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Purpose: COVID-19 has been extensively researched; however, the lack of standardized COVID-19 severity categorization in register-based research complicates comparison of studies. The WHO COVID-19 Clinical Progression Scale is a standardized disease severity tool for clinical data, though not adapted to data available in health registries. We aimed to develop and validate such a novel categorization with international applicability.

Methods: The WHO Clinical Progression Scale was translated to a severity index utilizing ICD-and procedure-codes from outpatient, inpatient, intensive care, and mortality registries using the adult Swedish population and SARS-CoV-2 positive-test data (January 2020 – July 2022). Cox proportional hazards were applied to determine whether increasing severity correlates with mortality in COVID-19 patients compared to the population.

Results: The WHO-Scale was translated to ten categories reflecting the increasing need for advanced care, encompassing 8,245,474 individuals including 1,981,946 SARS-CoV-2 infections. Fatal COVID-19 cases were older with more comorbidities. Those receiving mechanical ventilation and ECMO were younger with fewer comorbidities. Among survivors beyond 30 days, 90-day all-cause mortality increased with severity using category zero (no laboratory-verified SARS-CoV-2) as reference. Mortality was lowest for patients without health care adjusted for age, sex, comorbidities and socio-economic variables (adjusted hazard ratio (aHR) 1.18, 95% confidence interval (CI) 1.13–1.22). Those hospitalized >5 days had higher mortality (aHR 5.83, 5.5–6.17). Those requiring ECMO/ ECLS had the highest mortality (aHR 593.54, 317.77–1108.65).

Conclusion: The novel COVID-19 severity index associated with all-cause 90-day mortality and aligned with previous literature. This index will enable comparative studies of COVID-19, which is important for public health policies and development of clinical guidelines. This is an innovative epidemiologic tool with potential applicability in all countries with centralised health registers. The index also has the potential to be used for other infectious diseases and in real-time data for modelling predictions.

Background Hantavirus causes hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Strong inflammatory responses and vascular leakage are important hallmarks of these often fatal diseases. The mechanism behind pathogenesis is unknown and no specific treatment is available. IL-6 was recently highlighted as a biomarker for HPS/HFRS severity. IL-6 signaling is complex and context dependent: while classical signaling generally provide protective responses, trans-signaling can cause severe pathogenic responses. Here, we investigated a potential role for IL-6 trans-signaling in hantavirus pathogenesis.

Methods Effects of IL-6 trans-signaling during in vitro hantavirus infection were assessed using primary human endothelial cells treated with recombinant soluble IL-6 receptor (sIL-6R). Plasma from Puumala orthohantavirus-infected HFRS patients (n=28) were analyzed for IL-6 trans-signaling potential and its associations to severity.

Findings In vitro, sIL-6R treatment of infected cells enhanced IL-6 and CCL2 secretion, upregulated ICAM-1, and affected VE-cadherin leading to a disrupted cell barrier integrity. HFRS patients showed altered plasma levels of sIL-6R and soluble gp130 (sgp130) resulting in an increased sIL-6R/sgp130 ratio suggesting enhanced IL-6 trans-signaling potential. Plasma sgp130 levels negatively correlated with number of interventions and positively with albumin levels. Patients receiving oxygen treatment displayed a higher sIL-6R/sgp130 ratio compared to patients that did not.

Interpretation IL-6 trans-signaling is linked to hantavirus pathogenesis. Targeting IL-6 trans-signaling might provide a therapeutic strategy for treatment of severe HFRS and perhaps also HPS.

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.

Hemorrhagic fever with renal syndrome (HFRS) caused by Puumala virus (PUUV) leads to vascular dysfunction contributing to acute kidney injury (AKI) and pulmonary complications. The endothelial glycocalyx (eGLX) is crucial for vascular integrity, and its degradation may exacerbate disease severity. In this study, we examined the association between eGLX degradation and renal and pulmonary dysfunction in 44 patients with laboratory-confirmed PUUV infection. We measured plasma levels of eGLX degradation markers—syndecan-1, heparan sulfate, soluble thrombomodulin, and albumin—and found that these correlated with severe AKI and the need for oxygen therapy. In vitro experiments showed that matrix metalloproteinase-9 (MMP-9) and heparanase can degrade eGLX components, but albumin at physiological concentrations can mitigate this degradation and protect endothelial barrier function. These findings indicate that eGLX degradation contributes to HFRS pathogenesis and suggest that targeting the eGLX could be a therapeutic strategy to improve patient outcomes.

Background: Olfactory impairment has been associated with adverse health outcomes, particularly in older populations, including cognitive decline, malnutrition, and frailty. The COVID-19 pandemic highlighted olfactory impairment as a key symptom affecting individuals across all age groups, raising concerns about its long-term impacts. This study investigates the association between post-acute olfactory impairment and long-term physical capacity in COVID-19 patients, hypothesizing that impaired olfaction is linked to reduced physical performance.

Methods: This prospective cohort study included 63 hospitalized and non-hospitalized COVID-19 patients (38.1 % women; median age 51 years, IQR 47.0–60.0) who underwent olfactory testing 1–3 months post-infection. Olfactory assessments included threshold screening, supra-threshold intensity ratings, and an odour identification test. Physical capacity was assessed using the 1-min sit-to-stand test at follow-ups (3, 6, 12, and 24 months). Partial correlation analysis and linear mixed models were used to analyse the data, adjusting for covariates such as age, sex, BMI, comorbidities, smoking status, and severity of infection.

Results: In the early post-acute phase, 36.5 % of participants exhibited olfactory impairment. We identified a significant, negative correlation between objectively tested olfactory impairment and physical capacity at all follow-ups. In a linear mixed model adjusted for relevant covariates, olfactory impairment was associated with reduced physical capacity up to 24 months after infection. The association strengthened over time, reflected by the increasing beta values for the interaction term: 0.09 (p = 0.200) at 6 months, 0.13 (p = 0.053) at 12 months, and 0.23 (p = 0.001) at 24 months.

Conclusion: Individuals with olfactory impairment in the early post-acute phase of COVID-19 infection were more likely to exhibit diminished physical capacity 24 months later. This study highlights the broader implications of olfactory impairment, previously noted mainly in older populations, demonstrating its relevance across age groups. The COVID-19 pandemic presented a unique opportunity to investigate this relationship, enhancing our understanding of how olfactory impairments relate to long-term physical performance. These findings emphasize the need for further research with larger, more diverse cohorts and objective longitudinal assessments to confirm and extend these observations.

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.

Thrombocytopenia is a cardinal symptom of hantavirus-induced diseases including Puumala virus (PUUV)-induced hemorrhagic fever with renal syndrome (HFRS), which is associated with impaired platelet function, bleeding manifestations and augmented thrombotic risk. However, the underlying mechanisms causing thrombocytopenia and platelet hypo-responsiveness are unknown. Thus, we investigated the direct and indirect impact of PUUV on platelet production, function and degradation. Analysis of PUUV-HFRS patient blood revealed that platelet hypo-responsiveness in PUUV infection was cell-intrinsic and accompanied by reduced platelet-leukocyte aggregates (PLAs) and upregulation of monocyte tissue factor (TF), whereas platelet vasodilator-stimulated phosphoprotein (VASP) phosphorylation was comparable to healthy controls. Plasma CXCL4 levels followed platelet count dynamics throughout disease course. PUUV activated both neutrophils and monocytes in vitro, but platelet desialylation, degranulation and GPIIb/IIIa activation as well as PLA formation and endothelial adhesion under flow remained unaltered in the presence of PUUV. Further, MEG-01 megakaryocytes infected with PUUV displayed unaltered polyploidization, expression of surface receptors and platelet production. However, infection of endothelial cells with PUUV significantly increased platelet sequestration. Our data thus demonstrate that although platelet production, activation or degradation are not directly modulated, PUUV indirectly fosters thrombocytopenia by sequestration of platelets to infected endothelium. Upregulation of immunothrombotic processes in PUUV-HFRS may further contribute to platelet dysfunction and consumption. Given the pathophysiologic similarities of hantavirus infections, our findings thus provide important insights into the mechanisms underlying thrombocytopenia and highlight immune-mediated coagulopathy as potential therapeutic target.

Orthohantaviruses, transmitted primarily by rodents, cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus pulmonary syndrome in the Americas. These viruses, with documented human-to-human transmission, exhibit a wide case-fatality rate, 0.5–40 %, depending on the virus species, and no vaccine or effective treatment for severe Orthohantavirus infections exists. In Europe, the Puumala virus (PUUV), carried by the bank vole Myodes glareolus, causes a milder form of HFRS. Despite the reliance on serology and PCR for diagnosis, the three genomic segments of Swedish wild-type PUUV have yet to be completely sequenced.

We have developed a targeted hybrid-capture method aimed at comprehensive genomic sequencing of wild-type PUUV isolates and the identification of other Orthohantaviruses. Our custom-designed panel includes >11,200 probes covering the entire Orthohantavirus genus. Using this panel, we sequenced complete viral genomes from bank vole lung tissue, human plasma samples, and cell-cultured reference strains. Analysis revealed that Swedish PUUV isolates belong to the Northern Scandinavian lineage, with nucleotide diversity ranging from 2.8 % to 3.7 % among them. Notably, no significant genotypic differences were observed between the viral sequences from reservoirs and human cases except in the nonstructural protein.

Despite the high endemicity of PUUV in Northern Sweden, these are the first complete Swedish wild-type PUUV genomes and substantially increase our understanding of PUUV evolution and epidemiology. The panel's sensitivity enables genomic sequencing of human samples with viral RNA levels reflecting the natural progression of infection and underscores our panel's diagnostic value, and could help to uncover novel Orthohantavirus transmission routes.

Objectives: To investigate the effectiveness of intravenous immunoglobulin (IVIG) as treatment for COVID-19 in immunocompromised patients.

Methods: This retrospective study investigated outcomes for immunocompromised, vaccine non-responsive, patients that between September 2022 and April 2023 received IVIG as treatment for COVID-19 in the region of Västerbotten, Sweden. We analyzed clinical data, viral load, and anti-SARS-CoV-2 IgG binding and neutralization levels of patient serum samples and IVIG production batches. Primary and secondary outcomes were clinical cure and viral clearance, respectively.

Results: Sixteen patients were analyzed. After a median COVID-19 duration of 4 weeks, a median 60 g IVIG infusion increased SARS-CoV-2 binding and neutralizing antibody levels, with broad in vitro activity against tested variants. The treatment resulted in abrogation of viremia in all patients and general improvement in 15 survivors that all met the primary endpoint. Thirteen patients met the secondary endpoint at follow-up after a median of four months. Two subjects with persistent SARS-CoV-2 carriage relapsed but were successfully retreated with IVIG.

Conclusions: Antibodies in IVIG efficiently neutralized several SARS-CoV-2 variants. Treatment with IVIG was associated with clinical cure and viral clearance in immunocompromised patients. Our data suggests that IVIG could be a novel treatment alternative for COVID-19 for this patient category.