Use of Azithromycin Attributable to Acute SARS-CoV-2 Infection.

PURPOSE: In the early stages of the COVID-19 pandemic, preliminary results that later proved to be incorrect suggested the possible efficacy of anti-infective drugs such as azithromycin for the treatment of SARS-CoV-2 infection. These preliminary data may have influenced the prescription of azithromycin. However, no individual-level data linking the use of this antibiotic to acute SARS-CoV-2 infection are available. The present analysis aims to fill this gap. METHODS: A retrospective population-based cohort design was used including patients diagnosed with SARS-CoV-2 infection in the period ranging from February 2020 to February 2022. The data source for antibiotic consumption was the drug database of outpatient prescriptions of Emilia-Romagna Region (Italy). Antibiotics were classified according to the Anatomical Therapeutic Chemical (ATC) classification system. Consumption rates and percentages of azithromycin DDDs (defined daily doses) during the acute phase of the infection were compared with a previous control period and with the post-acute phase. Analyses were stratified by four groups according to the prevalent virus variant at time of diagnosis. RESULTS: Comparing the previous control period with the acute phase of infections, the rates of azithromycin consumption (DDD per 1000 individuals per day) increased from 1.17 to 23.11, from 0.80 to 33.03, from 0.81 to 21.01, and from 1.02 to 9.76, in the pre-Alpha, Alpha, Delta, and Omicron periods, respectively. Similarly, the percentages of individuals receiving azithromycin, and the azithromycin DDDs percentages over total systemic antibiotics DDDs increased in acute phases of infection compared with control periods. The consumption rates and percentages returned to preinfection levels in the post-acute phase. In the study period, 12.9% of the use of azithromycin in the entire adult population of Emilia-Romagna was attributable to acute SARS-CoV-2 infection. CONCLUSIONS: Considering the low likelihood of bacterial coinfections, the increased azithromycin consumption in the acute phase of SARS-CoV-2 infection suggests inappropriate prescribing of this antibiotic.

Efficacy and safety of baricitinib in 446 patients with rheumatoid arthritis: a real-life multicentre study.

OBJECTIVES: Baricitinib, an oral Janus kinase (JAK) 1-2 inhibitor, is currently used along biologic DMARDs (bDMARDs) after the failure of methotrexate (MTX) in rheumatoid arthritis (RA). We investigated the efficacy and safety of baricitinib in real life. METHODS: We prospectively enrolled 446 RA patients treated with baricitinib from 11 Italian centres. Patients were evaluated at baseline and after 3, 6, and 12 months. They were arrayed based on previous treatments as bDMARD-naïve and bDMARD-insufficient responders (IR) after the failure or intolerance to bDMARDs. A sub-analysis differentiated the effects of methotrexate (MTX) and the use of oral glucocorticoids (OGC). RESULTS: Our cohort included 150 (34%) bDMARD-naïve and 296 (66%) bDMARD-IR patients, with 217 (49%) using baricitinib as monotherapy. Considering DAS-28-CRP as the primary outcome, at 3 and 6 months, 114/314 (36%) and 149/289 (51.6%) patients achieved remission, while those in low disease activity (LDA) were 62/314 (20%) and 46/289 (15.9%), respectively; finally at 12 months 81/126 (64%) were in remission and 21/126 (17%) in LDA. At all-timepoints up to 12 months, bDMARDs-naïve patients demonstrated a better clinical response, independently of MTX. A significant reduction in the OGC dose was observed at 3 and 12 months in all groups. The serum positivity for both rheumatoid factors (RF) and anti-citrullinated protein antibodies (ACPA) conferred a lower risk of stopping baricitinib due to inefficacy. Fifty-eight (13%) patients discontinued baricitinib due to adverse events, including thrombotic events and herpes zoster reactivation. CONCLUSIONS: Real-life data confirm the efficacy and safety profiles of baricitinib in patients with RA and provide evidence that drug survival is higher in bDMARDs-naïve and seropositive patients.

Modelling antimicrobial resistance transmission to guide personalized antimicrobial stewardship interventions and infection control policies in healthcare setting: a pilot study.

Infection control programs and antimicrobial stewardship have been proven effective in reducing the burden of diseases due to multidrug-resistant organisms, but quantifying the effect of each intervention is an open issue. For this aim, we propose a model to characterize the effect of interventions at single ward level. We adapted the Ross-Macdonald model to describe hospital cross-transmission dynamics of carbapenem resistant Klebsiella pneumoniae (CRKP), considering healthcare workers as the vectors transmitting susceptible and resistant pathogens among admitted patients. The model parameters were estimated from a literature review, further adjusted to reproduce observed clinical outcomes, and validated using real life data from a 2-year study in a university hospital. The model has been further explored through extensive sensitivity analysis, in order to assess the relevance of single interventions as well as their synergistic effects. Our model has been shown to be an effective tool to describe and predict the impact of interventions in reducing the prevalence of CRKP colonisation and infection, and can be extended to other specific hospital and pathological scenarios to produce tailored estimates of the most effective strategies.

The incidence and risk factors of selected drug prescriptions and outpatient care after SARS-CoV-2 infection in low-risk subjects: a multicenter population-based cohort study.

Background: Knowledge about the dynamics of transmission of SARS-CoV-2 and the clinical aspects of COVID-19 has steadily increased over time, although evidence of the determinants of disease severity and duration is still limited and mainly focused on older adult and fragile populations. Methods: The present study was conceived and carried out in the Emilia-Romagna (E-R) and Veneto Regions, Italy, within the context of the EU's Horizon 2020 research project called ORCHESTRA (Connecting European Cohorts to increase common and effective response to SARS-CoV-2 pandemic) (www.orchestra-cohort.eu). The study has a multicenter retrospective population-based cohort design and aimed to investigate the incidence and risk factors of access to specific healthcare services (outpatient visits and diagnostics, drug prescriptions) during the post-acute phase from day-31 to day-365 after SARS-CoV-2 infection, in a healthy population at low risk of severe acute COVID-19. The study made use of previously recorded large-scale healthcare data available in the administrative databases of the two Italian Regions. The statistical analysis made use of methods for competing risks. Risk factors were assessed separately in the two Regions and results were pooled using random effects meta-analysis. Results: There were 35,128 subjects in E-R and 88,881 in Veneto who were included in the data analysis. The outcome (access to selected health services) occurred in a high percentage of subjects in the post-acute phase (25% in E-R and 21% in Veneto). Outpatient care was observed more frequently than drug prescriptions (18% vs. 12% in E-R and 15% vs. 10% in Veneto). Risk factors associated with the outcome were female sex, age greater than 40 years, baseline risk of hospitalization and death, moderate to severe acute COVID-19, and acute extrapulmonary complications. Conclusion: The outcome of interest may be considered as a proxy for long-term effects of COVID-19 needing clinical attention. Our data suggest that this outcome occurs in a substantial percentage of cases, even among a previously healthy population with low or mild severity of acute COVID-19. The study results provide useful insights into planning COVID-19-related services.

Antimicrobial Stewardship in COVID-19 Patients: Those Who Sow Will Reap Even through Hard Times.

BACKGROUND: Since the SARS-CoV-2 pandemic emerged, antimicrobial stewardship (AS) activities need to be diverted into COVID-19 management. METHODS: In order to assess the impact of COVID-19 on AS activities, we analyzed changes in antibiotic consumption in moderate-to-severe COVID-19 patients admitted to four units in a tertiary-care hospital across three COVID-19 waves. The AS program was introduced at the hospital in 2018. During the first wave, COVID-19 forced the complete withdrawal of hospital AS activities. In the second wave, antibiotic guidance calibration for COVID-19 patients was implemented in all units, with enhanced stewardship activities in Units 1, 2, and 3 (intervention units). In a controlled before and after study, antimicrobial usage during the three waves of the COVID-19 pandemic was compared to the 12-month prepandemic unit (Unit 4 acted as the control). Antibiotic consumption data were analyzed as the overall consumption, stratified by the World Health Organization AWaRe classification, and expressed as defined-daily-dose (DDD) and days-of-therapy (DOT) per 1000 patient-day (PD). RESULTS: In the first wave, the overall normalized DOT in units 2-4 significantly exceeded the 2019 level (2019: 587 DOT/1000 PD ± 42.6; Unit 2: 836 ± 77.1; Unit 3: 684 ± 122.3; Unit 4: 872, ± 162.6; p < 0.05). After the introduction of AS activities, consumption decreased in the intervention units to a significantly lower level when compared to 2019 (Unit 1: 498 DOT/1000 PD ± 49; Unit 2: 232 ± 95.7; Unit 3: 382 ± 96.9; p < 0.05). Antimicrobial stewardship activities resulted in a decreased amount of total antibiotic consumption over time and positively affected the watch class and piperacillin-tazobactam use in the involved units. CONCLUSIONS: During a pandemic, the implementation of calibrated AS activities represents a sound investment in avoiding inappropriate antibiotic therapy.

How European Research Projects Can Support Vaccination Strategies: The Case of the ORCHESTRA Project for SARS-CoV-2.

ORCHESTRA ("Connecting European Cohorts to Increase Common and Effective Response To SARS-CoV-2 Pandemic") is an EU-funded project which aims to help rapidly advance the knowledge related to the prevention of the SARS-CoV-2 infection and the management of COVID-19 and its long-term sequelae. Here, we describe the early results of this project, focusing on the strengths of multiple, international, historical and prospective cohort studies and highlighting those results which are of potential relevance for vaccination strategies, such as the necessity of a vaccine booster dose after a primary vaccination course in hematologic cancer patients and in solid organ transplant recipients to elicit a higher antibody titer, and the protective effect of vaccination on severe COVID-19 clinical manifestation and on the emergence of post-COVID-19 conditions. Valuable data regarding epidemiological variations, risk factors of SARS-CoV-2 infection and its sequelae, and vaccination efficacy in different subpopulations can support further defining public health vaccination policies.

Clinical phenotypes and quality of life to define post-COVID-19 syndrome: a cluster analysis of the multinational, prospective ORCHESTRA cohort.

Background: Lack of specific definitions of clinical characteristics, disease severity, and risk and preventive factors of post-COVID-19 syndrome (PCS) severely impacts research and discovery of new preventive and therapeutics drugs. Methods: This prospective multicenter cohort study was conducted from February 2020 to June 2022 in 5 countries, enrolling SARS-CoV-2 out- and in-patients followed at 3-, 6-, and 12-month from diagnosis, with assessment of clinical and biochemical features, antibody (Ab) response, Variant of Concern (VoC), and physical and mental quality of life (QoL). Outcome of interest was identification of risk and protective factors of PCS by clinical phenotype, setting, severity of disease, treatment, and vaccination status. We used SF-36 questionnaire to assess evolution in QoL index during follow-up and unsupervised machine learning algorithms (principal component analysis, PCA) to explore symptom clusters. Severity of PCS was defined by clinical phenotype and QoL. We also used generalized linear models to analyse the impact of PCS on QoL and associated risk and preventive factors. CT registration number: NCT05097677. Findings: Among 1796 patients enrolled, 1030 (57%) suffered from at least one symptom at 12-month. PCA identified 4 clinical phenotypes: chronic fatigue-like syndrome (CFs: fatigue, headache and memory loss, 757 patients, 42%), respiratory syndrome (REs: cough and dyspnoea, 502, 23%); chronic pain syndrome (CPs: arthralgia and myalgia, 399, 22%); and neurosensorial syndrome (NSs: alteration in taste and smell, 197, 11%). Determinants of clinical phenotypes were different (all comparisons p < 0.05): being female increased risk of CPs, NSs, and CFs; chronic pulmonary diseases of REs; neurological symptoms at SARS-CoV-2 diagnosis of REs, NSs, and CFs; oxygen therapy of CFs and REs; and gastrointestinal symptoms at SARS-CoV-2 diagnosis of CFs. Early treatment of SARS-CoV-2 infection with monoclonal Ab (all clinical phenotypes), corticosteroids therapy for mild/severe cases (NSs), and SARS-CoV-2 vaccination (CPs) were less likely to be associated to PCS (all comparisons p < 0.05). Highest reduction in QoL was detected in REs and CPs (43.57 and 43.86 vs 57.32 in PCS-negative controls, p < 0.001). Female sex (p < 0.001), gastrointestinal symptoms (p = 0.034) and renal complications (p = 0.002) during the acute infection were likely to increase risk of severe PCS (QoL <50). Vaccination and early treatment with monoclonal Ab reduced the risk of severe PCS (p = 0.01 and p = 0.03, respectively). Interpretation: Our study provides new evidence suggesting that PCS can be classified by clinical phenotypes with different impact on QoL, underlying possible different pathogenic mechanisms. We identified factors associated to each clinical phenotype and to severe PCS. These results might help in designing pathogenesis studies and in selecting high-risk patients for inclusion in therapeutic and management clinical trials. Funding: The study received funding from the Horizon 2020 ORCHESTRA project, grant 101016167; from the Netherlands Organisation for Health Research and Development (ZonMw), grant 10430012010023; from Inserm, REACTing (REsearch & ACtion emergING infectious diseases) consortium and the French Ministry of Health, grant PHRC 20-0424.

Short-Term Adverse Events and Antibody Response to the BNT162b2 SARS-CoV-2 Vaccine in 4156 Health Care Professionals.

Short-term adverse events are common following the BNT162b2 vaccine for SARS-Cov-2 and have been possibly associated with IgG response. We aimed to determine the incidence of adverse reactions to the vaccine and the impact on IgG response. Our study included 4156 health-care professionals who received two doses of the BNT162b2 vaccine 21 days apart and obtained 6113 online questionnaires inquiring about adverse events. The serum response was tested in 2765 subjects 10 days after the second dose. Adverse events, most frequently a local reaction at the site of injection, were reported by 39% of subjects. Multivariate analysis showed that female sex (odds ratio­OR­1.95; 95% confidence interval­CI­1.74−2.19; p < 0.001), younger age (OR 0.98 per year, p < 0.001), second dose of vaccine (OR 1.36, p < 0.001), and previous COVID-19 infection (OR 1.41, p < 0.001) were independently associated with adverse events. IgG response was significantly higher in subjects with adverse events (1110 AU/mL­IQR 345-1630 vs. 386 AU/mL, IQR 261-1350, p < 0.0001), and the association was more pronounced in subjects experiencing myalgia, fever, and lymphadenopathy. We demonstrate that a more pronounced IgG response is associated with specific adverse events, and these are commonly reported by health care professionals after the BNT162b2 vaccine for SARS-Cov-2.

Diagnostic accuracy of point-of-care tests in acute community-acquired lower respiratory tract infections. A systematic review and meta-analysis.

BACKGROUND: Point-of-care tests could be essential in differentiating bacterial and viral acute community-acquired lower respiratory tract infections and driving antibiotic stewardship in the community. OBJECTIVES: To assess diagnostic test accuracy of point-of-care tests in community settings for acute community-acquired lower respiratory tract infections. DATA SOURCES: Multiple databases (MEDLINE, EMBASE, Web of Science, Cochrane Library, Open Gray) from inception to 31 May 2021, without language restrictions. STUDY ELIGIBILITY CRITERIA: Diagnostic test accuracy studies involving patients at primary care, outpatient clinic, emergency department and long-term care facilities with a clinical suspicion of acute community-acquired lower respiratory tract infections. The comparator was any test used as a comparison to the index test. In order not to limit the study inclusion, the comparator was not defined a priori. ASSESSMENT OF RISK OF BIAS: Four investigators independently extracted data, rated risk of bias, and assessed the quality using QUADAS-2. METHODS OF DATA SYNTHESIS: The measures of diagnostic test accuracy were calculated with 95% CI. RESULTS: A total of 421 studies addressed at least one point-of-care test. The diagnostic performance of molecular tests was higher compared with that of rapid diagnostic tests for all the pathogens studied. The accuracy of stand-alone signs and symptoms or biomarkers was poor. Lung ultrasound showed high sensitivity and specificity (90% for both) for the diagnosis of bacterial pneumonia. Rapid antigen-based diagnostic tests for influenza, respiratory syncytial virus, human metapneumovirus, and Streptococcus pneumoniae had sub-optimal sensitivity (range 49%-84%) but high specificity (>80%). DISCUSSION: Physical examination and host biomarkers are not sufficiently reliable as stand-alone tests to differentiate between bacterial and viral pneumonia. Lung ultrasound shows higher accuracy than chest X-ray for bacterial pneumonia at emergency department. Rapid antigen-based diagnostic tests cannot be considered fully reliable because of high false-negative rates. Overall, molecular tests for all the pathogens considered were found to be the most accurate.

Bronchoalveolar lavage in suspected COVID-19 cases with a negative nasopharyngeal swab: a retrospective cross-sectional study in a high-impact Northern Italy area.

COVID-19 diagnosis relies on molecular testing for SARS-CoV-2 via nasopharyngeal swab in the presence of suggestive clinical, radiological and laboratory findings. Since bronchoalveolar lavage liquid (BAL) collected during fibrobronchoscopy may increase test sensitivity compared to nasopharyngeal swabs, it was performed during the 2020 pandemic in clinically or radiologically suspected cases. Our aim was to determine whether clinical features, chest computed tomography (CT) findings or laboratory tests may predict patients testing positive for SARS-CoV-2 at BAL after a negative nasopharyngeal swab. We performed a retrospective cross-sectional study with multivariable analysis of suspected patients who were tested for SARS-CoV-2 at BAL after at least one negative nasopharyngeal swab. Univariable logistic regression for odds ratio and multivariate models was calculated to determine clinical, radiological and laboratory predictors. 32/198 (16%) patients had BAL positive for SARS-CoV-2, while 65/198 tested positive for other pathogens at BAL. Of the 32 patients positive for COVID, 4 had a coinfection at BAL, being thus positive both for COVID as well as for another pathogen while the remaining 105 patients were negative for COVID and other pathogens at BAL. COVID-19 patients had more often highly suggestive CT findings, higher number of involved lobes, more often ground glass opacity of more than 50% of lung parenchyma, and less frequently other radiologically suspected infections. At multivariate model, temperature also predicted BAL positivity. The procedure was well tolerated-with only one desaturation episode-while no healthcare worker was infected. In conclusion, when nasopharyngeal swabs are negative but there is clinical or imaging suspicion of COVID-19, BAL represents a complementary diagnostic tool, particularly in conjunction with suggestive/more extensive lung involvement at CT scan. The procedure did not carry increased risks for patients nor for operators, while allowing to free hospital resources, avoiding unnecessary isolations.