promote and strengthen the antimicrobial stewardship programmes in Latin America.

Genomic, transcriptomic, and protein landscape profile of CFTR and cystic fibrosis.

Cystic Fibrosis (CF) is caused most often by removal of amino acid 508 (Phe508del, deltaF508) within CFTR, yet dozens of additional CFTR variants are known to give rise to CF and many variants in the genome are known to contribute to CF pathology. To address CFTR coding variants, we developed a sequence-to-structure-to-dynamic matrix for all amino acids of CFTR using 233 vertebrate species, CFTR structure within a lipid membrane, and 20 ns of molecular dynamic simulation to assess known variants from the CFTR1, CFTR2, ClinVar, TOPmed, gnomAD, and COSMIC databases. Surprisingly, we identify 18 variants of uncertain significance within CFTR from diverse populations that are heritable and a likely cause of CF that have been understudied due to nonexistence in Caucasian populations. In addition, 15 sites within the genome are known to modulate CF pathology, where we have identified one genome region (chr11:34754985-34836401) that contributes to CF through modulation of expression of a noncoding RNA in epithelial cells. These 15 sites are just the beginning of understanding comodifiers of CF, where utilization of eQTLs suggests many additional genomics of CFTR expressing cells that can be influenced by genomic background of CFTR variants. This work highlights that many additional insights of CF genetics are needed, particularly as pharmaceutical interventions increase in the coming years.

An international inventory of antimicrobial stewardship (AMS) training programmes for AMS teams.

BACKGROUND: Healthcare professionals are increasingly expected to lead antimicrobial stewardship (AMS) initiatives. This role in complex healthcare environments requires specialized training. OBJECTIVES: Little is known about the types of AMS training programmes available to clinicians seeking to play a lead role in AMS. We aimed to identify clinicians' awareness of AMS training programmes, characteristics of AMS training programmes available and potential barriers to participation. METHODS: AMS training programmes available were identified by members of the ESCMID Study Group for Antimicrobial Stewardship (ESGAP) via an online survey and through an online search in 2018. Individual training programme course coordinators were then contacted (September-October 2018) for data on the target audience(s), methods of delivery, intended outcomes and potential barriers to accessing the training programme. RESULTS: A total of 166/250 ESGAP members (66%) responded to the survey, nominating 48 unique AMS training programmes. An additional 32 training programmes were identified through an online search. AMS training programmes were from around the world. Less than half (44.4%) of respondents were aware of one or more AMS training programmes available, with pharmacists more aware compared with medical doctors and other professionals (73% versus 46% and 25%, respectively). AMS training programmes were most commonly delivered online (59%) and aimed at medical doctors (46%). Training costs and a lack of recognition by health professional societies were the most frequently cited barriers to participation in AMS training programmes. CONCLUSIONS: The development of a systematic inventory of AMS training programmes around the globe identifies opportunities and limitations to current training available. Improving access and increasing awareness amongst target participants will support improved education in AMS.

Antimicrobial stewardship in hospitals in Latin America and the Caribbean: a scoping review.

OBJECTIVES: To examine published antimicrobial stewardship (AMS) initiatives in hospitals in Latin America and the Caribbean (LAC) in order to characterize AMS terminology usage, geotemporality, and elements of structure (human resources), process (interventions), and outcomes, and to set priority areas for improving AMS reporting. METHODS: This was a scoping review that searched PubMed, LILACS, EMBASE, and 12 other databases, along with a manual search for academic and grey literature to identify documents on AMS initiatives in hospitals in 33 countries of LAC, up to August 2019. Keywords included 'antibiotic' or 'antimicrobial' AND 'stewardship, policy, strategies, management, control, rational use, appropriate use, surveillance, or interventions' and 33 country names. RESULTS: Selected articles totalled 147 studies published in 1985 - 2019; of those, 22% used 'antimicrobial stewardship' in the title. Eighteen countries published AMS hospital initiatives, one-half of which were implemented in capital cities. Brazil, Argentina, Colombia, Cuba, Mexico, and Chile, in descending frequency, made up > 59% of published initiatives. Educational interventions were the most frequently reported, followed by persuasive and restrictive strategies. Antimicrobial consumption was the most common outcome measure reported. About one-third of the studies (35%) referred to baseline measures-only in preparation for AMS interventions. Fifty-nine studies from 6 countries reported AMS comprehensively, using structure, process, and outcome (SPO) elements. CONCLUSIONS: Published hospital AMS initiatives have increased over time and have expanded across LAC. However, more programs need to be developed. Complete reporting of SPO elements is imperative to evaluating and replicating AMS actions.

Cystic Fibrosis Plasma Blunts the Immune Response to Bacterial Infection.

Cystic fibrosis (CF) is caused by mutations of the gene encoding the CF transmembrane conductance regulator. It remains unclear whether the abnormal immune response in CF involves extrinsic signals released from the external or internal environment. We sought to characterize the peripheral immune signatures in CF and its association with clinical phenotypes. Healthy peripheral blood mononuclear cells (PBMCs) were cultured with plasma from CF probands (CFPs) or healthy control subjects (HCs) followed by nCounter gene and microRNA (miRNA) profiling. A discovery cohort of 12 CFPs and 12 HCs and a validation cohort of 103 CFPs and 31 HCs (our previous microarray data [GSE71799]) were analyzed to characterize the composition of cultured immune cells and establish a miRNA‒mRNA network. Cell compositions and miRNA profiles were associated with clinical characteristics of the cohorts. Significantly differentially expressed genes and abundance of myeloid cells were downregulated in PMBCs after culture with CF plasma (P < 0.05). Top-ranked miRNAs that increased in response to CF plasma (adjusted P < 0.05) included miR-155 and miR-146a, which target many immune-related genes, such as IL-8. Pseudomonas aeruginosa infection was negatively associated with abundance of monocytes and the presence of those regulatory miRNAs. Extrinsic signals in plasma from patients with CF led to monocyte inactivation and miRNA upregulation in PBMCs. An improved understanding of the immune effects of extrinsic factors in CF holds great promise for integrating immunomodulatory cell therapies into current treatment strategies in CF.

Identification of molecular signatures of cystic fibrosis disease status with plasma-based functional genomics.

Although cystic fibrosis (CF) is attributed to dysfunction of a single gene, the relationships between the abnormal gene product and the development of inflammation and progression of lung disease are not fully understood, which limits our ability to predict an individual patient's clinical course and treatment response. To better understand CF progression, we characterized the molecular signatures of CF disease status with plasma-based functional genomics. Peripheral blood mononuclear cells (PBMCs) from healthy donors were cultured with plasma samples from CF patients ( n = 103) and unrelated, healthy controls ( n = 31). Gene expression levels were measured with an Affymetrix microarray (GeneChip Human Genome U133 Plus 2.0). Peripheral blood samples from a subset of the CF patients ( n = 40) were immunophenotyped by flow cytometry, and the data were compared with historical data for age-matched healthy controls ( n = 351). Plasma samples from another subset of CF patients ( n = 56) and healthy controls ( n = 16) were analyzed by multiplex enzyme-linked immunosorbent assay (ELISA) for numerous cytokines and chemokines. Principal component analysis and hierarchical clustering of induced transcriptional data revealed disease-specific plasma-induced PBMC profiles. Among 1,094 differentially expressed probe sets, 51 genes were associated with pancreatic sufficient status, and 224 genes were associated with infection with Pseudomonas aeruginosa. The flow cytometry and ELISA data confirmed that various immune modulators are relevant contributors to the CF molecular signature. This study provides strong evidence for distinct molecular signatures among CF patients. An understanding of these molecular signatures may lead to unique molecular markers that will enable more personalized prognoses, individualized treatment plans, and rapid monitoring of treatment response.

Impact of Intermediate Cystic Fibrosis Classification on Parents' Perceptions of Child Vulnerability and Protectiveness.

This cross-sectional, mixed-method study examined factors associated with parent perceptions of child vulnerability and protectiveness in three groups: cystic fibrosis (CF-group, n = 40), intermediate CF classification (I-group, n = 20), and healthy (H-group, n = 50). A composite indicator structural equation (CISE) using Bayesian estimation tested two mediational models: psychological and biological. Significant results ( p < .05) from the psychological model showed I-group and CF-group parents perceived their children to be more vulnerable than H-group parents but reported lower levels of protectiveness than H-group parents. Perceptions of vulnerability mediated protectiveness for CF- and I-groups. The biological model showed I-group children had significantly less severe genotype and phenotype, and lower sweat chloride levels than the CF-group; I-group parents had lower expectations about children developing CF symptoms. Both models showed negative associations between children's ages and protectiveness. Psychological factors explained perceptions of child vulnerability and protectiveness; biological factors explained protectiveness. Parent perceptions of vulnerability and protectiveness are separate, independent constructs.

Clinical course and significance of nontuberculous mycobacteria and its subtypes in cystic fibrosis.

BACKGROUND: Nontuberculous mycobacteria (NTM) infections in patients with cystic fibrosis (CF) is increasing globally. However, the related epidemiology, comorbidities, and clinical impact of NTM infection remains unclear in the progress of CF lung disease and patient survival. METHODS: We performed a retrospective, case-control, cohort study (10 years), comparing NTM culture-positive CF patients (N = 28) to matched controls (N = 26). NTM positive patients were divided in to two groups of slow-growing (N = 17) and rapid- growing NTM (N = 8). Three patients were positive for both slow and rapid NTM. For independent group comparisons, a non-parametric Mann-Whitney test (Kruskal-Wallis test for more than two groups) was used to compare the continuous variables, and a Fisher's exact test was used for the categorical variables. Paired comparisons were performed using a Wilcoxon signed-rank test. RESULTS: The prevalence of NTM isolation was 8%. The age at CF diagnosis was significantly lower in the slow-growing NTM group compared to the rapidly growing NTM group (P = 0.04). The median percent predicted forced expiratory flow of 25% - 75% (FEF25-75) was significantly higher before NTM acquisition in slow-growing (P = 0.013) and rapidly growing NTM group (P = 0.028). The slow-growing NTM group received significantly more penicillin/beta lactamase (P = 0.010) and rifampin (P = 0.042) following isolation. Macrolide use was significantly higher after isolation in both the slow-growing NTM (P = 0.018) and rapidly growing NTM groups (P = 0.042). CONCLUSIONS: An earlier CF diagnosis was associated with a higher isolation of slow-growing NTM and greater antimicrobial use after infection. NTM acquisition is associated with a worsening of FEF25-75. Thus, both the early diagnosis and treatment of an NTM infection in patients with CF may positively impact lung function.

Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome and Cystic Fibrosis Screen Positive, Inconclusive Diagnosis.

OBJECTIVE: An unintended consequence of cystic fibrosis (CF) newborn screening (NBS) is the identification of infants with a positive NBS test but inconclusive diagnostic testing. These infants are classified as CF transmembrane conductance regulator-related metabolic syndrome (CRMS) in the US and CF screen positive, inconclusive diagnosis (CFSPID) in other countries. Diagnostic and management decisions of these infants are challenges for CF healthcare professionals and stressful situations for families. As CF NBS has become more widespread across the world, increased information about the epidemiology and outcomes of these infants is becoming available. These data were reviewed at the 2015 CF Foundation Diagnosis Consensus Conference, and a harmonized definition of CRMS and CFSPID was developed. STUDY DESIGN: At the consensus conference, participants reviewed published and unpublished studies of CRMS/CFSPID and used a modified Delphi methodology to develop a harmonized approach to the definition of CRMS/CFSPID. RESULTS: Several studies of CRMS/CFSPID from populations around the world have been published in the past year. Although the studies vary in the number of infants studied, study design, and outcome measures, there have been some consistent findings. CRMS/CFSPID occurs relatively frequently, with CF:CRMS that ranges from 3 to 5 cases of CF for every 1 case of CRMS/CFSPID in regions where gene sequencing is not used. The incidence varies by NBS protocol used, and in some regions more cases of CRMS/CFSPID are detected than cases of CF. The majority of individuals with CRMS/CFSPID do not develop CF disease or progress to a diagnosis of CF. However, between 10% and 20% of asymptomatic infants can develop clinical features concerning for CF, such as a respiratory culture positive for Pseudomonas aeruginosa. Most studies have only reported short-term outcomes in the first 1-3 years of life; the long-term outcomes of CRMS/CFSPID remain unknown. The European CF Society definition of CFSPID and the CF Foundation definition of CRMS differ only slightly, and the consensus conference was able to create a unified definition of CRMS/CFSPID. CONCLUSIONS: CRMS/CFSPID is a relatively common outcome of CF NBS, and clinicians need to be prepared to counsel families whose NBS test falls into this classification. The vast majority of infants with CRMS/CFSPID will remain free from disease manifestations early in life. However, a small proportion may develop clinical features concerning for CF or demonstrate progression to a clinical phenotype compatible with a CF diagnosis, and their long-term outcomes are not known. A consistent international definition of CRMS/CFSPID will allow for better data collection for study of outcomes and result in improved patient care.

Increased Expression of Plasma-Induced ABCC1 mRNA in Cystic Fibrosis.

The ABCC1 gene is structurally and functionally related to the cystic fibrosis transmembrane conductance regulator gene (CFTR). Upregulation of ABCC1 is thought to improve lung function in patients with cystic fibrosis (CF); the mechanism underlying this effect is unknown. We analyzed the ABCC1 promoter single nucleotide polymorphism (SNP rs504348), plasma-induced ABCC1 mRNA expression levels, and ABCC1 methylation status and their correlation with clinical variables among CF subjects with differing CFTR mutations. We assigned 93 CF subjects into disease severity groups and genotyped SNP rs504348. For 23 CF subjects and 7 healthy controls, donor peripheral blood mononuclear cells (PBMCs) stimulated with plasma underwent gene expression analysis via qRT-PCR. ABCC1 promoter methylation was analyzed in the same 23 CF subjects. No significant correlation was observed between rs504348 genotypes and CF disease severity, but pancreatic insufficient CF subjects showed increased colonization with any form of Pseudomonas aeruginosa (OR = 3.125, 95% CI: 1.192-8.190) and mucoid P. aeruginosa (OR = 5.075, 95% CI: 1.307-28.620) compared to the pancreatic sufficient group. A significantly higher expression of ABCC1 mRNA was induced by CF plasma compared to healthy control plasma (p < 0.001). CF subjects with rs504348 (CC/CG) also had higher mRNA expression compared to those with the ancestral GG genotype (p < 0.005). ABCC1 promoter was completely unmethylated; therefore, we did not detect any association between methylation and CF disease severity. In silico predictions suggested that histone modifications are crucial for regulating ABCC1 expression in PBMCs. Our results suggest that ABCC1 expression has a role in CFTR activity thereby increasing our understanding of the molecular underpinnings of the clinical heterogeneity in CF.

An international cross-sectional survey of antimicrobial stewardship programmes in hospitals.

OBJECTIVES: To report the extent and components of global efforts in antimicrobial stewardship (AMS) in hospitals. METHODS: An Internet-based survey comprising 43 questions was disseminated worldwide in 2012. RESULTS: Responses were received from 660 hospitals in 67 countries: Africa, 44; Asia, 50; Europe, 361; North America, 72; Oceania, 30; and South and Central America, 103. National AMS standards existed in 52% of countries, 4% were planning them and 58% had an AMS programme. The main barriers to implementing AMS programmes were perceived to be a lack of funding or personnel, a lack of information technology and prescriber opposition. In hospitals with an existing AMS programme, AMS rounds existed in 64%; 81% restricted antimicrobials (carbapenems, 74.3%; quinolones, 64%; and cephalosporins, 58%); and 85% reported antimicrobial usage, with 55% linking data to resistance rates and 49% linking data to infection rates. Only 20% had electronic prescribing for all patients. A total of 89% of programmes educated their medical, nursing and pharmacy staff on AMS. Of the hospitals, 38% had formally reviewed their AMS programme: reductions were reported by 96% of hospitals for inappropriate prescribing, 86% for broad-spectrum antibiotic use, 80% for expenditure, 71% for healthcare-acquired infections, 65% for length of stay or mortality and 58% for bacterial resistance. CONCLUSIONS: The worldwide development and implementation of AMS programmes varies considerably. Our results should inform and encourage the further evaluation of this with a view to promoting a worldwide stewardship framework. The prospective measurement of well-defined outcomes of the impact of these programmes remains a significant challenge.

Variants in Solute Carrier SLC26A9 Modify Prenatal Exocrine Pancreatic Damage in Cystic Fibrosis.

OBJECTIVES: To test the hypothesis that multiple constituents of the apical plasma membrane residing alongside the causal cystic fibrosis (CF) transmembrane conductance regulator protein, including known CF modifiers SLC26A9, SLC6A14, and SLC9A3, would be associated with prenatal exocrine pancreatic damage as measured by newborn screened (NBS) immunoreactive trypsinogen (IRT) levels. STUDY DESIGN: NBS IRT measures and genome-wide genotype data were available on 111 subjects from Colorado, 37 subjects from Wisconsin, and 80 subjects from France. Multiple linear regression was used to determine whether any of 8 single nucleotide polymorphisms (SNPs) in SLC26A9, SLC6A14, and SLC9A3 were associated with IRT and whether other constituents of the apical plasma membrane contributed to IRT. RESULTS: In the Colorado sample, 3 SLC26A9 SNPs were associated with NBS IRT (min P=1.16×10(-3); rs7512462), but no SLC6A14 or SLC9A3 SNPs were associated (P>.05). The rs7512462 association replicated in the Wisconsin sample (P=.03) but not in the French sample (P=.76). Furthermore, rs7512462 was the top-ranked apical membrane constituent in the combined Colorado and Wisconsin sample. CONCLUSIONS: NBS IRT is a biomarker of prenatal exocrine pancreatic disease in patients with CF, and a SNP in SLC26A9 accounts for significant IRT variability. This work suggests SLC26A9 as a potential therapeutic target to ameliorate exocrine pancreatic disease.

Comparison of WHO and CDC growth charts in predicting pulmonary outcomes in cystic fibrosis.

OBJECTIVES: The relation of weight-for-length (WFL) and weight-for-age (WFA) measurements with pulmonary function in patients with cystic fibrosis (CF) using the World Health Organization (WHO) growth standards has not been evaluated. The objective of the present study was to show that the relation of WFL and WFA measurements at 2 years with forced expiratory volume in 1 second (FEV1) at 6 to 8 years differs when using the WHO versus the Centers for Disease Control and Prevention (CDC) growth charts. METHODS: We assessed 1155 patients in the CF Foundation Patient Registry born between 2001 and 2004. Comparisons were made between the CDC and WHO growth charts. RESULTS: The WFL percentiles are significantly higher for the WHO growth standards compared with those for the CDC growth charts (median and interquartile range [IQR] WHO--64.8 [41.7-84.9], CDC--48.1 [23.7-75.7], P < 0.0001). WFL and WFA percentiles at 2 years on both charts are strongly associated with FEV1 at 6 to 8 years of age. The FEV1 at 6 to 8 years was statistically significantly lower for children who were classified as reaching a WFL ≥ 50 th percentile at 2 years by WHO standards alone versus those who qualified by both growth charts (median and IQR 103 [94-115] vs 107 [96-117], P < 0.05). Continued weight gain between 2 and 6 years was associated with a higher lung function at age 6 to 8 years. CONCLUSIONS: Although children attaining the 50th WFL percentile on the WHO growth chart by age 2 years have a lower FEV1 at 6 years than children attaining the same percentile on the CDC chart, both groups of children attain clinically normal FEV1. Further studies are needed to determine whether this difference is clinically meaningful.

Diversity of CFTR variants across ancestries characterized using 454,727 UK biobank whole exome sequences.

BACKGROUND: Limited understanding of the diversity of variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene across ancestries hampers efforts to advance molecular diagnosis of cystic fibrosis (CF). The consequences pose a risk of delayed diagnoses and subsequently worsened health outcomes for patients. Therefore, characterizing the spectrum of CFTR variants across ancestries is critical for revolutionizing molecular diagnoses of CF. METHODS: We analyzed 454,727 UK Biobank (UKBB) whole-exome sequences to characterize the diversity of CFTR variants across ancestries. Using the PanUKBB classification, the participants were assigned into six major groups: African (AFR), American/American Admixed (AMR), Central South Asia (CSA), East Asian (EAS), European (EUR), and Middle East (MID). We segregated ancestry-specific CFTR variants, including those that are CF-causing or clinically relevant. The ages of certain CF-causing variants were determined and analyzed for selective pressure effects, and curated phenotype analysis was performed for participants with clinically relevant CFTR genotypes. RESULTS: We detected over 4000 CFTR variants, including novel ancestry-specific variants, across six ancestries. Europeans had the most unique CFTR variants [n = 2212], while the American group had the least unique variants [n = 23]. F508del was the most prevalent CF-causing variant found in all ancestries, except in EAS, where V520F was the most prevalent. Common EAS variants such as 3600G > A, V456A, and V520, which appeared approximately 270, 215, and 338 generations ago, respectively, did not show evidence of selective pressure. Sixteen participants had two CF-causing variants, with two being diagnosed with CF. We found 154 participants harboring a CF-causing and varying clinical consequences (VCC) variant. Phenotype analysis performed for participants with multiple clinically relevant variants returned significant associations with CF and its pulmonary phenotypes [Bonferroni-adjusted p < 0.05]. CONCLUSIONS: We leveraged the UKBB database to comprehensively characterize the broad spectrum of CFTR variants across ancestries. The detection of over 4000 CFTR variants, including several ancestry-specific and uncharacterized CFTR variants, warrants the need for further characterization of their functional and clinical relevance. Overall, the presentation of classical CF phenotypes seen in non-CF diagnosed participants with more than one CF-causing variant indicates that they may benefit from current CFTR modulator therapies.

[Inter-society consensus for the management of respiratory infections: acute bronchitis and chronic obstructive pulmonary disease]. / Consenso Intersociedades para el manejo de infecciones respiratorias: bronquitis aguda y enfermedad pulmonar obstructiva crónica.

The Argentine Society for Infectious Diseases and other national societies issued updated practical guidelines for the management of acute bronchitis (AB) and reactivations of chronic obstructive pulmonary disease (COPD) with the aim of promoting rational use of diagnostic and therapeutic resources. AB is a condition characterized by inflammation of the bronchial airways which affects adults and children without underlying pulmonary disease. It is usually caused by a virus. The diagnosis is based on clinical findings after community acquired pneumonia has been ruled out. Treatment of AB is mainly symptomatic. Antibiotics should be used in immune-compromised hosts, patients with chronic respiratory or cardiac diseases and in the elderly with co-morbidities. Reactivation of COPD is defined as an acute change in the patient's baseline clinical situation beyond normal day to day variations, with an increase in dyspnea, sputum production and/or sputum purulence, warranting a change in medication. An increase in one symptom is considered a mild exacerbation, two as moderate, and the presence of three symptoms is considered a severe exacerbation. An infectious agent can be isolated in sputum in 50 to 75% of COPD reactivations. Moderate and severe episodes must be treated with antibiotics, amoxicillin/ beta-lactamase inhibitor, macrolides and fluoroquinolones are first choice drugs.

The battle against fungi: lessons in antifungal stewardship from COVID 19 times

The COVID-19 pandemic has highlighted the detrimental effect of secondary pathogens in patients with a primary viral insult. In addition to superinfections with bacterial pathogens, invasive fungal infections were increasingly reported. The diagnosis of pulmonary fungal infections has always been challenging; however, it became even more problematic in the setting of COVID-19, particularly regarding the interpretation of radiological findings and mycology test results in patients with these infections. Moreover, prolonged hospitalization in ICU, coupled with underlying host factors. such as preexisting immunosuppression, use of immunomodulatory agents, and pulmonary compromise, caused additional vulnerability to fungal infections in this patient population. In addition, the heavy workload, redeployment of untrained staff, and inconsistent supply of gloves, gowns, and masks during the COVID-19 outbreak made it harder for healthcare workers to strictly adhere to preventive measures for infection control. Taken together, these factors favored patient-to-patient spread of fungal infections, such as those caused by Candida auris, or environment-to-patient transmission, including nosocomial aspergillosis. As fungal infections were associated with increased morbidity and mortality, empirical treatment was overly used and abused in COVID-19-infected patients, potentially contributing to increased resistance in fungal pathogens. The aim of this paper was to focus on essential elements of antifungal stewardship in COVID-19 for three fungal infections, COVID-19-associated candidemia (CAC), -pulmonary aspergillosis (CAPA), and -mucormycosis (CAM).

SARS-CoV-2 mRNA Vaccine Response in People Living with HIV According to CD4 Count and CD4/CD8 Ratio.

BACKGROUND: Our aim was to estimate the rates of not achieving a robust/above-average humoral response to the COVID-19 mRNA vaccine in people living with HIV (PLWH) who received ≥2 doses and to investigate the role of the CD4 and CD4/CD8 ratio in predicting the humoral response. METHODS: We evaluated the humoral anti-SARS-CoV-2 response 1-month after the second and third doses of COVID-19 mRNA vaccine as a proportion of not achieving a robust/above-average response using two criteria: (i) a humoral threshold identified as a correlate of protection against SARS-CoV-2 (<90% vaccine efficacy): anti-RBD < 775 BAU/mL or anti-S < 298 BAU/mL, (ii) threshold of binding antibodies equivalent to average neutralization activity from the levels of binding (nAb titer < 1:40): anti-RBD < 870 BAU/mL or anti-S < 1591 BAU/mL. PLWH were stratified according to the CD4 count and CD4/CD8 ratio at first dose. Logistic regression was used to compare the probability of not achieving robust/above-average responses. A mixed linear model was used to estimate the mean anti-RBD titer at various time points across the exposure groups. RESULTS: a total of 1176 PLWH were included. The proportions of participants failing to achieve a robust/above-average response were significantly higher in participants with a lower CD4 and CD4/CD8 ratio, specifically, a clearer gradient was observed for the CD4 count. The CD4 count was a better predictor of the humoral response of the primary cycle than ratio. The third dose was pivotal in achieving a robust/above-average humoral response, at least for PLWH with CD4 > 200 cells/mm3 and a ratio > 0.6. CONCLUSIONS: A robust humoral response after a booster dose has not been reached by 50% of PLWH with CD4 < 200 cells mm3. In the absence of a validated correlate of protections in the Omicron era, the CD4 count remains the most solid marker to guide vaccination campaigns in PLWH.

Association of cystic fibrosis transmembrane conductance regulator gene variants with acute lung injury in African American children with pneumonia*.

OBJECTIVES: The cystic fibrosis transmembrane conductance regulator regulates fluid balance in alveolar epithelial cells and appears to modulate the inflammatory response. To determine whether more severe lung injury in children who develop community-acquired pneumonia is associated with variations known to affect function in the gene coding for cystic fibrosis transmembrane conductance regulator. DESIGN: A prospective cohort genetic association study of lung injury in children with community-acquired pneumonia. SETTING: Three major tertiary care children's hospitals. SUBJECTS: Caucasian and African American children with community-acquired pneumonia either evaluated in the emergency department or admitted to the hospital. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Caucasian and African American children with pneumonia were genotyped for the most common variants reported to affect cystic fibrosis transmembrane conductance regulator function, the p.508del mutation, the (TG)mTn variable repeat region, and the M470V polymorphism in the cystic fibrosis transmembrane conductance regulator gene. Genotypes and haplotypes were determined, and the association of high-risk alleles or high-risk haplotypes (defined as the presence of at least one variant known to decrease the level of functional cystic fibrosis transmembrane conductance regulator) with the need for mechanical ventilation or the development of acute lung injury was evaluated. Forty-two children in the Caucasian cohort (n = 304) required mechanical ventilation; 32 developed acute lung injury. Forty-three children in the African American cohort (n = 474) required mechanical ventilation; 29 developed acute lung injury. In African American children, high-risk (TG)mTn alleles known to result in decreased levels of functional cystic fibrosis transmembrane conductance regulator were associated with the need for mechanical ventilation (p = .0013) and the development of acute lung injury (p = .0061). Multivariable analysis demonstrated that high-risk (TG)mTn alleles were independently associated with mechanical ventilation (odds ratios = 3.19; 95% confidence interval, 1.63-6.26) and acute lung injury (odds ratios = 3.36; 95% confidence interval, 1.50-7.53) in African American children. CONCLUSION: Genetic variation in cystic fibrosis transmembrane conductance regulator is associated with acute lung injury in African American children with community-acquired pneumonia.