Rheumatoid arthritis and risk of osteoarticular infection and death following Staphylococcus aureus bacteraemia: A nationwide cohort study.

OBJECTIVES: Osteoarticular infection (OAI) is a feared complication of Staphylococcus aureus bacteraemia (SAB) and is associated with poor outcomes. We aimed to explore risk of OAI and death following SAB in patients with and without rheumatoid arthritis (RA) and to identify risk factors for OAI in patients with RA. METHODS: Danish nationwide cohort study of all patients with microbiologically verified first-time SAB between 2006-2018. We identified RA, SAB, comorbidities, and RA-related characteristics (e.g. orthopaedic implants, antirheumatic treatment) in national registries including the rheumatology registry DANBIO. We estimated cumulative incidence of OAI and death and adjusted hazard ratios (HRs, multivariate Cox regression). RESULTS: We identified 18 274 patients with SAB (n = 367 with RA). The 90-day cumulative incidence of OAI was 23.1%(95%CI 18.8; 27.6) for patients with RA and 12.5%(12.1; 13.0) for patients without RA (non-RA) (HR 1.93(1.54; 2.41)). For RA patients with orthopaedic implants cumulative incidence was 29.4%(22.9; 36.2) (HR 1.75(1.08; 2.85), and for current users of tumor necrosis factor inhibitors (TNFi) it was 41.9%(27.0; 56.1) (HR 2.27(1.29; 3.98) compared with non-users). All-cause 90-day mortality following SAB was similar in RA (35.4%(30.6; 40.3)) and non-RA (33.9%(33.2; 34.5), HR 1.04(0.87; 1.24)). CONCLUSION: Following SAB, almost one in four patients with RA contracted OAI corresponding to a doubled risk compared with non-RA. In RA, orthopaedic implants and current TNFi use were associated with approximately doubled OAI risk. One in three died within 90 days in both RA and non-RA. These findings encourage vigilance in RA patients with SAB to avoid treatment delay of OAI.

Blood neutrophil to lymphocyte ratio is associated with 90-day mortality and 60-day readmission in Gram negative bacteremia: a multi-center cohort study.

INTRODUCTION: The Neutrophil-Lymphocyte Ratio (NLR) in blood has demonstrated its capability to predict bacteremia in emergency departments, and its association with mortality has been established in patients with sepsis in intensive care units. However, its potential concerning mortality and readmission in patients with Gram-negative bacteremia (GNB) is unexplored. METHODS: This retrospective cohort study included patients with GNB between 2018 and 2022 from six hospitals in the Capital Region of Denmark. Patients who were immunosuppressed or had missing NLR values on the day of blood culture were excluded. Logistic regression models were used to analyze the association between NLR levels and 90-day all-cause mortality, while the logit link interpretation of the cumulative incidence function was used to assess the association between NLR levels and 60-day readmission. Associations were quantified as odds ratios (OR) with corresponding 95% confidence intervals (CI). RESULTS: The study included 1763 patients with a median age was 76.8 years and 51.3% were female. The median NLR was 17.3 and 15.8% of patients had a quick sequential organ failure assessment score of two or three. Urinary tract infection (UTI) was the most frequent focus and Escherichia coli the most frequent pathogen. Statistically significant differences in median NLR were found by age group and pathogen, and for patients with or without hypertension, liver disease, chronic obstructive pulmonary disease, dementia, and alcohol abuse. 378 patients (21.4%) died before 90 days. 526 (29.8%) patients were readmitted to the hospital within 60 days. For each doubling of the NLR, the OR for all-cause 90-day mortality was 1.15 (95% CI, 1.04-1.27) and 1.12 (95% CI, 1.02-1.24) for 60-day readmission. Analysis of subgroups did not show statistically significant differences between groups in relation to the association between NLR and mortality. The discriminatory ability of NLR for mortality was limited and comparable to blood neutrophil or lymphocyte count, producing receiver operating characteristic curves with an area under the curve of 0.59 (95% CI, 0.56-0.63), 0.60 (95% CI, 0.56-0.65) and 0.53 (95% CI, 0.49-0.56), respectively. CONCLUSION: Blood neutrophil-lymphocyte ratio was associated with 90-day all-cause mortality and 60-day readmission in patients with GNB. However, the ratio has limited ability in predicting mortality or readmission.

Risk of long COVID and associated symptoms after acute SARS-COV-2 infection in ethnic minorities: A nationwide register-linked cohort study in Denmark.

BACKGROUND: Ethnic minorities living in high-income countries have been disproportionately affected by Coronavirus Disease 2019 (COVID-19) in terms of infection rates, hospitalisations, and deaths; however, less is known about long COVID in these populations. Our aim was to examine the risk of long COVID and associated symptoms among ethnic minorities. METHODS AND FINDINGS: We used nationwide register-based cohort data on individuals diagnosed with COVID-19 aged ≥18 years (n = 2,287,175) between January 2020 and August 2022 in Denmark. We calculated the risk of long COVID diagnosis and long COVID symptoms among ethnic minorities compared with native Danes using multivariable Cox proportional hazard regression and logistic regression, respectively. Among individuals who were first time diagnosed with COVID-19 during the study period, 39,876 (1.7%) were hospitalised and 2,247,299 (98.3%) were nonhospitalised individuals. Of the diagnosed COVID-19 cases, 1,952,021 (85.3%) were native Danes and 335,154 (14.7%) were ethnic minorities. After adjustment for age, sex, civil status, education, family income, and Charlson comorbidity index, ethnic minorities from North Africa (adjusted hazard ratio [aHR] 1.41, 95% confidence interval [CI] [1.12,1.79], p = 0.003), Middle East (aHR 1.38, 95% CI [1.24,1.55], p < 0.001), Eastern Europe (aHR 1.35, 95% CI [1.22,1.49], p < 0.001), and Asia (aHR 1.23, 95% CI [1.09,1.40], p = 0.001) had significantly greater risk of long COVID diagnosis than native Danes. In the analysis by largest countries of origin, the greater risks of long COVID diagnosis were found in people of Iraqi origin (aHR 1.56, 95% CI [1.30,1.88], p < 0.001), people of Turkish origin (aHR 1.42, 95% CI [1.24,1.63], p < 0.001), and people of Somali origin (aHR 1.42, 95% CI [1.07,1.91], p = 0.016). A significant factor associated with an increased risk of long COVID diagnosis was COVID-19 hospitalisation. The risk of long COVID diagnosis among ethnic minorities was more pronounced between January 2020 and June 2021. Furthermore, the odds of reporting cardiopulmonary symptoms (including dyspnoea, cough, and chest pain) and any long COVID symptoms were higher among people of North African, Middle Eastern, Eastern European, and Asian origins than among native Danes in both unadjusted and adjusted models. Despite including the nationwide sample of individuals diagnosed with COVID-19, the precision of our estimates on long COVID was limited to the sample of patients with symptoms who had contacted the hospital. CONCLUSIONS: Belonging to an ethnic minority group was significantly associated with an increased risk of long COVID, indicating the need to better understand long COVID drivers and address care and treatment strategies in these populations.

Elevated plasma apolipoprotein E levels in people living with HIV: Associations with biomarkers and HIV-specific risk factors.

BACKGROUND AND AIMS: Apolipoprotein E (apoE) plays a crucial role in cholesterol metabolism, and high levels of apoE in plasma are associated with cardiovascular disease and all-cause mortality. We aimed to assess if HIV is independently associated with high plasma apoE and to determine HIV-related risk factors for high plasma apoE. METHODS: We included 661 people with HIV (PWH) from the Copenhagen Comorbidity in HIV (COCOMO) study with available measurement of plasma apoE. COCOMO participants were frequency matched 1:1 on age and sex with controls from the Copenhagen General Population Study. High plasma apoE was defined as levels above the 90th percentile (66.2 mg/L). The association between HIV and high plasma apoE was assessed using logistic regression models. Among PWH, both linear and logistic regression models were used to determine HIV-specific risk factors for high plasma apoE. RESULTS: Mean age was 52 years and 89 % were male. Median plasma apoE was 49.0 mg/L in PWH and 43.3 mg/L in controls, p < 0.001. HIV was associated with higher plasma apoE after adjusting for potential confounders, including triglycerides (odds ratio 2.14 [95 % CI: 1.39-3.29], p < 0.001). In PWH, higher plasma apoE was associated with a previous AIDS-defining condition in linear models before adjustment for triglycerides and integrase strand transfer inhibitor use in fully adjusted linear models. CONCLUSIONS: PWH had higher plasma apoE than controls even after adjusting for triglycerides. Further studies are needed to elucidate the clinical impact of high plasma apoE in PWH.

Lung function trajectories in mild COVID-19 with two-year follow-up.

OBJECTIVE: To characterize lung function dynamics in individuals with mild COVID-19 from pre-infection to two years post-infection. METHODS: We re-invited participants two years after infection from our matched cohort study of the Copenhagen General Population who had initially been examined 5.4 months after infection. We repeated lung tests and questionnaires. Linear mixed models were used to estimate lung volume changes in individuals with COVID-19 patients versus uninfected controls over two intervals: from pre-infection to six months post-infection and six months post-infection to two years post-infection. RESULTS: 52 individuals (48.6%) attended the two-year examination at median 1.9 years (IQR 1.8; 2.4) after COVID-19, all with mild infection. Individuals with COVID-19 had an adjusted excess decline in FEV1 of 13.0 mL per year (CI 23.5; 2.5), p=0.02 from prior infection to 6 months after infection compared to uninfected controls. From 6 to 24 months after infection, they had an excess decline of 7.5 mL per year (CI 25.6; 9.6), p=0.40. A similar pattern was observed for FVC. Participants had a mean increase in DLco of 3.33 (SD 7.97) between the 6- and 24-month examination. CONCLUSION: Our results indicate that mild COVID-19 infection affects lung function at time of infection with limited recovery two years after infection.

Gut Microbiota Alterations and Circulating Imidazole Propionate Levels Are Associated With Obstructive Coronary Artery Disease in People With HIV.

BACKGROUND: The impact of gut microbiota and its metabolites on coronary artery disease (CAD) in people with human immunodeficiency virus (PWH) is unknown. Emerging evidence suggests that imidazole propionate (ImP), a microbial metabolite, is linked with cardiometabolic diseases. METHODS: Fecal samples from participants of the Copenhagen Comorbidity in HIV infection (COCOMO) study were processed for 16S rRNA sequencing and ImP measured with liquid chromatography-tandem mass spectrometry. CAD severity was investigated by coronary computed tomography-angiography, and participants grouped according to obstructive CAD (n = 60), nonobstructive CAD (n = 80), or no CAD (n = 114). RESULTS: Participants with obstructive CAD had a gut microbiota with lower diversity and distinct compositional shift, with increased abundance of Rumiococcus gnavus and Veillonella, known producers of ImP. ImP plasma levels were associated with this dysbiosis, and significantly elevated in participants with obstructive CAD. However, gut dysbiosis but not plasma ImP was independently associated with obstructive CAD after adjustment for traditional and HIV-related risk factors (adjusted odds ratio, 2.7; 95% confidence interval, 1.1-7.2; P = .048). CONCLUSIONS: PWH with obstructive CAD displays a distinct gut microbiota profile and increased circulating ImP plasma levels. Future studies should determine whether gut dysbiosis and related metabolites such as ImP are predictive of incident cardiovascular events.

Early Switch From Intravenous to Oral Antibiotics for Patients With Uncomplicated Gram-Negative Bacteremia.

Importance: Gram-negative bacteremia is a global health concern, and optimizing the transition from intravenous (IV) to oral antibiotics is a critical step in improving patient treatment and resource utilization. Objective: To assess the association of switching to oral antibiotics within 4 days after initial blood culture with 90-day all-cause mortality compared with prolonged IV antibiotic treatment for patients with uncomplicated gram-negative bacteremia. Design, Setting, and Participants: This cohort study conducted using the target trial emulation framework included observational data from adults with uncomplicated gram-negative bacteremia in 4 hospitals in Copenhagen, Denmark, from January 1, 2018, through December 31, 2021. The duration of follow-up was 90 days. Eligibility criteria included a blood culture positive for growth of gram-negative bacteria, clinical stability within 4 days of initial blood culture, an available susceptibility report on day 4, and initiation of appropriate empirical IV antibiotic treatment within 24 hours of blood culture. Exposure: Switching to oral antibiotics within 4 days after initial blood culture compared with continuing IV antibiotic treatment for at least 5 days after initial blood culture. Main Outcomes and Measures: The main outcome was 90-day all-cause mortality. Inverse probability of treatment weighting was applied to adjust for confounding. Intention-to-treat and per-protocol analyses were performed using pooled logistic regression to estimate absolute risk, risk difference (RD), and risk ratio (RR); 95% CIs were computed using bootstrapping. Results: A total of 914 individuals were included in the target trial emulation analysis (512 [56.0%] male; median age, 74.5 years [IQR, 63.3-83.2 years]); 433 (47.4%) transitioned early to oral antibiotic treatment, and 481 (52.6%) received prolonged IV treatment. Ninety-nine individuals (10.8%) died during follow-up. The proportion of individuals who died was higher in the group receiving prolonged IV treatment (69 [14.3%] vs 30 [6.9%]). In the intention-to-treat analysis, 90-day all-cause mortality risk was 9.1% (95% CI, 6.7%-11.6%) for the early-switch group and 11.7% (95% CI, 9.6%-13.8%) for the group receiving prolonged IV treatment; the RD was -2.5% (95% CI, -5.7% to 0.7%) and RR was 0.78 (95% CI, 0.60-1.10). In the per-protocol analysis, the RD was -0.1% (95% CI, -3.4% to 3.1%) and RR was 0.99 (95% CI, 0.70-1.40). Conclusions and Relevance: In this cohort study of uncomplicated gram-negative bacteremia, early transition to oral antibiotics within 4 days of initial blood culture was associated with 90-day all-cause mortality risk comparable to that of continuing IV antibiotic treatment and may be an effective alternative to prolonged IV treatment.

Clonal hematopoiesis of indeterminate potential in persons with HIV.

BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with older age, inflammation and with risk of coronary artery disease (CAD). We aimed to characterize the burden of CHIP, and to explore the association between CHIP, inflammatory markers, and CAD in older persons with HIV (PWH). METHODS: From the Copenhagen Comorbidity in HIV Infection (COCOMO) study, we included 190 individuals older than 55 years of age. We defined CHIP as variant allele fraction at least 2%. CAD was categorized according to the most severe coronary artery lesion on coronary computed tomography (CT) angiography as no coronary atherosclerosis; any atherosclerosis defined as at least 1% stenosis and obstructive CAD defined as at least 50% stenosis. RESULTS: In the entire population (median age 66 years, 87% men), we identified a total of 62 mutations distributed among 49 (26%) participants. The three most mutated genes were DNMT3A , TET2 , and ASXL1 , accounting for 49, 25, and 16% of mutations, respectively. Age and sex were the only variables associated with CHIP. IL-1ß, IL-1Ra, IL-2, IL-6, IL-10, soluble CD14, soluble CD163 and TNF-α were not associated with CHIP, and CHIP was not associated with any atherosclerosis or with obstructive CAD in adjusted analyses. CONCLUSION: In older, well treated, Scandinavian PWH, more than one in four had at least one CHIP mutation. We did not find evidence of an association between CHIP and inflammatory markers or between CHIP and CAD. CHIP is an unlikely underlying mechanism to explain the association between inflammation and CAD in treated HIV disease.

Emulating a Target Trial of Shorter Compared to Longer Course of Antibiotic Therapy for Gram-Negative Bacteremia.

BACKGROUND: Despite the availability of antimicrobial therapies, gram-negative bacteremia remains a significant cause of morbidity and mortality on a global level. Recent randomized controlled trials support shorter antibiotic treatment duration for individuals with uncomplicated gram-negative bacteremia. The target trial framework using the cloning approach utilizes real-world data but eliminates the issue of immortal time bias seen in observational studies by emulating the analysis of randomized trials with full adherence. METHOD: A hypothetical target trial allocating individuals with gram-negative bacteremia to either short antibiotic treatment duration (5-7 days) or longer antibiotic treatment duration (8-14 days) was specified and emulated using the cloning, censoring, and weighting approach. The primary outcome was 90-day all-cause mortality. Secondary outcome was a composite endpoint of clinical and microbiological relapse. The emulated trial included individuals from four hospitals in Copenhagen from 2018 through 2021. RESULTS: In sum, 1040 individuals were included. The median age of the cohort was 76 years, the majority were male (54%), had community-acquired gram-negative bacteremia (86%), urinary tract infection as the source of the infection (78%), and Escherichia coli as the pathogen of the infection (73%). The adjusted 90-day risk difference in all-cause mortality was 1.3% (95% confidence interval [CI]: -.7, 3.3), and the risk ratio was 1.12 (95% CI: .89, 1.37). The adjusted 90-day risk difference in relapse was 0.7% (95% CI: -2.3, 3.8), and the risk ratio was 1.07 (95% CI: .71, 1.45). CONCLUSIONS: We found comparative outcomes for shorter treatment duration compared to longer treatment duration in patients with gram-negative bacteremia.

Using BCG Vaccine to Enhance Nonspecific Protection of Health Care Workers During the COVID-19 Pandemic: A Randomized Controlled Trial.

BACKGROUND: The BCG (Bacillus Calmette-Guérin) vaccine can induce nonspecific protection against unrelated infections. We aimed to test the effect of BCG on absenteeism and health of Danish health care workers (HCWs) during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: A single-blinded randomized controlled trial included 1221 HCWs from 9 Danish hospitals. Participants were randomized 1:1 to standard dose BCG or placebo. Primary outcome was days of unplanned absenteeism. Main secondary outcomes were incidence of COVID-19, all-cause hospitalization, and infectious disease episodes. RESULTS: There was no significant effect of BCG on unplanned absenteeism. Mean number of days absent per 1000 workdays was 20 in the BCG group and 17 in the placebo group (risk ratio, 1.23; 95% credibility interval, 0.98-1.53). BCG had no effect on incidence of COVID-19 or all-cause hospitalization overall. In secondary analyses BCG revaccination was associated with higher COVID-19 incidence (hazard ratio [HR], 2.47; 95% confidence interval [CI], 1.07-5.71), but also reduced risk of hospitalization (HR, 0.28; 95% CI, .09-.86). The incidence of infectious disease episodes was similar between randomization groups (HR, 1.09; 95% CI, .96-1.24). CONCLUSIONS: In this relatively healthy cohort of HCWs, there was no overall effect of BCG on any of the study outcomes. CLINICAL TRIALS REGISTRATION: NCT0437329 and EU Clinical Trials Register (EudraCT number 2020-001888-90).

Temporal trends in 90-day survival of hospitalised individuals during two years of the COVID-19 pandemic in Denmark.

BACKGROUND: Mortality rates peaked early in the COVID-19 pandemic and then declined. Possible explanations are pharmacological and non-pharmacological treatments, vaccines and changing demographics. We sought to evaluate temporal trends in clinical characteristics and survival of patients hospitalised with COVID-19 during the first two years of the pandemic in Denmark. METHODS: In this observational study, we included all adults with COVID-19 consecutively admitted to three hospitals in Copenhagen, Denmark, from March 2020 through March 2022. The primary outcome was overall survival up to day 90 from admission. We used multivariable Cox proportional hazards models to estimate the association of survival within five consecutive time-periods, based on admission date, adjusted for baseline characteristics, vaccination status, remdesivir and dexamethasone treatment. RESULTS: In 1630 included patients, the median age [IQR] was 68 [52, 79] years, 56.6% were men and 86.2% had comorbidity. Clinical characteristics changed over time. The crude 90-day mortality rate peaked in March-June 2020 with 28.9%, decreased from July 2020 to 17.5%, and increased again in January-March 2022 to 28.6%. Lower hazard ratios for death were observed in individuals admitted from July 2020 and persisted after adjusting for baseline characteristics. Adjusting for vaccination, remdesivir treatment and dexamethasone treatment attenuated the association in patients requiring low-flow oxygen. CONCLUSIONS: Our study suggests lower hazard rates for mortality in patients hospitalised with COVID-19 from July 2020 compared to March-June 2020, mainly driven by lower mortality in patients with a need of oxygen at baseline.

Incidence of bacterial respiratory infection and pneumonia in people with HIV with and without airflow limitation.

OBJECTIVES: We aimed to determine the incidence rate, pathogen composition, and risk factors, particularly airflow limitation, associated with bacterial respiratory infection and pneumonia in a prospective cohort of well-treated people with HIV (PWH) between 2015-2021. METHODS: We included 1007 PWH from the Copenhagen Comorbidity in HIV infection (COCOMO) study. Spirometry was performed at inclusion. Microbiology samples were collected prospectively. Cumulative incidence was determined by the Aalen-Johansen estimator. Cox proportional hazard models were used to calculate risk factors, adjusted for traditional and HIV-specific variables. RESULTS: The incidence rates of first bacterial respiratory infection and pneumonia were 12.4 (95% CI 9.7-15.5) and 5.5 (95% CI: 3.8-7.7) per 1000 person-years, respectively. The cumulative incidence of pneumonia was four times higher in PWH with airflow limitation (11.8% vs 3.2%, P <0.001). Risk factors for bacterial respiratory infection were airflow limitation (hazard ratio [HR] 2.9, [95% CI: 1.7-5.1], P <0.001), smoking (HR 2.3, [95% CI: 1.4-3.8], P <0.001), and previous AIDS-defining event (HR 2.0, [95% CI: 1.2-3.3], P = 0.009). For pneumonia, airflow limitation (HR 2.7, [95% CI: 1.2-6.3], P = 0.016), smoking (HR 2.5, [95% CI: 1.2-5.4], P = 0.016), and older age (HR 1.5, [95% CI: 1.1-2.1], P = 0.015) were identified as risk factors. CONCLUSIONS: Increased emphasis on airflow limitation prevention, including smoking cessation, may reduce the burden of bacterial respiratory infection and pneumonia in PWH.