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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.

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: 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.

Pathogenic bacteria encounter various stressors while residing in the host. They respond through intricate mechanisms of gene expression regulation, ensuring their survival and adaptation. Understanding how bacteria adapt to different stress conditions through regulatory processes of specific genes requires exploring complex transcriptional responses using gene co-expression networks. We employed a large transcriptome data set comprising 32 diverse human bacterial pathogens exposed to the same 11 host-mimicking stress conditions. Using the weighted gene co-expression network analysis algorithm, we generated bacterial gene co-expression networks. By associating modular eigengene expression with specific stress conditions, we identified gene co-expression modules and stress-specific stimulons, including genes with unique expression patterns under specific stress conditions. Suggesting a new potential role of the frm operon in responding to bile stress in enteropathogenic bacteria demonstrates the effectiveness of our approach. We also revealed the regulation of streptolysin S genes, involved in the production, processing, and export of streptolysin S, a toxin responsible for the beta-hemolytic phenotype of group A Streptococcus. In a comparative analysis of stress responses in three Escherichia coli strains from the core transcriptome, we revealed shared and unique expression patterns across the strains, offering insights into convergent and divergent stress responses. To help researchers perform similar analyses, we created the user-friendly web application Co-PATHOgenex. This tool aids in deepening our understanding of bacterial adaptation to stress conditions and in deciphering complex transcriptional responses of bacterial pathogens.IMPORTANCEUnveiling gene co-expression networks in bacterial pathogens has the potential for gaining insights into their adaptive strategies within the host environment. Here, we developed Co-PATHOgenex, an interactive and user-friendly web application that enables users to construct networks from gene co-expressions using custom-defined thresholds (https://avicanlab.shinyapps.io/copathogenex/). The incorporated search functions and visualizations within the tool simplify the usage and facilitate the interpretation of the analysis output. Co-PATHOgenex also includes stress stimulons for various bacterial species, which can help identify gene products not previously associated with a particular stress condition. Unveiling gene co-expression networks in bacterial pathogens has the potential for gaining insights into their adaptive strategies within the host environment. Here, we developed Co-PATHOgenex, an interactive and user-friendly web application that enables users to construct networks from gene co-expressions using custom-defined thresholds (https://avicanlab.shinyapps.io/copathogenex/). The incorporated search functions and visualizations within the tool simplify the usage and facilitate the interpretation of the analysis output. Co-PATHOgenex also includes stress stimulons for various bacterial species, which can help identify gene products not previously associated with a particular stress condition.

Introduction: SARS-CoV-2 infection causes acute COVID-19 and may result in post-COVID syndrome (PCS). We aimed to investigate how clinicians diagnose PCS and identify associated clinical and demographic characteristics.

Methods: We analysed multiregistry data of all SARS-CoV-2 test-positive individuals in Sweden (n=1 057 174) between 1 February 2020 and 25 May 2021. We described clinical characteristics that prompt PCS diagnosis in outpatient and inpatient settings. In total, there were 6389 individuals with a hospital inpatient or outpatient diagnosis for PCS. To understand symptomatology, we examined individuals diagnosed with PCS at least 3 months after COVID-19 onset (n=6389) and assessed factors associated with PCS diagnosis.

Results: Mechanical ventilation correlated with PCS (OR 114.7, 95% CI 105.1 to 125.3) compared with no outpatient/inpatient contact during initial COVID-19. Dyspnoea (13.4%), malaise/fatigue (8%) and abnormal pulmonary diagnostic imaging findings (4.3%) were the most common features linked to PCS. We compared clinical features of PCS with matched controls (COVID-19 negative, n=23 795) and COVID-19 severity-matched patients (COVID-19 positive, n=25 556). Hypertension associated with PCS cohort (26.61%) than in COVID-19-negative (OR 17.16, 95% CI 15.23 to 19.3) and COVID-19-positive (OR 9.25, 95% CI 8.41 to 10.16) controls, although most individuals received this diagnosis before COVID-19. Dyspnoea was the second most common feature in the PCS cohort (17.2%), and new to the majority compared with COVID-19-negative (OR 54.16, 95% CI 42.86 to 68.45) and COVID-19-positive (OR 18.7, 95% CI 16.21 to 21.57) controls.

Conclusions: Our findings highlight factors Swedish physicians associate with PCS.

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.

mRNA vaccines are likely to become widely used for the prevention of infectious diseases in the future. Nevertheless, a notable gap exists in mechanistic data, particularly concerning the potential effects of sequential mRNA immunization or preexisting immunity on the early innate immune response triggered by vaccination. In this study, healthy adults, with or without documented prior SARS-CoV-2 infection, were vaccinated with the BNT162b2/Comirnaty mRNA vaccine. Prior infection conferred significantly stronger induction of proinflammatory and type I IFN-related gene signatures, serum cytokines, and monocyte expansion after the prime vaccination. The response to the second vaccination further increased the magnitude of the early innate response in both study groups. The third vaccination did not further increase vaccine-induced inflammation. In vitro stimulation of PBMCs with TLR ligands showed no difference in cytokine responses between groups, or before or after prime vaccination, indicating absence of a trained immunity effect. We observed that levels of preexisting antigen-specific CD4 T cells, antibody, and memory B cells correlated with elements of the early innate response to the first vaccination. Our data thereby indicate that preexisting memory formed by infection may augment the innate immune activation induced by mRNA vaccines.

Background: Olfactory dysfunction together with neurological and cognitive symptoms are common after COVID-19. We aimed to study whether performance on olfactory and neuropsychological tests following infection predict post-COVID condition (PCC), persisting symptoms, and reduced health-related quality of life.

Methods: Both hospitalized (N = 10) and non-hospitalized individuals (N = 56) were enrolled in this prospective cohort study. Participants were evaluated 1–3 months after infection with an olfactory threshold test and neuropsychological tests, which was used as predictors of PCC. A questionnaire outlining persisting symptoms and the validated instrument EuroQol five-dimension five-level for health-related quality of life assessment were used as outcome data 1 year after infection (N = 59). Principal component analysis was used to identify relevant predictors for PCC at 1 year.

Results: Objectively assessed olfactory dysfunction at 1–3 months post infection, but not subjective olfactory symptoms, predicted post-COVID condition with reduced health-related quality of life (PCC+) at 1 year. The PCC+ group scored more often below the cut off for mild cognitive impairment on the Montreal Cognitive Assessment (61.5% vs. 21.7%) and higher on the Multidimensional Fatigue Inventory-20, compared to the group without PCC+.

Conclusion: Our results indicate that objectively assessed, olfactory dysfunction is a predictor for PCC+. These findings underscore the importance of objective olfactory testing. We propose that olfactory screening in the early post-acute phase of COVID-19 infection might identify individuals that are at higher risk of developing long-term health sequalae.