To Örebro University

The human blood proteome provides a holistic readout of health states through the assessment of thousands of circulating proteins. Here, we present a pan-disease resource to enable the study of diverse disease phenotypes within a harmonized proteomics dataset. By profiling protein concentrations across 59 diseases and healthy cohorts, we identified proteins associated with age, sex, and BMI, as well as disease-specific signatures. This study highlights shared and distinct protein patterns across conditions, demonstrating the power of a unified proteomics approach to uncover biological insights. The dataset, covering 8,262 individuals and up to 5,416 proteins, serves as an online resource for exploring disease-specific protein profiles and advancing precision medicine research.

Staphylococcus aureus is an important human pathogen causing severe invasive infections. Pathogenesis is attributed to a wide array of virulence factors, including several potent exotoxins such as the pore-forming α-toxin. In this study, we found that patients with S. aureus respiratory tract infections had elevated CX3CL1 levels in airway fluid and plasma. Using human-organotypic lung models, we observed that stimulation of lung epithelium with α-toxin induces an intensified CX3CL1 expression apically in the epithelium as well as the release of CX3CL1. Blocking α-toxin or ADAM10 activity in organotypic lung using an α-toxin-blocking antibody or a specific ADAM10 inhibitor confirmed their role in modulating CX3CL1 cleavage and release. Analyses of CD14+ human monocytes in combination with a CX3CR1 inhibitor revealed that α-toxin-mediated CX3CL1 release induces CX3CL1-dependent chemotaxis. In line with these data, lung tissue from patients with S. aureus respiratory tract infection showed elevated CX3CL1 and CD14 staining as compared with tissue from patients with non-infectious lung diseases. Functional studies of monocytes showed that CX3CL1 released by lung models resulted in upregulated CD83 and downregulated CD86, as well as impaired killing of phagocytosed S. aureus. Furthermore, stimulation of monocytes with soluble CX3CL1 hampered their reactive-oxygen and nitric-oxide production. Taken together our data show that S. aureus triggers the release of lung epithelial CX3CL1, and we identify an immunomodulatory effect of α-toxin involving its cytotoxic and ADAM10-interacting properties, inducing CX3CL1 release leading to impaired monocyte effector function.IMPORTANCEExotoxins are essential virulence factors for the pathobiont S. aureus and contribute toward severe invasive infections such as pneumonia. S. aureus α-toxin is a pore-forming exotoxin that causes host cell lysis and severe lung pathology. We found that α-toxin drives the release of membrane-bound chemokine CX3CL1 by involving ADAM10-mediated proteolytic activity. Furthermore, the release of CX3CL1 modulated immune responses locally, as demonstrated by enhanced monocyte migration and reduced capacity of monocytes to kill ingested bacteria. CX3CL1-induced reduction in bacterial killing coincided with impaired production of reactive oxygen and nitric oxide species. This reveals a novel mechanism in the pathogenesis of S. aureus lung infections involving α-toxin-induced release of CX3CL1, leading to impaired bacterial killing by monocytes.

Severe COVID-19 disease is accompanied by high plasma levels of proinflammatory, prothrombotic NETs, and NET-inducing cytokine IL-18. We found that both, IL-18 and NETs, are elevated in men with severe disease, but not in women of the same category. Our findings warrant further investigation of sex-related differences in SARS-CoV-2 infection.

OBJECTIVES: COVID-19 impacts physical and respiratory health, and the clinical presentation ranges from asymptomatic cases to severe infections requiring hospitalisation. While the long-term effects on lung function and physical capacity are well-documented in moderate to severe cases, the long-term outcome for individuals with mild COVID-19 remains poorly understood. This study investigates the long-term recovery of physical capacity and breathlessness among both hospitalised and non-hospitalised individuals.

METHODS: This prospective cohort study enrolled individuals with confirmed SARS-CoV-2 infection between April 2020 and May 2021 through the CoVUm-study. Participants underwent assessments of lung function at 3-6 months after infection and attended follow-ups up to three years post-infection. Physical capacity was evaluated at follow-ups, using the one-minute sit-to-stand test and the modified Medical Research Council scale to assess breathlessness.

RESULTS: The cohort included 291 participants, 35% of whom were hospitalised during SARS-CoV-2 infection. At the 3-year follow-up, 191 participants completed the physical capacity test and 179 had an assessment of breathlessness. Physical capacity improved significantly in the total cohort up to two years post-infection where improvement plateaued. Hospitalisation and impaired diffusing capacity were significantly associated with reduced physical capacity (beta -6.4, p < 0.001; beta -8.9, p < 0.001, respectively) and breathlessness (beta 3.9, p < 0.001; beta 1.6, p = 0.012, respectively). While non-hospitalised participants demonstrated improvements in physical capacity for up to two years, improvement for hospitalised individuals plateaued by six months.

CONCLUSION: Hospitalisation and impaired diffusing capacity are strong independent predictors of reduced physical capacity and persistent breathlessness up to three years post-infection. Non-hospitalised individuals also experience long-term reductions in physical capacity, underscoring the need for targeted rehabilitation strategies.

BACKGROUND: Current evidence indicates that Post COVID-19 Condition (PCC) is multifaceted with distinct phenotypes. While previous studies have identified symptom clusters-commonly featuring fatigue, respiratory symptoms, and cognitive impairment-findings have been inconsistent, and no clear consensus exists. Moreover, how these symptom clusters evolve over time, particularly beyond the first year post-infection, remains poorly understood.

METHODS: This multicentre prospective cohort study included 470 hospitalised and non-hospitalised adult individuals from the CoVUm study across four sites in Sweden between 2020 and 2021. Follow-ups were conducted up to 3 years after infection to assess persistent symptoms, health-related quality of life (HRQoL), and work capacity. Symptom clusters at 6 months were identified via hierarchical cluster analysis, and participants were tracked using a k-nearest neighbour algorithm.

RESULTS: The most common symptoms at 6 months were fatigue (33 %), dyspnoea (32 %), mental fatigue (30 %), and concentration difficulties (28 %), with a median EQ-5D-5L index of 0.98 (IQR 0.93-1). Four distinct symptom clusters were identified: (i) "Few Symptoms" (n = 265, 57 %), (ii) "Respiratory Symptoms" (n = 66, 14 %), (iii) "Neurocognitive Symptoms" (n = 75, 16 %), and (iv) "Multisystem Symptoms" (n = 52, 11 %). Participants in the latter three clusters were older, had more comorbidities, and were more often hospitalised during primary COVID-19 infection. These clusters also had significantly lower HRQoL compared to the "Few Symptoms" cluster. Over time, more than half of participants transitioned to a cluster with fewer or no symptoms, with significant perceived HRQoL improvement in the "Multisystem Symptoms" cluster.

CONCLUSION: While many patients with PCC improved over time, a subset had persistent symptoms at 3 years, especially if primary infection required hospitalisation. The identification of symptom clusters and their trajectories over time contributes to a better understanding of PCC heterogeneity, ultimately bringing the field closer to consensus on the classification and long-term impact of PCC.

BACKGROUND: Recent studies have reported an increasing prevalence of penicillin-susceptible Staphylococcus aureus (PSSA) worldwide. The reliability of disc diffusion testing for detecting penicillin-resistance has been questioned, and the molecular epidemiology of PSSA has not been studied to the same extent as that of MRSA strains.

OBJECTIVES: To investigate the reliability of the disc diffusion method for detecting penicillin-resistance in S. aureus, and to examine the prevalence and molecular epidemiology of PSSA in bloodstream infections.

METHODS: A total of 258 bacteraemic isolates obtained from one geographic region in Sweden during 2018-2019 were analysed using the disc diffusion test to detect penicillin-resistance, and genome sequenced to examine the prevalence of the blaZ gene and the molecular epidemiology of PSSA.

RESULTS: Phenotypic susceptibility to penicillin correlated strongly with the absence of the blaZ gene, with nearly 98% concordance. The prevalence of PSSA among patients with bacteraemia was 35.1%, highlighting the need for penicillin-susceptibility testing. Additionally, population structure analyses revealed substantial genetic diversity, underscoring the complexity of the PSSA epidemiology. The PSSA belonged to diverse clonal lineages, with CC5 and CC45 dominating our cohort, similar to findings in Spain, Australia, and other parts of Sweden. However, our study revealed a higher prevalence of CC12 compared with other regions, underscoring the importance of local epidemiological surveillance.

CONCLUSIONS: These findings validate the reliability of EUCAST's disc diffusion method, showing a high prevalence of PSSA, and provide insight into the genetic underpinnings of penicillin-susceptibility in S. aureus.

Sepsis is a life-threatening, dysregulated host response to infection. Immunosuppression is a risk factor for infections and sepsis. However, the specific immune derangements elevating the risk for infections and sepsis remain unclear in the individual patient, raising the question of whether a general state of immunosuppression exists. In this Review, we explore the relationship between immunosuppression and sepsis, detailing the definitions, causes, and clinical implications. We address the effect of primary immunodeficiencies, acquired conditions, and drugs on the risk of infection and the development of sepsis. Patients with sepsis who are immunocompromised often present with atypical symptoms and diagnostic test results can differ, making early recognition difficult. Future perspectives entail novel biomarkers to improve early sepsis detection and tailored treatments to modulate immune function. Including patients who are immunocompromised in clinical trials is crucial to enhance the relevance of research findings and improve treatment strategies for this vulnerable population.

Influenza infection is a well-established trigger of acute cardiovascular events, particularly myocardial infarction, mediated by systemic inflammation, endothelial dysfunction, and thrombosis. In this review, we examine the evidence supporting influenza vaccination as a preventive strategy in cardiovascular disease. Observational studies and randomized trials consistently show reduced cardiovascular event rates among vaccinated individuals, with the most pronounced benefit seen after myocardial infarction. Emerging data suggest that the effects of vaccination extend beyond infection prevention, involving immunomodulatory effects, including regulatory T cell activity, features of trained innate immunity, and mechanisms promoting resolution of inflammation. Unlike conventional anti-inflammatory therapies, vaccination appears to rebalance immune responses without compromising host defence. We also consider an evolutionary perspective, proposing that historical influenza exposure may have contributed to the genetic architecture of atherosclerosis. Taken together, current evidence positions influenza vaccination as a safe, low-cost, and biologically plausible intervention in the prevention of cardiovascular events. However, important questions remain. Whether revaccination during hospitalization provides added benefit in previously immunized individuals, and the potential of high-dose or next-generation vaccine platforms such as mRNA, warrant further study. Dedicated outcome trials conducted outside the influenza season are especially needed to clarify nonspecific cardiovascular benefits. Cardiologists and other stakeholders share a responsibility to implement existing guidelines with the same commitment given to statins and platelet inhibitors.

OBJECTIVE: To study infection, hospitalisation, and admission to ICU for COVID-19 in different occupations and pandemic waves in a Swedish county.

METHODS: Individual registry data of infection and hospitalisation were merged with occupational data in, this cross-sectional study. Infected, hospital- and ICU-admission were analysed by occupational groups.

RESULTS: 22,095 cases of COVID-19 from 21 February 2021 to 31 August 2022 were identified. Healthcare workers and others working in close physical proximity showed a higher rate of confirmed COVID-19 infections in all waves and higher risk for hospital admission early in the pandemic. Exposure to diseases and physical proximity played a decisive role.

CONCLUSION: Workers in close-contact occupations experienced a higher rate of confirmed infections throughout the pandemic and higher hospitalisation rates in the first pandemic wave, suggesting a need for more effective initial safety measures in a future pandemic.