SARS-CoV-2 testing, positivity, and factors associated with COVID-19 among people with HIV across Europe in the multinational EuroSIDA cohort.

BACKGROUND: Although people with HIV might be at risk of severe outcomes from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; coronavirus 2019 [COVID-19]), regional and temporal differences in SARS-CoV-2 testing in people with HIV across Europe have not been previously described. METHODS: We described the proportions of testing, positive test results, and hospitalizations due to COVID-19 between 1 January 2020 and 31 December 2021 in the EuroSIDA cohort and the factors associated with being tested for SARS-CoV-2 and with ever testing positive. RESULTS: Of 9012 participants, 2270 (25.2%, 95% confidence interval [CI] 24.3-26.1) had a SARS-CoV-2 polymerase chain reaction test during the study period (range: 38.3% in Northern to 14.6% in Central-Eastern Europe). People from Northern Europe, women, those aged <40 years, those with CD4 cell count <350 cells/mm3 , and those with previous cardiovascular disease or malignancy were significantly more likely to have been tested, as were people with HIV in 2021 compared with those in 2020. Overall, 390 people with HIV (4.3%, 95% CI 3.9-4.8) tested positive (range: 2.6% in Northern to 7.1% in Southern Europe), and the odds of testing positive were higher in all regions than in Northern Europe and in 2021 than in 2020. In total, 64 people with HIV (0.7%, 95% CI 0.6-0.9) were hospitalized, of whom 12 died. Compared with 2020, the odds of positive testing decreased in all regions in 2021, and the associations with cardiovascular disease, malignancy, and use of tenofovir disoproxil fumarate disappeared in 2021. Among study participants, 58.9% received a COVID-19 vaccine (range: 72.0% in Southern to 14.8% in Eastern Europe). CONCLUSIONS: We observed large heterogeneity in SARS-CoV-2 testing and positivity and a low proportion of hospital admissions and deaths across the regions of Europe.

Hospital-based antimicrobial stewardship in Denmark, Greenland and the Faroe Islands - current landscape and barriers.

OBJECTIVES: To describe the current organization and implementation of formalized, multi-disciplinary hospital-based antimicrobial stewardship (AMS) structures in Denmark, the Faroe Islands and Greenland. METHODS: A structured electronic questionnaire was sent to all trainees and specialists in clinical microbiology (N=207) and infectious diseases (N=260), as well as clinical pharmacists (N=20) and paediatricians (N=10) with expertise in infectious diseases. The survey had 30 multiple-choice, rating-scale, and open-ended questions based on an international consensus checklist for hospital AMS, adapted to a Danish context. RESULTS: Overall, 145 individual responses representing 20 hospitals were received. Nine hospitals (45%) reported a formal AMS strategy, eight (40%) a formal organizational multi-disciplinary structure and a multi-disciplinary AMS team, and six (30%) a designated professional as a leader of the AMS team. A majority of hospitals reported access to updated guidelines (80%) and regularly monitored and reported the quantity of antibiotics prescribed (70% and 65%, respectively). Only one hospital (5%) reported a dedicated, sustainable and sufficient AMS budget, three hospitals (15%) audited courses of therapy for specific agents/clinical conditions and four hospitals (20%) had a document clearly defining roles, procedures of collaboration and responsibilities for AMS. A total of 42% of all individual respondents had received formal AMS training. Main barriers were a lack of financial resources (52%), a lack of mandate from the hospital management (30%) and AMS not being a priority (18%). CONCLUSIONS: Core elements important for multi-disciplinary hospital-based AMS can be strengthened in Danish hospitals. Funding, clear mandates, prioritization from the hospital management and the implementation of multi-disciplinary AMS structures may help close the identified gaps.

Risk of Staphylococcus aureus bacteraemia in patients with rheumatoid arthritis and the effect of orthopaedic implants on the risk: a nationwide observational cohort study.

OBJECTIVE: It remains disputed how much the risk of Staphylococcus aureus bacteraemia (SAB) is increased in patients with rheumatoid arthritis (RA), and the extent to which orthopaedic implants explain the risk. We assessed SAB incidence rates (IRs) and incidence rate ratios (IRRs), comparing RA patients with a general population cohort (GPC) and individuals with versus without orthopaedic implants. METHOD: Danish residents aged ≥ 18 years without prior RA or SAB (=GPC) were followed up for RA and microbiologically verified SAB events (1996-2017). IRRs were calculated by age- and sex-stratified Poisson regression adjusted for age, comorbidities, calendar year, and socioeconomic status. RESULTS: The GPC comprised 5 398 690 individuals. We identified 33 567 incident RA patients (=RA cohort) (median follow-up 7.3 years, IQR 3.6-12.3). We observed 25 023 SAB events (n = 224 in the RA cohort). IRs per 100 000 person-years were 81.0 (RA cohort) and 29.9 (GPC). IRs increased with age. Adjusted IRRs in 18-59-year-old RA patients were 2.6 (95% confidence interval 1.8-3.7) for women and 1.8 (1.1-3.1) for men, compared with same sex and age group GPC. IRRs declined with age. Compared with the GPC without implants, IRRs for RA patients with implants ranged from 1.9 (1.3-2.8) (women ≥ 70 years) to 5.3 (2.2-12.8) (18-59-year-old men). CONCLUSION: In this nationwide registry-based cohort study RA was a risk factor for SAB, and orthopaedic implants further increased the risk. Clinicians should be aware of potential SAB in patients with RA and orthopaedic implants.

Association of the Kynurenine Pathway of Tryptophan Metabolism With Human Immunodeficiency Virus-Related Gut Microbiota Alterations and Visceral Adipose Tissue Accumulation.

BACKGROUND: The aim of the study was to investigate the association between human immunodeficiency virus (HIV)-related gut microbiota changes, alterations in the kynurenine (Kyn) pathway of tryptophan (Trp) metabolism, and visceral adipose tissue in the context of HIV infection. METHODS: Three hundred eighty-three people with HIV (PWH) were included from the Copenhagen comorbidity in HIV infection (COCOMO) study. Gut microbiota composition was analyzed by 16S ribosomal ribonucleic acid sequencing. Plasma metabolites were analyzed by liquid chromatography-tandem mass spectrometry. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were measured by single-slice computed tomography (CT) scan (4th lumbar vertebra). RESULTS: The HIV-related gut microbiota alterations were associated with lower Trp (ß -.01; 95% confidence interval [CI], -0.03 to -0.00) and higher Kyn-to-Trp ratio (ß 0.03; 95% CI, 0.01-0.05), which in turn was associated with higher VAT-to-SAT ratio (ß 0.50; 95% CI, 0.10-0.90) and larger VAT area (ß 30.85; 95% CI, 4.43-57.28). In mediation analysis, the Kyn-to-Trp ratio mediated 10% (P = .023) of the association between the VAT-to-SAT ratio and HIV-related gut microbiota. CONCLUSIONS: Our data suggest HIV-related gut microbiota compositional changes and gut microbial translocation as potential drivers of high Kyn-to-Trp ratio in PWH. In turn, increased activity in the Kyn pathway of Trp metabolism was associated with larger visceral adipose tissue area. Taken together, our findings suggest a possible role for this pathway in the gut-adipose tissue axis in the context of HIV infection.

Increased risk of incident primary cancer after Staphylococcus aureus bacteremia: A matched cohort study.

Susceptibility to infectious disease may be a marker of immunodeficiency caused by unrecognized cancer. To test the hypothesis, the risk of incident primary cancer was estimated among survivors of Staphylococcus aureus bacteremia (SAB) and compared to a random population cohort.Nation-wide population-based matched cohort study. Cases of SAB were identified from a national database and incident primary cancers were ascertained by record linkage. Incidence rate (IR) and ratio (IRR) with 95% confidence interval (CI) of 27 cancers was calculated by Poisson regression.During the first year of follow-up, 165 and 943 incident cases of cancer occurred in the case cohort (n = 12,918 (1.3%)) and the population cohort (n = 117,465 (0.8%)) for an IR of 3.78 (3.22-4.40) and 2.28 (2.14-2.43) per 100,000 person-years. The IRR was 1.65 (1.40-1.95). Of 27 cancers, 7 cancers occurred more frequently amongst cases than controls: cervical cancer (IRR 37.83 (4.23-338.47)), multiple myeloma (IRR 6.31 (2.58-15.44)), leukemia (IRR 4.73 (2.21-10.10)), sarcoma (IRR 4.73 (1.18-18.91)), liver cancer (IRR 3.64 (1.30-10.21)), pancreatic cancer (IRR 2.8 (1.27-6.16)), and urinary tract cancer (IRR 2.58 (1.23-5.39)). Compared to the control population, the risk of cancer was higher for those without comorbidity and with younger age. The overall risk of cancer during 2 to 5 years of follow-up was not increased (IRR 0.99 (95% CI: 0.89-1.11). However, the risk of pharyngeal cancer was increased (IRR 1.88 (1.04-3.39)) and the risk of liver cancer remained increased (IRR 3.93 (2.36-6.55)).The risk of primary incident cancer was 65% higher in the SAB cohort compared to the population cohort during the first year of follow-up and included 7 specific cancers. The risk was higher for those without comorbidity and with younger age. Screening for these specific cancers in selected populations may allow for earlier detection.

Associations between blood cultures after surgery for colorectal cancer and long-term oncological outcomes.

BACKGROUND: Systemic inflammation following curative surgery for colorectal cancer may be associated with increased risk of recurrence. [Correction added on 29 November 2019, after first online publication: text amended for accuracy.] This study investigated whether a clinically suspected infection, for which blood cultures were sent within 30 days after surgery for colorectal cancer, was associated with long-term oncological outcomes. METHODS: This register-based national cohort study included all Danish residents undergoing surgery with curative intent for colorectal cancer between January 2003 and December 2013. Patients who developed recurrence or died within 180 days after surgery were not included. Associations between blood cultures taken within 30 days after primary surgery and overall survival, disease-free survival and recurrence-free survival were analysed using Cox regression models adjusted for relevant clinical confounders, including demographic data, cancer stage, co-morbidity, blood transfusion, postoperative complications and adjuvant chemotherapy. RESULTS: The study included 21 349 patients, of whom 3390 (15·9 per cent) had blood cultures taken within 30 days after surgery. Median follow-up was 5·6 years. Patients who had blood cultures taken had an increased risk of all-cause mortality (hazard ratio (HR) 1·27, 95 per cent c.i. 1·20 to 1·35; P < 0·001), poorer disease-free survival (HR 1·22, 1·16 to 1·29; P < 0·001) and higher risk of recurrence (HR 1·15, 1·07 to 1·23; P < 0·001) than patients who did not have blood cultures taken. CONCLUSION: A clinically suspected infection requiring blood cultures within 30 days of surgery for colorectal cancer was associated with poorer oncological outcomes.

ANTECEDENTES: La inflamación sistémica en el cáncer colorrectal puede asociarse con un aumento del riesgo de recidiva. En este estudio se investigó si la sospecha clínica de infección, en la que se obtuvieron cultivos de sangre periférica durante los primeros 30 días de la cirugía por cáncer colorrectal, se asociaba con los resultados oncológicos a largo plazo. MÉTODOS: Se trata de un estudio de cohortes de un registro de una base de datos nacional, que incluyía todos los sujetos residentes en Dinamarca sometidos a cirugía por cáncer colorrectal con intención curativa desde enero de 2003 a diciembre de 2013. Los pacientes con recidiva o que fallecieron durante los primeros 180 días después de la cirugía fueron excluidos. Se estimaron las asociaciones entre los cultivos de sangre periférica efectuados en los primeros 30 días tras la cirugía primaria y la supervivencia global, supervivencia libre de enfermedad y supervivencia libre de recidiva mediante modelos de regresión de Cox, ajustados por variables clínicas confusoras relevantes (incluyendo datos demográficos, estadio del cáncer, comorbilidad, transfusión de sangre, complicaciones postoperatorias y quimioterapia adyuvante). RESULTADOS: El estudio incluyó 21.349 pacientes, de los cuales en 3.390 (16%) se habían obtenido cultivos de sangre periférica durante los primeros 30 días tras la cirugía. La mediana de seguimiento fue de 5,6 años. Los pacientes en los que se había obtenido cultivos de sangre periférica presentaron un riesgo aumentado de mortalidad por cualquier causa (cociente de riesgos instantáneos, hazard ratio, HR 1,27, i.c. del 95% 1,20-1,35; P < 0.0001), peor supervivencia libre de enfermedad (HR 1,22, i.c. del 95% 1,16-1,29; P < 0,0001) y mayor riesgo de recidiva (HR 1,15, i.c. del 95% 1,07-1,23; P < 0,0001) que los pacientes en los que no se habían obtenido cultivos. CONCLUSIÓN: La presencia de una infección sospechada clínicamente para la cual se requiere obtener cultivos de sangre periférica en los primeros 30 días tras cirugía por cancer colorrectal se asoció con peores resultados oncológicos.

Prevalence of impaired renal function in virologically suppressed people living with HIV compared with controls: the Copenhagen Comorbidity in HIV Infection (COCOMO) study.

OBJECTIVES: While renal impairment is reported more frequently in people living with HIV (PLWH) than in the general population, the PLWH samples in previous studies have generally been dominated by those at high renal risk. METHODS: Caucasian PLWH who were virologically suppressed on antiretroviral treatment and did not have injecting drug use or hepatitis C were recruited from the Copenhagen Comorbidity in HIV Infection (COCOMO) study. Sex- and age-matched controls were recruited 1:4 from the Copenhagen General Population Study up to November 2016. We defined renal impairment as one measurement of estimated glomerular filtration rate ≤ 60 mL/min/1.73 m2 , and assessed associated factors using adjusted logistic regression models. The impact of HIV-related factors was explored in a subanalysis. RESULTS: Among 598 PLWH and 2598 controls, the prevalence of renal impairment was 3.7% [95% confidence interval (CI) 2.3-5.5%] and 1.7% (95% CI 1.2-2.2%; P = 0.0014), respectively. After adjustment, HIV status was independently associated with renal impairment [odds ratio (OR) 3.4; 95% CI 1.8-6.3]. In addition, older age [OR 5.4 (95% CI 3.9-7.5) per 10 years], female sex [OR 5.0 (95% CI 2.6-9.8)] and diabetes [OR 2.9 (95% CI 1.3-6.7)] were strongly associated with renal impairment. The association between HIV status and renal impairment became stronger with older age (P = 0.02 for interaction). Current and nadir CD4 counts, duration of HIV infection and previous AIDS-defining diagnosis were not associated with renal impairment among virologically suppressed PLWH. CONCLUSIONS: The prevalence of renal impairment is low among low-risk virologically suppressed Caucasian PLWH, but remains significantly higher than in controls. Renal impairment therefore remains a concern in all PLWH and requires ongoing attention.

Diagnostic performance of clinical characteristics to detect airflow limitation in people living with HIV and in uninfected controls.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is underdiagnosed in the general population and possibly also in people living with HIV (PLWH). We evaluated the diagnostic performance of symptoms and risk factors for assessment of airflow limitation in PLWH and in uninfected controls. METHODS: Spirometry was performed in the Copenhagen Comorbidity in HIV Infection (COCOMO) study and Copenhagen General Population Study (CGPS), and airflow limitation was defined by forced expiratory volume in 1 s/forced vital capacity < lower limit of normal. We calculated the sensitivity, specificity, predictive values and area under the curve (AUC) of symptoms and risk factors for assessment of airflow limitation in PLWH and uninfected controls. RESULTS: A total of 1083 PLWH and 12 074 uninfected controls were included in the study. The sensitivity for sputum, chronic cough, breathlessness, wheezing, current and cumulative smoking and self-reported COPD was higher, but the specificity lower, in PLWH than in uninfected controls. The negative and positive predictive values were largely similar between the groups. The AUCs were similar or slightly higher in PLWH and highest for > 20 pack-years smoked [0.65; 95% confidence interval (CI) 0.58-0.72] and wheezing (0.64; 95% CI 0.57-0.71). A summed score for five variables was associated with slightly higher AUC in PLWH compared with uninfected controls [0.71 (95% CI 0.63-0.79) versus 0.65 (95% CI 0.63-0.68), respectively; P = 0.06]. CONCLUSIONS: Clinical variables were relatively poor discriminators of airflow limitation in PLWH and uninfected controls. Active COPD case finding by screening for symptoms and relevant exposures, as recommended in the general population, is likely to yield similar diagnostic power in PLWH.

HIV infection is independently associated with a higher concentration of alpha-1 antitrypsin.

OBJECTIVES: Alpha-1 antitrypsin (AAT) deficiency is associated with an increased risk of chronic obstructive pulmonary disease and has been related to CD4 T-cell count decline in people living with HIV (PLWH). We determined whether HIV status is associated with AAT concentrations and assessed associations between AAT concentration, pulmonary function and immunological status. METHODS: Alpha-1 antitrypsin was measured and spirometry performed in 1011 PLWH from the Copenhagen Comorbidity in HIV Infection (COCOMO) study and in 11 962 age- and sex-matched uninfected controls. We studied associations between AAT concentration, HIV status, pulmonary function, and current and nadir CD4 T-cell counts using multivariate linear regression analyses. RESULTS: The mean age of PLWH was 50.7 [standard deviation (SD) 11.3] years and 98.6% were receiving combination antiretroviral therapy (cART). The mean current CD4 T-cell count was 718 (SD 284) cells/µL. PLWH had a higher median AAT concentration than uninfected controls [1.4 (interquartile range (IQR) 1.3-1.6) versus 1.3 (IQR 1.2-1.4) g/L; P < 0.0001] and HIV infection was independently associated with higher AAT concentration [adjusted ß = 0.10 g/L; 95% confidence interval (CI) 0.08; 0.11 g/L; P < 0.001]. Low AAT concentration (< 1.0 g/L) was not more common in PLWH with airflow limitation (defined as forced expiratory volume in 1 second/forced vital capacity (FEV1 /FVC) < 0.7 with FEV1 -predicted < 80%) compared with uninfected controls with airflow limitation, and the effect of AAT on FEV1 %-predicted was comparable to that in uninfected controls (P-interaction = 0.66). AAT concentration was not associated with current or nadir CD4 T-cell count. CONCLUSIONS: HIV infection was independently associated with a higher concentration of AAT through unknown mechanisms. However, AAT does not seem to contribute to lower pulmonary function or to low CD4 T-cell counts in PLWH.

The TLR9 agonist MGN1703 triggers a potent type I interferon response in the sigmoid colon.

Toll-like receptor 9 (TLR9) agonists are being developed for treatment of colorectal and other cancers, yet the impact of these drugs on human intestines remains unknown. This, together with the fact that there are additional potential indications for TLR9 agonist therapy (e.g., autoimmune and infectious diseases), led us to investigate the impact of MGN1703 (Lefitolimod) on intestinal homeostasis and viral persistence in HIV-positive individuals. Colonic sigmoid biopsies were collected (baseline and week four) from 11 HIV+ individuals on suppressive antiretroviral therapy, who received MGN1703 (60 mg s.c.) twice weekly for 4 weeks in a single-arm, phase 1b/2a study. Within sigmoid mucosa, global transcriptomic analyses revealed 248 modulated genes (false discovery rate<0.05) including many type I interferon (IFN)-stimulated genes. MGN1703 increased the frequencies of cells exhibiting MX1 (P=0.001) and ISG15 (P=0.014) protein expression. No changes were observed in neutrophil infiltration (myeloperoxidase; P=0.97). No systematic effect on fecal microbiota structure was observed (analysis of similarity Global R=-0.105; P=0.929). TLR9 expression at baseline was inversely proportional to the change in integrated HIV DNA during MGN1703 treatment (P=0.020). In conclusion, MGN1703 induced a potent type I IFN response, without a concomitant general inflammatory response, in the intestines.

Early versus late diagnosis in community-acquired bacterial meningitis: a retrospective cohort study.

OBJECTIVES: To examine clinical characteristics and outcome of patients with late diagnosis of community-acquired bacterial meningitis (CABM). METHODS: We conducted a chart review of all adults with proven CABM in three centres in Denmark from 1998 through to 2014. Patients were categorized as early diagnosis of CABM immediately on admission, or late diagnosis if CABM was not listed in referral or admission records and neither lumbar puncture nor antibiotic therapy for meningitis was considered immediately on admission. We used modified Poisson regression analysis to compute adjusted relative risks with 95% CIs for predictors of late diagnosis and in-hospital mortality. RESULTS: A total of 113/358 (32%) patients were categorized as late diagnosis demonstrating a variety of tentative diagnoses of which 81/113 (72%) were non-infectious. We observed several statistically significant baseline differences (p <0.05) in patients with late versus early diagnosis including age >65 years (56/113, 50% versus 67/245, 27%), neck stiffness (35/97, 36% versus 183/234, 78%), concomitant pneumonia (26/113, 23% versus 26/245, 11%), and meningococcal meningitis (6/113, 5% versus 52/245, 21%). These variables remained statistically significant in multivariate analysis. Moreover, late diagnosis was associated with increased in-hospital mortality (41/113, 36% versus 43/245, 18%; adjusted relative risk 1.7, 95% CI 1.2-2.5). CONCLUSIONS: Late diagnosis of CABM was common and patients were admitted with mostly non-infectious diagnoses. Absence of neck stiffness did not rule out CABM and special attention should be given to patients with pneumonia and the elderly. Late diagnosis was associated with incorrect patient management and increased mortality.

Reduced risk of decompensation and death associated with use of statins in patients with alcoholic cirrhosis. A nationwide case-cohort study.

BACKGROUND: Reports have indicated that the use of statins may ameliorate the course of cirrhosis. AIM: To determine the relationship between use of statins and mortality rate in patients with cirrhosis. METHODS: We did a retrospective case-cohort analysis based on data from the Danish registers from the period 1995 through 2014. Index date was time of diagnosis of cirrhosis (ICD-10: K703) and cohort entry depended on whether the patient was statin user or not. We used propensity score matching with a statin:non-statin ratio of 1:2. We included the exposure to statins (ATC classification C10AA) from the index date until death or end of follow-up based on prescription claims. Use of statins based on at least two statin claims as well as the longitudinal pattern over time of statin claims was tested against mortality. The main outcome was mortality rate. RESULTS: A total of 24 748 patients with alcoholic cirrhosis were identified and 5417 were eligible for matching. The mean age was 56 (SD 10) years and 36% were females. The prevalence of use of statins was 15%. We included 744 in the matched cohort. Mortality rates were 88 (95% CI 73-105) per 1000 years for patients using statin and 127 (95% CI 114-141) for non-statin patients with a HR of 0.57 (95% CI 0.45-0.71). A more regular pattern of statin claims was related to a lower risk of death. CONCLUSIONS: Our results showed an association between regular use of statins and reduced mortality in patients with alcoholic cirrhosis.