Innate IRE1α-XBP1 activation by viral single-stranded RNA and its influence on lung cytokine production during SARS-CoV-2 pneumonia.

The utilization of host-cell machinery during SARS-CoV-2 infection can overwhelm the protein-folding capacity of the endoplasmic reticulum and activate the unfolded protein response (UPR). The IRE1α-XBP1 arm of the UPR could also be activated by viral RNA via Toll-like receptors. Based on these premises, a study to gain insight into the pathogenesis of COVID-19 disease was conducted using nasopharyngeal exudates and bronchioloalveolar aspirates. The presence of the mRNA of spliced XBP1 and a high expression of cytokine mRNAs were observed during active infection. TLR8 mRNA showed an overwhelming expression in comparison with TLR7 mRNA in bronchioloalveolar aspirates of COVID-19 patients, thus suggesting the presence of monocytes and monocyte-derived dendritic cells (MDDCs). In vitro experiments in MDDCs activated with ssRNA40, a synthetic mimic of SARS-CoV-2 RNA, showed induction of XBP1 splicing and the expression of proinflammatory cytokines. These responses were blunted by the IRE1α inhibitor MKC8866, the TLR8 antagonist CU-CPT9a, and knockdown of TLR8 receptor. In contrast, the IRE1α-XBP1 activator IXA4 enhanced these responses. Based on these findings, the TLR8/IRE1α system seems to play a significant role in the induction of the proinflammatory cytokines associated with severe COVID-19 disease and might be a druggable target to control cytokine storm.

N-antigenemia detection by a rapid lateral flow test predicts 90-day mortality in COVID-19: A prospective cohort study.

OBJECTIVES: To evaluate if the detection of N antigen of SARS-CoV-2 in plasma by a rapid lateral flow test predicts 90-day mortality in COVID-19 patients hospitalized at the wards. METHODS: The presence of N-antigenemia was evaluated in the first 36 hours after hospitalization in 600 unvaccinated COVID-19 patients, by using the Panbio COVID-19 Ag Rapid Test Device from Abbott (Abbott Laboratories Inc., Chicago, IL, USA). The impact of N-antigenemia on 90-day mortality was assessed by multivariable Cox regression analysis. RESULTS: Prevalence of N-antigenemia at hospitalization was higher in nonsurvivors (69% (82/118) vs. 52% (250/482); p < 0.001). The patients with N-antigenemia showed more frequently RNAemia (45.7% (148/324) vs. 19.8% (51/257); p < 0.001), absence of anti-SARS-CoV-2 N antibodies (80.7% (264/327) vs. 26.6% (69/259); p < 0.001) and absence of S1 antibodies (73.4% (240/327) vs. 23.6% (61/259); p < 0.001). The patients with antigenemia showed more frequently acute respiratory distress syndrome (30.1% (100/332) vs. 18.7% (50/268); p = 0.001) and nosocomial infections (13.6% (45/331) vs. 7.9% (21/267); p = 0.026). N-antigenemia was a risk factor for increased 90-day mortality in the multivariable analysis (HR, 1.99 (95% CI,1.09-3.61), whereas the presence of anti-SARS-CoV-2 N-antibodies represented a protective factor (HR, 0.47 (95% CI, 0.26-0.85). DISCUSSION: The presence of N-antigenemia or the absence of anti-SARS-CoV-2 N-antibodies after hospitalization is associated to increased 90-day mortality in unvaccinated COVID-19 patients. Detection of N-antigenemia by using lateral flow tests is a quick, widely available tool that could contribute to early identify those COVID-19 patients at risk of deterioration.

Inadequate empirical antimicrobial treatment in older people with bacteremic urinary tract infection who reside in nursing homes: A multicenter prospective observational study.

AIM: The aim of the study was to determine the rate of inadequate empirical antimicrobial treatment in older nursing home residents with bacteremic urinary tract infection and its influence on prognosis. METHODS: We carried out a multicentric prospective observational study in five Spanish hospitals. Patients aged >65 years with pyelonephritis or urinary sepsis with bacteremia were included. Clinical characteristics, the percentage of inadequate empirical antibiotic treatment, length of hospital stay and mortality were evaluated. RESULTS: A total of 181 patients, 54.7% women, were included in the study, and 35.9% of the patients came from nursing homes. These patients had higher percentages of ultimately or rapidly fatal disease (92.3% vs 53.4%; P < 0.001), were older (83.15 ± 6.97 years vs 79.34 ± 7.25 years; P = 0.001) and had higher Acute Physiology And Chronic Health Evaluation II (28.38 ± 8.57 vs 19.83 ± 5.88). The percentage of extended-spectrum beta-lactamases was higher in patients from nursing homes (30.6% vs 16.3%; P = 0.045), as was the percentage of inadequate empirical antibiotic treatment (40% vs 20.7%; P = 0.005). Length of hospital stay was longer (10.82 ± 3.62 days vs 9.04 ± 4.88 days; P < 0.001). However, 30-day mortality was not related to nursing home by multivariate analysis (OR 1.905, 95% CI 0.563-6.446; P = 0.300). CONCLUSIONS: Nursing home patients with bacteremic urinary tract infections had a higher rate of extended-spectrum beta-lactamase-producing enterobacteriacea and inadequate empirical antimicrobial treatment. Clinicians should consider these findings and avoid inappropriate antimicrobial agents for empirical treatment. Geriatr Gerontol Int 2019; 19: 1112-1117.

The clinical impact of bacteremia on outcomes in elderly patients with pyelonephritis or urinary sepsis: A prospective multicenter study.

BACKGROUND: Bacteremia is common in severe urinary infections, but its influence on the outcomes is not well established. The aim of this study was to assess the association of bacteremia with outcomes in elderly patients admitted to hospital with pyelonephritis or urinary sepsis. METHODS: This prospective muticenter observational study was conducted at 5 Spanish hospitals. All patients aged >65 years with pyelonephritis or urinary sepsis admitted to the departments of internal medicine and with urine and blood cultures obtained at admission to hospital were eligible. Transfer to ICU, length of hospital stay, hospital mortality and all cause 30-day mortality in bacteremic and non-bacteremic groups were compared. Risk factors for all cause 30-day mortality was also estimated. RESULTS: Of the 424 patients included in the study 181 (42.7%) had bacteremia. Neither transfer to ICU (4.4% vs. 2.9%, p = 0.400), nor length of hospital stay (9.7±4.6 days vs. 9.0±7.3 days, p = 0.252), nor hospital mortality (3.3% vs. 6.2%, p = 0.187), nor all cause 30-day mortality (9.4% vs. 13.2%, p = 0.223) were different between bacteremic and non-bacteremic groups. By multivariate analysis, risk factors for all cause 30-day mortality were age (OR 1.05, 95% CI 1.00-1.10), McCabe index ≥2 (OR 10.47, 95% CI 2.96-37.04) and septic shock (OR 8.56, 95% CI 2.86-25.61); whereas, bacteremia was inversely associated with all cause 30-day mortality (OR 0.33, 95% CI 0.15-0.71). CONCLUSIONS: In this cohort, bacteremia was not associated with a worse prognosis in elderly patients with pyelonephritis or urinary sepsis.

Assessment of antibiotic prescription in acute urinary tract infections in adults.

OBJECTIVES: To assess the appropriateness of antibiotic prescription for urinary tract infections in several hospital emergency services and to evaluate the variability of antibiotic prescription among these services. METHODS: A cross-sectional study was carried out in the emergency services of 10 hospitals from different Spanish regions. The sample was composed of patients diagnosed with acute urinary infection, aged> or =14 years. A Consensus Conference, held by a panel of experts, established first-choice, second-choice and inappropriate antibiotic treatments for each type of urinary tract infection, based on the available scientific evidence. All the observed prescriptions in our study were classified according to this pattern. The main variables were: type of urinary infection, antibiotic prescription, urine culture request, comorbidity and hospital admission. RESULTS: A sample of 3797 acute urinary tract infections was studied. Eighty-one percent were lower urinary tract infections. The most commonly used antibiotics were ciprofloxacin and amoxicillin-clavulanate. The global percentages of first-choice, alternative-choice and inappropriate antibiotic prescriptions were: 42.4% (95% CI: 40.8-43.9), 44.1 (95% CI: 42.5-45.7) and 13.6% (95% CI: 12.5-14.7), respectively. We observed a significant variability in appropriateness of antibiotic prescriptions among the participating centres (p<0.001). CONCLUSIONS: Physicians at Spanish emergency rooms prescribe an excessive number of second-choice antibiotics for urinary tract infection treatment. There exists a high variability in antibiotic prescription among hospitals from different regions.