Effects of triple therapy on disease burden in patients of GOLD groups C and D: results from the observational COPD cohort COSYCONET.

BACKGROUND: Randomized controlled trials described beneficial effects of inhaled triple therapy (LABA/LAMA/ICS) in patients with chronic obstructive pulmonary disease (COPD) and high risk of exacerbations. We studied whether such effects were also detectable under continuous treatment in a retrospective observational setting. METHODS: Data from baseline and 18-month follow-up of the COPD cohort COSYCONET were used, including patients categorized as GOLD groups C/D at both visits (n = 258). Therapy groups were defined as triple therapy at both visits (triple always, TA) versus its complement (triple not always, TNA). Comparisons were performed via multiple regression analysis, propensity score matching and inverse probability weighting to adjust for differences between groups. For this purpose, variables were divided into predictors of therapy and outcomes. RESULTS: In total, 258 patients were eligible (TA: n = 162, TNA: n = 96). Without adjustments, TA patients showed significant (p < 0.05) impairments regarding lung function, quality of life and symptom burden. After adjustments, most differences in outcomes were no more significant. Total direct health care costs were reduced but still elevated, with inpatient costs much reduced, while costs of total and respiratory medication only slightly changed. CONCLUSION: Without statistical adjustment, patients with triple therapy showed multiple impairments as well as elevated treatment costs. After adjusting for differences between treatment groups, differences were reduced. These findings are compatible with beneficial effects of triple therapy under continuous, long-term treatment, but also demonstrate the limitations encountered in the comparison of controlled intervention studies with observational studies in patients with severe COPD using different types of devices and compounds.

Key summary of German national treatment guidance for hospitalized COVID-19 patients : Key pharmacologic recommendations from a national German living guideline using an Evidence to Decision Framework (last updated 17.05.2021).

PURPOSE: This executive summary of a national living guideline aims to provide rapid evidence based recommendations on the role of drug interventions in the treatment of hospitalized patients with COVID-19. METHODS: The guideline makes use of a systematic assessment and decision process using an evidence to decision framework (GRADE) as recommended standard WHO (2021). Recommendations are consented by an interdisciplinary panel. Evidence analysis and interpretation is supported by the CEOsys project providing extensive literature searches and living (meta-) analyses. For this executive summary, selected key recommendations on drug therapy are presented including the quality of the evidence and rationale for the level of recommendation. RESULTS: The guideline contains 11 key recommendations for COVID-19 drug therapy, eight of which are based on systematic review and/or meta-analysis, while three recommendations represent consensus expert opinion. Based on current evidence, the panel makes strong recommendations for corticosteroids (WHO scale 5-9) and prophylactic anticoagulation (all hospitalized patients with COVID-19) as standard of care. Intensified anticoagulation may be considered for patients with additional risk factors for venous thromboembolisms (VTE) and a low bleeding risk. The IL-6 antagonist tocilizumab may be added in case of high supplemental oxygen requirement and progressive disease (WHO scale 5-6). Treatment with nMABs may be considered for selected inpatients with an early SARS-CoV-2 infection that are not hospitalized for COVID-19. Convalescent plasma, azithromycin, ivermectin or vitamin D3 should not be used in COVID-19 routine care. CONCLUSION: For COVID-19 drug therapy, there are several options that are sufficiently supported by evidence. The living guidance will be updated as new evidence emerges.

Treatment with long acting muscarinic antagonists stimulates serum levels of irisin in patients with COPD.

Long acting muscarinic antagonists (LAMA) are currently considered the therapeutic mainstay for patients with COPD and have been shown to improve clinical outcomes including symptoms, exercise capacity and airflow limitation. Irisin, is a newly discovered hormone-like myokine generated by skeletal muscle cells in response to exercise and it is suggested to regulate energy expenditure and exercise capacity. The aim of the present study was to investigate if treatment with LAMA alters serum irisin levels in patients with COPD. Irisin was assessed by ELISA in the serum of 506 patients with COPD, GOLD II-IV, with a smoking history >10 PY, who were included in the PROMISE-COPD cohort. The effect of inhaled LAMA on serum irisin levels was evaluated in a proof-of-concept cohort of 40 COPD patients. Univariate linear regression analysis revealed that there was a significant negative association of irisin with age-adjusted Charlson score (p = 0.003) and a positive association of irisin with 6-min walking distance (6MWD) (p = 0.018) and treatment with LAMA (p = 0.004) but not with LABA or ICS. Multivariate analysis revealed that the association of irisin with LAMA treatment remains significant after adjustment for age-adjusted score and 6MWD. In the proof-of-concept cohort a single inhalation of LAMA stimulated serum irisin levels after 4 h. These findings imply that treatment of COPD patients with LAMA increase circulating irisin, thus explaining some of the beneficial extra-pulmonary effects of these drugs when used in the treatment of COPD.

α-1-Antitrypsin (AAT)-modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics.

Hematopoietic cell transplantation is curative in many patients. However, graft-versus-host disease (GVHD), triggered by alloreactive donor cells, has remained a major complication. Here, we show an inverse correlation between plasma α-1-antitrypsin (AAT) levels in human donors and the development of acute GVHD in the recipients (n = 111; P = .0006). In murine models, treatment of transplant donors with human AAT resulted in an increase in interleukin-10 messenger RNA and CD8(+)CD11c(+)CD205(+) major histocompatibility complex class II(+) dendritic cells (DCs), and the prevention or attenuation of acute GVHD in the recipients. Ablation of DCs (in AAT-treated CD11c-DTR donors) decreased CD4(+)CD25(+)FoxP3(+) regulatory T cells to one-third and abrogated the anti-GVHD effect. The graft-versus-leukemia (GVL) effect of donor cells (against A20 tumor cells) was maintained or even enhanced with AAT treatment of the donor, mediated by an expanded population of NK1.1(+), CD49B(+), CD122(+), CD335(+) NKG2D-expressing natural killer (NK) cells. Blockade of NKG2D significantly suppressed the GVL effect. Metabolic analysis showed a high glycolysis-high oxidative phosphorylation profile for NK1.1(+) cells, CD4(+)CD25(+)FoxP3(+) T cells, and CD11c(+) DCs but not for effector T cells, suggesting a cell type-specific effect of AAT. Thus, via altered metabolism, AAT exerts effective GVHD protection while enhancing GVL effects.

Allergen-specific immunotherapy increases plasma gelsolin levels.

BACKGROUND: It has been observed that patients with allergic asthma/rhinitis have increased apoptosis of peripheral blood cells. This study was designed to explore the idea that the markers of apoptosis may help predict the response of allergen immunotherapy. METHODS: The Allergy Department of University Hospital, Malmö, Sweden, recruited a total of 58 young adults (<35 years) with a history of birch pollen/grass pollen-induced allergic rhinitis. Their diagnoses were verified by positive skin-prick tests and the presence of serum-specific immunoglobulin E antibodies toward birch and/or grass pollen. Plasma samples were obtained from 34 patients before the start of immunotherapy and 24 patients after treatment. The control group consisted of 38 nonallergic individuals. The levels of plasma gelsolin, soluble forms of Fas (sFas) and Fas ligand (Fas-L), the chemokine CCL17 (thymus- and activation-regulated chemokine), and tissue inhibitor of metalloprotease (TIMP) 1, were measured by enzyme-linked immunosorbent assay. RESULTS: In patients receiving immunotherapy plasma gelsolin levels were higher relative to those without immunotherapy (the median level was 23.97 µg/mL [range, 18-35.8 µg/mL] versus 21.2 µg/mL [range, 13.9-29.8 µg/mL]; p = 0.012) and were similar to those of healthy controls (24.7 µg/mL [range, 17.4-35.3 µg/mL]). Plasma levels of sFas, Fas-L, CCL17, and TIMP-1 did not differ between study groups. Only in controls did the plasma gelsolin levels inversely correlate to the levels of soluble Fas. CONCLUSION: Allergen-specific immunotherapy increases plasma levels of gelsolin, an antioxidant and antiapoptotic protein.

Vitamin D deficiency in community-acquired pneumonia: low levels of 1,25(OH)2 D are associated with disease severity.

OBJECTIVES: We aimed to explore the association between vitamin D levels and the severity, mortality and microbiological etiology of community-acquired pneumonia. METHODS: Vitamin D levels (both, the reservoir form 25-OH and the activated form 1,25-OH2) of 300 randomly selected patients with community-acquired pneumonia due to pre-specified pathogens included in the German competence network (CAPNETZ) study were measured. Prior to statistical analysis, values of 25-OH and 1,25-OH2 were power-transformed to achieve parametric distribution. All further analyses were performed with seasonally and age adjusted values. RESULTS: There was only a modest (Spearman Coefficient 0.38) positive correlation between 25-OH and 1,25-OH2. For 1,25-OH2 but not 25-OH, the general linear model revealed a significant inverse correlation between serum concentration and CURB score (p = 0.011). Liver and respiratory co-morbidity were associated with significantly lower 25-OH values and renal co-morbidity with significantly lower 1,25-OH2 values. No significant differences of 1,25-OH2 or 25-OH between different pathogens (influenza virus, Legionella spp., Streptococcus pneumoniae) were detected. CONCLUSION: For 1,25-OH2, we found a significant and independent (controlled for age, season and pathogen) negative correlation to pneumonia severity. Therefore, supplementation of non-activated vitamin D to protect from pneumonia may be non-sufficient in patients that have a decreased capacity to hydroxylate 25-OH to 1,25-OH2.

Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial.

CONTEXT: Early appropriate antimicrobial therapy leads to lower mortality rates associated with severe sepsis. The role of empirical combination therapy comprising at least 2 antibiotics of different mechanisms remains controversial. OBJECTIVE: To compare the effect of moxifloxacin and meropenem with the effect of meropenem alone on sepsis-related organ dysfunction. DESIGN, SETTING, AND PATIENTS: A randomized, open-label, parallel-group trial of 600 patients who fulfilled criteria for severe sepsis or septic shock (n = 298 for monotherapy and n = 302 for combination therapy). The trial was performed at 44 intensive care units in Germany from October 16, 2007, to March 23, 2010. The number of evaluable patients was 273 in the monotherapy group and 278 in the combination therapy group. INTERVENTIONS: Intravenous meropenem (1 g every 8 hours) and moxifloxacin (400 mg every 24 hours) or meropenem alone. The intervention was recommended for 7 days and up to a maximum of 14 days after randomization or until discharge from the intensive care unit or death, whichever occurred first. MAIN OUTCOME MEASURE: Degree of organ failure (mean of daily total Sequential Organ Failure Assessment [SOFA] scores over 14 days; score range: 0-24 points with higher scores indicating worse organ failure); secondary outcome: 28-day and 90-day all-cause mortality. Survivors were followed up for 90 days. RESULTS: Among 551 evaluable patients, there was no statistically significant difference in mean SOFA score between the meropenem and moxifloxacin group (8.3 points; 95% CI, 7.8-8.8 points) and the meropenem alone group (7.9 points; 95% CI, 7.5-8.4 points) (P = .36). The rates for 28-day and 90-day mortality also were not statistically significantly different. By day 28, there were 66 deaths (23.9%; 95% CI, 19.0%-29.4%) in the combination therapy group compared with 59 deaths (21.9%; 95% CI, 17.1%-27.4%) in the monotherapy group (P = .58). By day 90, there were 96 deaths (35.3%; 95% CI, 29.6%-41.3%) in the combination therapy group compared with 84 deaths (32.1%; 95% CI, 26.5%-38.1%) in the monotherapy group (P = .43). CONCLUSION: Among adult patients with severe sepsis, treatment with combined meropenem and moxifloxacin compared with meropenem alone did not result in less organ failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00534287.

Proteomic bronchiolitis obliterans syndrome risk monitoring in lung transplant recipients.

BACKGROUND: Obliterative bronchiolitis poses a primary obstacle for long-term survival of lung transplant recipients and manifests clinically as bronchiolitis obliterans syndrome (BOS). Establishing a molecular level screening method to detect BOS-related proteome changes before its diagnosis by forced expiratory volume surrogate marker criteria was the main objective of this study. METHODS: Bronchoalveolar lavage was performed in 82 lung transplant recipients (48/34 with/without known BOS development) at different time points between 12 and 48 months after lung transplantation. A mass spectrometry-based method was devised to generate bronchoalveolar lavage fluid proteome profiles that were screened for BOS-specific alterations. Statistically significant marker peptides and proteins were identified and validated by in-gel digestion, tandem mass spectrometric sequencing, and quantitative immunoassays. RESULTS: Among the panel of statistically significant markers were Clara cell protein, calgranulin A, human neutrophil peptides, and the antimicrobial agent histatin. To assess their clinical relevance, a highly sensitive and specific classifier model was developed. Positive BOS classification by monitoring of seven polypeptides correlated strongly with a significant decrease in BOS-free time. Thus, it was possible to detect high-risk patients early on in the pathogenetic process. CONCLUSIONS: Monitoring the bronchoalveolar lavage fluid levels of seven polypeptides detected by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry allows a reliable prediction of early BOS using a Random Forest decision tree-based classifier model. The high accuracy of this robust model and its synergistic potential in combination with established forced expiratory volume-based diagnostics could make it an effective tool to supplement the current diagnostic regime after multicentric validation.

Intravenous tigecycline as adjunctive or alternative therapy for severe refractory Clostridium difficile infection.

Clostridium difficile infection (CDI) has become more refractory to standard therapy. We describe 4 patients with severe refractory CDI who were successfully treated with tigecycline. Symptoms improved within 1 week. No relapses were observed. This favorable outcome suggests that tigecycline might be a useful alternative for treating severe refractory CDI.

Treatment with sequential intravenous or oral moxifloxacin was associated with faster clinical improvement than was standard therapy for hospitalized patients with community-acquired pneumonia who received initial parenteral therapy.

BACKGROUND: Although third-generation cephalosporins, such as ceftriaxone (CTRX), and pneumococcal fluoroquinolones, such as moxifloxacin (MXF), are currently recommended first-line antibiotics for empirical treatment of inpatients with community-acquired pneumonia, CTRX and MXF have never undergone a head-to-head comparison. We therefore compared the efficacy, safety, and speed and quality of defervescence of sequential intravenous or oral MXF and high-dose CTRX with or without erythromycin (CTRX+/-ERY) for patients with community-acquired pneumonia requiring parenteral therapy. METHODS: In this prospective, multicenter, randomized, controlled, nonblinded study, 397 patients were randomly assigned to receive either MXF (400 mg once daily intravenously, possibly followed by oral tablets) or CTRX (2 g intravenously once daily) with or without ERY (1 g intravenously every 6-8 h) for 7-14 days. RESULTS: Among 317 patients evaluable for efficacy and safety, 138 (85.7%) of 161 MXF-treated patients and 135 (86.5%) of 156 CTRX+/-ERY-treated patients (59 [37.8%] of whom received CTRX and ERY) achieved continued clinical resolution. Defervescence and relief of symptoms, such as chest pain, occurred significantly earlier in the MXF-treated group than in the CTRX+/-ERY-treated group. Both regimens were generally well tolerated. CONCLUSIONS: For adult patients hospitalized with community-acquired pneumonia, sequential MXF therapy was clinically equivalent to high-dose CTRX+/-ERY therapy but led to a faster clinical improvement.

Recurrent tendinitis after treatment with two different fluoroquinolones.

Tendinopathies with and without tendon rupture are rare adverse events, occurring mainly following older fluoroquinolones, but recently also to an increasing extent following levofloxacin. We report the first case of tendinitis after treatment with moxifloxacin, and of recurrent tendinitis after treatment with 2 different fluoroquinolones. From these findings we conclude hitherto unexplained class effect of fluoroquinolones in respect of the development of tendinitis.