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Aims: To evaluate the experience with use of sotrovimab following severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection in high‐risk groups. Methods: In a nationwide, population‐based cohort study, we identified all individuals treated with sotrovimab (N = 2933) and stratified them by 4 high‐risk groups: (A) malignant haematological disease, (B) solid organ transplantation, (C) anti‐CD20 therapy ≤1 year and (D) other risks. Cox regression analysis was used to calculate hazard ratios for hospitalization, death and associated prognostic factors. Results: Of 2933 sotrovimab‐treated individuals, 83% belonged to high‐risk groups (37.6% haematological malignancy, 27.4% solid organ transplantation and 17.5% treatment with anti‐CD20 ≤1 year). Only 17.8% had other risks (11.8% were pregnant, 10.7% primary immunodeficiency, 21.2% other malignancy, 4.3% received anti‐CD20 >1 year and 52.0% other/unknown causes). Within 90 days of infusion, 30.2% were hospitalized and 5.3% died. The main prognostic factors were the predefined high‐risk groups, mainly malignant haematological disease and age ≥65 years. Number of COVID‐19 vaccines (≥3) was associated with a decreased risk of hospitalization. The Delta but not the Omicron BA.2 variant was associated with a higher risk of death compared to the BA.1 variant. Conclusion: More than 90% of the patients treated with sotrovimab belonged to the very high‐risk groups as described in the Danish guidelines. Sotrovimab‐treated individuals remained at a high risk of hospitalization and death which was strongly associated with the underlying immunocompromised state and age. Having received >3 COVID‐19 vaccines was association with decreased risk of death and hospitalization. [ABSTRACT FROM AUTHOR]

Manifestations and outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are not well documented in patients with common variable immunodeficiency disorder (CVID). A Danish nationwide retrospective clinician-reported survey. Eleven patients with CVID and SARS-CoV-2 infection were identified. The median age was 50 years (range 22–72). All were on immunoglobulin replacement therapy. Eight patients had other pre-existing co-morbidities. Three patients were asymptomatic during the SARS-CoV-2 infection while seven developed mild coronavirus disease 2019 (COVID-19). One patient had more severe disease with hypoxia and required oxygen therapy. This patient had multiple co-morbidities including well known risk factors for severe COVID-19. All patients recovered. The results suggest that CVID may not be a risk factor for severe COVID-19. However, further monitoring of this immunodeficient population is needed to confirm our observation. [ABSTRACT FROM AUTHOR]

• COVID-19 in Danish hospitalised patients with equal and free access to health care. • Early lock down and preparedness of the health system. • Multidisciplinary team approach to COVID-19 patients. • Low overall mortality less than 5% and mortality of 0% for ICU patients. We aimed to describe clinical characteristics and outcomes of admitted COVID-19 patients in a Danish hospital setting where an early active government intervention was taken. Prospective cohort study including all admitted patients to the COVID-19 unit at Odense University Hospital from March 10 to April 21, 2020. Patients were assessed by a multidisciplinary team at admission. Outcome parameters were development of acute respiratory distress syndrome (ARDS), intensive care unit (ICU) admission, death and admission time. We included 83 patients (median age 62 years, 62.7% male). At hospitalization, 31.3% needed oxygen supplementation and the median National Early Warning Score was four. Median admission time was 7 days (Interquartile ranges (IQR) 3-12). In total, ARDS was diagnosed in 33.7% (28/83) of the patients corresponding to an incidence rate of 7.1 per 100 person days (95% CI: 4.1-10.2). Overall 13 patients (15.7%) were transferred to the ICU of whom 11 (84.6%) received corticosteroids.. No patients died while admitted to the ICU. Four patients (4.8%) died during admission. Despite similar patient characteristics compared to those reported by others, we found a low overall mortality of < 5%. [ABSTRACT FROM AUTHOR]

• Hybrid-immunity (both vaccine induced and natural immunity) to SARS-CoV-2 is common. • Hybrid-immunity has an important impact on the antibody trajectories. • More antibodies were seen in people with hybrid compared to vaccine-only immunity. • Antibodies declined slower in people with hybrid compared to vaccine-only immunity. • People with comorbidities had lower antibody levels independent of hybrid-immunity. This study aimed to compare antibody trajectories among individuals with SARS-CoV-2 hybrid and vaccine-induced immunity. Danish adults receiving three doses of BTN162b2 or mRNA-1237 were included prior to first vaccination (Day 0). SARS-CoV-2 anti-spike IgG levels were assessed before each vaccine dose, at Day 90, Day 180, 28 days after 3rd vaccination (Day 251), Day 365, and prior to 4th vaccination (Day 535). SARS-CoV-2 PCR results were extracted from the national microbiology database. Mixed-effect multivariable linear regression investigated the impact of hybrid-immunity (stratified into 4 groups: no hybrid immunity, PCR+ prior to 3rd dose, PCR+ after 3rd dose and before Day 365, PCR+ after Day 365) on anti-spike IgG trajectories. A total of 4,936 individuals were included, 47% developed hybrid-immunity. Anti-spike IgG increases were observed in all groups at Day 251, with the highest levels in those PCR+ prior to 3rd dose (Geometric Mean; 535,647AU/mL vs. 374,665AU/mL with no hybrid-immunity, P <0.0001). Further increases were observed in participants who developed hybrid immunity after their 3rd dose. Anti-spike IgG levels declined from Day 251-535 in individuals without hybrid-immunity and in those who developed hybrid-immunity prior to their 3rd dose, with lower rate of decline in those with hybrid-immunity. Hybrid-immunity results in higher and more durable antibody trajectories in vaccinated individuals. [ABSTRACT FROM AUTHOR]

To explore changes over time in the epidemiology of tuberculosis (TB) in Denmark in people living with human immunodeficiency virus (HIV) (PLWH). In this nationwide, population-based cohort study we included all adult PLWH from the Danish HIV Cohort Study (1995–2017) without previous TB. We estimated TB incidence rate (IR), all-cause mortality rate (MR), associated risk and prognostic factors using Poisson regression. Among 6982 PLWH (73 596 person-years (PY)), we observed 217 TB events (IR 2.9/1000 PY, 95% CI 2.6–3.4: IR 6.7, 95% CI 5.7–7.9 among migrants and IR 1.4, 95% CI 1.1–1.7 among Danish-born individuals; p < 0.001). The IR of concomitant HIV/TB remained high and unchanged over time. The IR of TB diagnosed >3 months after HIV diagnosis declined with calendar time, longer time from HIV diagnosis, and CD4 cell recovery. Independent TB risk factors were African/Asian/Greenland origin (adjusted incidence rate ratio (aIRR) 5.2, 95% CI 3.5–7.6, aIRR 6.5, 95% CI 4.2–10.0, aIRR 7.0, 95% CI 3.4–14.6, respectively), illicit drug use (aIRR 6.9, 95% CI 4.2–11.2), CD4 <200 cells/μL (aIRR 2.7, 95% CI 2.0–3.6) and not receiving antiretroviral therapy (aIRR 3.7, 95% CI 2.5–5.3). Fifty-five patients died (MR 27.9/1000 PY, 95% CI 21.4–36.3), with no improvement in mortality over time. Mortality prognostic factors were Danish-origin (adjusted mortality rate ratio (aMRR) 2.3, 95% CI 1.3–4.3), social burden (aMRR 3.9, 95% CI 2.2–7.0), CD4 <100 cells/μL at TB diagnosis (aMRR 2.6, 95% CI 1.3–4.9), TB diagnosed >3 months after HIV versus concomitant diagnosis (aMRR 4.3, 95% CI 2.2–8.7) and disseminated TB (aMRR 3.3, 95% CI 1.1–9.9). Late HIV presentation with concomitant TB remains a challenge. Declining TB rates in PLWH were observed over time and with CD4 recovery, highlighting the importance of early and successful antiretroviral therapy. However, MR remained high. Our findings highlight the importance of HIV and TB screening strategies and treatment of latent TB in high-risk groups. [Display omitted] [ABSTRACT FROM AUTHOR]

Background Limited data exist examining the association between incident cancer and cumulative integrase inhibitor (INSTI) exposure. Methods Participants were followed from baseline (latest of local cohort enrollment or January 1, 2012) until the earliest of first cancer, final follow-up, or December 31, 2019. Negative binomial regression was used to assess associations between cancer incidence and time-updated cumulative INSTI exposure, lagged by 6 months. Results Of 29 340 individuals, 74% were male, 24% were antiretroviral treatment (ART)-naive, and median baseline age was 44 years (interquartile range [IQR], 36–51). Overall, 13 950 (48%) individuals started an INSTI during follow-up. During 160 657 person-years of follow-up ([PYFU] median 6.2; IQR, 3.9–7.5), there were 1078 cancers (incidence rate [IR] 6.7/1000 PYFU; 95% confidence interval [CI], 6.3–7.1). The commonest cancers were non-Hodgkin lymphoma (n = 113), lung cancer (112), Kaposi's sarcoma (106), and anal cancer (103). After adjusting for potential confounders, there was no association between cancer risk and INSTI exposure (≤6 months vs no exposure IR ratio: 1.15 [95% CI, 0.89–1.49], >6–12 months; 0.97 [95% CI, 0.71–1.32], >12–24 months; 0.84 [95% CI, 0.64–1.11], >24–36 months; 1.10 [95% CI, 0.82–1.47], >36 months; 0.90 [95% CI, 0.65–1.26] [ P  = .60]). In ART-naive participants, cancer incidence decreased with increasing INSTI exposure, mainly driven by a decreasing incidence of acquired immune deficiency syndrome cancers; however, there was no association between INSTI exposure and cancer for those ART-experienced (interaction P  < .0001). Conclusions Cancer incidence in each INSTI exposure group was similar, despite relatively wide CIs, providing reassuring early findings that increasing INSTI exposure is unlikely to be associated with an increased cancer risk, although longer follow-up is needed to confirm this finding. [ABSTRACT FROM AUTHOR]

Introduction: We aimed to examine if severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) cycle quantification (Cq) value, as a surrogate for SARS-CoV-2 viral load, could predict hospitalisation and disease severity in adult patients with coronavirus disease 2019 (COVID-19). Methods: We performed a prospective cohort study of adult patients with PCR positive SARS-CoV-2 airway samples including all out-patients registered at the Department of Infectious Diseases, Odense University Hospital (OUH) March 9-March 17 2020, and all hospitalised patients at OUH March 10-April 21 2020. To identify associations between Cq-values and a) hospital admission and b) a severe outcome, logistic regression analyses were used to compute odds ratios (OR) and 95% Confidence Intervals (CI), adjusting for confounding factors (aOR). Results: We included 87 non-hospitalised and 82 hospitalised patients. The median baseline Cq-value was 25.5 (interquartile range 22.3–29.0). We found a significant association between increasing Cq-value and hospital-admission in univariate analysis (OR 1.11, 95% CI 1.04–1.19). However, this was due to an association between time from symptom onset to testing and Cq-values, and no association was found in the adjusted analysis (aOR 1.08, 95% CI 0.94–1.23). In hospitalised patients, a significant association between lower Cq-values and higher risk of severe disease was found (aOR 0.89, 95% CI 0.81–0.98), independent of timing of testing. Conclusions: SARS-CoV-2 PCR Cq-values in outpatients correlated with time after symptom onset, but was not a predictor of hospitalisation. However, in hospitalised patients lower Cq-values were associated with higher risk of severe disease. [ABSTRACT FROM AUTHOR]

Understanding alterations in HIV-specific immune responses during antiretroviral therapy (ART), such as antibody-dependent cellular cytotoxicity (ADCC), is important in the development of novel strategies to control HIV-1 infection. This study included 53 HIV-1 positive individuals. We evaluated the ability of effector cells and antibodies to mediate ADCC separately and in combination using the ADCC-PanToxiLux assay. The ability of the peripheral blood mononuclear cells (PBMCs) to mediate ADCC was significantly higher in individuals who had been treated with ART before seroconversion, compared to the individuals initiating ART at a low CD4+ T cell count (<350 cells/μl blood) and the ART-naïve individuals. The frequency of CD16 expressing natural killer (NK) cells correlated with both the duration of ART and Granzyme B (GzB) activity. In contrast, the plasma titer of antibodies mediating ADCC declined during ART. These findings suggest improved cytotoxic function of the NK cells if initiating ART early during infection, while the levels of ADCC mediating antibodies declined during ART. [ABSTRACT FROM AUTHOR]

Background: Germinal center derived memory B cells and plasma cells constitute, in health and during EBV reactivation, the largest functional EBV reservoir. Hence, by reducing germinal center derived formation of memory B cells and plasma cells, EBV loads may be reduced. Animal and in-vitro models have shown that IL-21 can support memory B and plasma cell formation and thereby potentially contribute to EBV persistence. However, IL-21 also displays anti-viral effects, as mice models have shown that CD4+ T cell produced IL-21 is critical for the differentiation, function and survival of anti-viral CD8+ T cells able to contain chronic virus infections.Case Presentation: We present immunological work-up (flow-cytometry, ELISA and genetics) related to a patient suffering from a condition resembling B cell chronic active EBV infection, albeit with moderately elevated EBV copy numbers. No mutations in genes associated with EBV disease, common variable immunodeficiency or pertaining to the IL-21 signaling pathway (including hypermorphic IL-21 mutations) were found. Increased (> 5-fold increase 7 days post-vaccination) CD4+ T cell produced (p < 0.01) and extracellular IL-21 levels characterized our patient and coexisted with: CD8+ lymphopenia, B lymphopenia, hypogammaglobulinemia, compromised memory B cell differentiation, absent induction of B-cell lymphoma 6 protein (Bcl-6) dependent peripheral follicular helper T cells (pTFH, p = 0.01), reduced frequencies of peripheral CD4+ Bcl-6+ T cells (p = 0.05), compromised plasmablast differentiation (reduced protein vaccine responses (p < 0.001) as well as reduced Treg frequencies. Supporting IL-21 mediated suppression of pTFH formation, pTFH and CD4+ IL-21+ frequencies were strongly inversely correlated, prior to and after vaccination, in the patient and in controls, Spearman's rho: - 0.86, p < 0.001.Conclusions: To the best of our knowledge, this is the first report of elevated CD4+ IL-21+ T cell frequencies in human EBV disease. IL-21 overproduction may, apart from driving T cell mediated anti-EBV responses, disrupt germinal center derived memory B cell and plasma cell formation, and thereby contribute to EBV disease control. [ABSTRACT FROM AUTHOR]