To Örebro University

During the COVID-19 pandemic, most countries implemented non-pharmaceutical interventions (NPIs) to mitigate virus transmission and decrease morbidity and mortality. The aim of this umbrella review was to identify and map systematic reviews on the effectiveness of NPIs to reduce widespread community transmission of infectious diseases with pandemic potential. We searched electronic databases (Medline, Embase, Scopus, INAHTA [International Network of Agencies for Health Technology Asseesment], and World Health Organization COVID-19) and websites (January 2024). Systematic reviews on NPIs during outbreaks, epidemics, or pandemics of COVID-19, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), influenza, or Ebola were included and organized in an interactive evidence map grouped by type of intervention (individual/population/environmental), disease, risk of bias, and search date. Five of the 132 included reviews were assessed as having low, 43 moderate, and 84 high risk of bias. COVID-19 was targeted in 100 reviews, influenza 66, SARS 39, MERS 34, and Ebola in five reviews. The most frequently investigated NPIs were use of face masks, hand washing, physical distancing, travel restrictions, restrictions on public gatherings, and school closures. The five reviews at low risk of bias concluded at low level of evidence about the effectiveness of most NPIs, with exceptions of hand hygiene and some measures in school settings where low- to moderate-certainty evidence was found. There is substantial lack of evidence regarding the effectiveness of several commonly used NPIs, including restrictions on public gatherings, travel restrictions, and visiting restrictions in long-term care facilities. There is a paucity not only of systematic reviews but also of primary studies at low risk of bias.

There is evidence that persistent dysregulation of the immune system caused by SARS-CoV-2 infection may increase susceptibility to other infections. Here, we assessed whether it is associated with subsequent diagnoses of infectious mononucleosis due to Epstein-Barr virus (EBV-IM). Residents of Sweden aged 3-100 years without a prior diagnosis of EBV-IM were followed between January 1, 2020, and November 30, 2022, comprising a total of 9 978 860 participants. Individuals were categorized into those without a COVID-19 diagnosis, those with a positive SARS-CoV-2 polymerase chain reaction (PCR) test only - less severe exposure, and those admitted to hospital with COVID-19 - more severe exposure. Cox regression was used to estimate hazard ratios (HR) with 95% confidence intervals (95% CI) for the association between the exposure, modeled as a time-varying covariate, and EBV-IM occurrence. EBV-IM rates per 100 000 person-years and 95% CIs were 4.6 (4.4-4.9) for individuals not diagnosed with COVID-19, 7.8 (6.9-8.9) for those with a positive SARS-CoV-2 test only, and 10.5 (6.2-17.6) for patients admitted to hospital with COVID-19. HR and 95% CI were 1.61 (1.39-1.88) for people with a positive PCR test only and 5.71 (3.33-9.79) for those admitted to hospital with COVID-19 compared with people without a COVID-19 diagnosis, after adjustment for birth year, sex, Swedish healthcare region, region of birth, and Charlson comorbidity index. SARS-CoV-2 infection was associated with a subsequent raised risk of EBV-IM, including among those with less severe acute infection, signaling immune perturbation and the possibility of further delayed sequelae linked with EBV-IM.

Background: Viral infections, particularly Epstein-Barr virus (EBV), have been linked with risk of multiple sclerosis (MS). Given the evidence that SARS- CoV-2 infection can have consequences for the central nervous system (CNS) and autoimmune disorders, it might increase risk of MS and other demyelinating diseases of the CNS.

Objectives: We aimed to assess whether SARS- CoV-2 infection is associated with subsequent diagnoses of non-MS demyelinating CNS diseases, MS, and infectious mononucleosis (IM) due to EBV—an important MS risk factor.

Methods: All residents of Sweden aged 3–100 years were followed between 1st January 2020 and 30th November 2022, excluding those with demyelinating disease prior to 2020, resulting in 9,981,915 individuals. Exposure was classified as SARS- Cov-2 uninfected or infected, the latter divided by severity, and mod-elled as a time-varying covariate (uninfected, infection without hospital admission and infected with hospital admission). Cox regression assessed the risk of three separate outcomes: hospital-diagnosed non-MS demyelinating diseases; MS; and IM due t oEBV, adjusting for sex, year of birth (age), Charlson comorbidity index, healthcare region and country of birth.

Results: Hospital admission for COVID-19 was associated with raised risk of subsequent non-MS demyelinating disease. Rates per 100 000 person years (and 95% confidence intervals [CI]) were 3.8 (3.6– 4.1) among those without a COVID-19 diagnosis and 9.0 (5.1–15.9) among those admitted to hospital for COVID-19, with an adjusted hazard ratio (aHR) and 95% CI of 2.31 (1.30– 4.10). Equivalent associations with MS were rates of 9.5 (9.1–9.9) and 21.0 (14.5–30.5) per 100,000, and an aHR of 2.48 (1.70–3.61). For subsequent IM due to EBV, hospital admission for COVID-19 was associated with a rate of 10.5 (6.2–17.8) per 100,000 compared with 4.7 (4.4–5.0) for those without COVID-19, and an aHR of 5.63 (3.29–9.66).

Conclusions: There was increased risk of CNS demyelinating diseases among people admitted to hospital for COVID-19. COVID-19 was also associated with a raised risk of IM due to EBV, an established risk factor for MS. It is possible that at least a proportion of these associations is due to surveillance or referral bias (due to a previous hospital admission for infection), so future research should continue to follow the population that had COVID-19 for development of MS and other demyelinating diseases, which can have long asymptomatic and prodromal phases.

Demyelinating diseases including multiple sclerosis are associated with prior infectious exposures, so we assessed whether SARS-CoV-2 infection is associated with subsequent diagnoses of non-multiple sclerosis demyelinating diseases and multiple sclerosis. All residents of Sweden aged 3-100 years were followed between 1 January 2020 and 30 November 2022, excluding those with demyelinating disease prior to 2020, comprising 9 959 818 individuals divided into uninfected and those who were infected were categorized into those with and without hospital admission for the infection as a marker of infection severity. Cox regression assessed the risk of two separate outcomes: hospital diagnosed non-multiple sclerosis demyelinating diseases of the CNS and multiple sclerosis. The exposures were modelled as time-varying covariates (uninfected, infection without hospital admission and infected with hospital admission). Hospital admission for COVID-19 was associated with raised risk of subsequent non-multiple sclerosis demyelinating disease, but only 12 individuals had this outcome among the exposed, and of those, 7 has an unspecified demyelinating disease diagnosis. Rates per 100 000 person-years (and 95% confidence intervals) were 3.8 (3.6-4.1) among those without a COVID-19 diagnosis and 9.0 (5.1-15.9) among those admitted to hospital for COVID-19, with an adjusted hazard ratio and (and 95% confidence interval) of 2.35 (1.32-4.18, P = 0.004). Equivalent associations with multiple sclerosis (28 individuals had this outcome among the exposed) were rates of 9.5 (9.1-9.9) and 21.0 (14.5-30.5) and an adjusted hazard ratio of 2.48 (1.70-3.61, P < 0.001). Only a small number of non-multiple sclerosis demyelinating disease diagnoses were associated with hospital admission for COVID-19, and while the number with multiple sclerosis was somewhat higher, longer duration of follow-up will assist in identifying whether the associations are causal or due to shared susceptibility or surveillance bias, as these diseases can have long asymptomatic and prodromal phases.

Incidence of tick-borne encephalitis (TBE) has increased during the last years in Scandinavia, but the underlying mechanism is not understood. TBE human case data reported between 2010 and 2021 were aggregated into postal codes within Örebro County, south-central Sweden, along with tick abundance and environmental data to analyse spatial patterns and identify drivers of TBE. We identified a substantial and continuing increase of TBE incidence in Örebro County during the study period. Spatial cluster analyses showed significant hotspots (higher number of cases than expected) in the southern and northern parts of Örebro County, whereas a cold spot (lower number of cases than expected) was found in the central part comprising Örebro municipality. Generalised linear models showed that the risk of acquiring TBE increased by 12.5% and 72.3% for every percent increase in relative humidity and proportion of wetland forest, respectively, whereas the risk decreased by 52.8% for every degree Celsius increase in annual temperature range. However, models had relatively low goodness of fit (R2 < 0.27). Results suggest that TBE in Örebro County is spatially clustered, however variables used in this study, i.e., climatic variables, forest cover, water, tick abundance, sheep as indicator species, alone do not explain this pattern.

BACKGROUND: To inform future preventive measures including repeated vaccinations, we have searched for a clinically useful immune correlate of protection against fatal COVID-19 among nursing homes residents.

METHODS: We performed repeated capillary blood sampling with analysis of S-binding IgG in an open cohort of nursing home residents in Sweden. We analyzed immunological and registry data from 16 September 2021 to 31 August 2022 with follow-up of deaths to 30 September 2022. The study period included implementation of the 3rd and 4th mRNA monovalent vaccine doses and Omicron virus waves.

FINDINGS: A total of 3012 nursing home residents with median age 86 were enrolled. The 3rd mRNA dose elicited a 99-fold relative increase of S-binding IgG in blood and corresponding increase of neutralizing antibodies. The 4th mRNA vaccine dose boosted levels 3.8-fold. Half-life of S-binding IgG was 72 days. A total 528 residents acquired their first SARS-CoV-2 infection after the 3rd or the 4th vaccine dose and the associated 30-day mortality was 9.1%. We found no indication that levels of vaccine-induced antibodies protected against infection with Omicron VOCs. In contrast, the risk of death was inversely correlated to levels of S-directed IgG below the 20th percentile. The death risk plateaued at population average above the lower 35th percentile of S-binding IgG.

INTERPRETATION: In the absence of neutralizing antibodies that protect from infection, quantification of S-binding IgG post vaccination may be useful to identify the most vulnerable for fatal COVID-19 among the oldest and frailest. This information is of importance for future strategies to protect vulnerable populations against neutralization resistant variants of concern.

FUNDING: Swedish Research Council, SciLifeLab via Knut and Alice Wallenberg Foundation, VINNOVA. Swedish Healthcare Regions, and Erling Persson Foundation.

BACKGROUND: Blood stream infection (BSI) and sepsis are serious clinical conditions and identification of the disease-causing pathogen is important for patient management. The RISE (Rapid Identification of SEpsis) study was carried out to collect a cohort allowing high-quality studies on different aspects of BSI and sepsis. The aim of this study was to identify patients at high risk for BSI who might benefit most from new, faster, etiological testing using neutrophil to lymphocyte count ratio (NLCR) and Shapiro score.

METHODS: Adult patients (≥ 18 years) presenting at the emergency department (ED) with suspected BSI were prospectively included between 2014 and 2016 at Örebro University Hospital. Besides extra blood sampling, all study patients were treated according to ED routines. Electronic patient charts were retrospectively reviewed. A modified Shapiro score (MSS) and NLCR were extracted and compiled. Continuous score variables were analysed with area under receiver operator characteristics curves (AUC) to evaluate the ability of BSI prediction.

RESULTS: The final cohort consisted of 484 patients where 84 (17%) had positive blood culture judged clinically significant. At optimal cut-offs, MSS (≥3 points) and NLCR (> 12) showed equal ability to predict BSI in the whole cohort (AUC 0.71/0.74; sensitivity 69%/67%; specificity 64%/68% respectively) and in a subgroup of 155 patients fulfilling Sepsis-3 criteria (AUC 0.71/0.66; sensitivity 81%/65%; specificity 46%/57% respectively). In BSI cases only predicted by NLCR> 12 the abundance of Gram-negative to Gram-positive pathogens (n = 13 to n = 4) differed significantly from those only predicted by MSS ≥3 p (n = 7 to n = 12 respectively) (p < 0.05).

CONCLUSIONS: MSS and NLCR predicted BSI in the RISE cohort with similar cut-offs as shown in previous studies. Combining the MSS and NLCR did not increase the predictive performance. Differences in BSI prediction between MSS and NLCR regarding etiology need further evaluation.

To improve management of Staphylococcus aureus bacteremia (SAB), better understanding of host-pathogen interactions is needed. In vitro studies have shown that S. aureus bacteria induce dose-dependent immunosuppression that is evidenced by reduced expression of major histocompatibility complex (MHC) class II on antigen presenting cells. Thus, the aim of this study was to determine whether expression of the MHC class II-related genes HLA-DRA and CD74 is more greatly reduced in complicated SAB, with its probable higher loads of S. aureus, than in uncomplicated SAB. Adult patients with SAB were prospectively included and blood samples taken on the day of confirmation of SAB (Day 1) and on Days 2, 3, 5 and 7. HLA-DRA and CD74 mRNA expression was determined by quantitative reverse transcription PCR. Sepsis was defined according to the Sepsis-3 classification and SAB was categorized as complicated in patients with deep-seated infection and/or hematogenous seeding. Twenty patients with SAB were enrolled and samples obtained on all assessment days. HLA-DRA and CD74 expression did not differ significantly between patients with SAB and sepsis (n=13) and those without sepsis (n=7) on any assessment day. However, patients with complicated SAB (n=14) had significantly weaker HLA-DRA expression on all five assessment days than patients with uncomplicated SAB (n=6). Additionally, they tended to have weaker CD74 expressions. Neutrophil, monocyte and leukocyte counts did not differ significantly between complicated and uncomplicated SAB. In conclusion, patients with complicated SAB show weaker HLA-DRA expression than those with uncomplicated SAB during the first week of bacteremia.

Staphylococcus aureus is a major pathogen responsible for a considerable disease burden worldwide. It may cause a wide array of infections, from superficial skin infections to invasive bacteremia and complications such as infective endocarditis (IE) and osteomyelitis. This thesis aimed to investigate aspects of the molecular epidemiology of S. aureus and host immune response in relation to disease manifestation, severity, and over time during S. aureus bacteremia (SAB).

Genotypic characteristics in isolates causing colonization, bacteremia, and bacteremia with IE were studied. The S. aureus population was genetically diverse and certain clones with their set of often lineage-specific virulence genes were associated with invasive disease. Characterization of the long-term molecular epidemiology of MSSA bacteremia showed an increased prevalence of CC5 and CC15, while CC8, CC25 and CC30 declined. Antibiotic resistance pattern was favorable and unaffected.

Further, different aspects of host immune response were explored in patients with SAB during the acute phase of bacteremia. When investigating the NLRP3 inflammasome signaling, induced caspase-1 activity was found, with a great inter-individual variation between patients, and subsequent release of IL-18, indicating inflammasome activity. Finally, the dynamics of MHC class II related genes HLA-DRA and CD74 were analyzed as markers of immunosuppression. Patients with complicated SAB had significantly lower HLA-DRA expression than patients with uncomplicated bacteremia, demonstrating an association between complicated SAB and impaired immune function.

In conclusion, the S. aureus genotype, as well as host factors reflected by inter-individual variations in inflammasome signaling and immune function, may all contribute to disease manifestation and outcome during SAB. An ability to measure the immune response early and continuously during the hospital stay and course of bacteremia could offer a way to tailor patient management and treatment in an individualized way.