Prevalence and Characteristics Associated With Post-COVID-19 Condition Among Nonhospitalized Adolescents and Young Adults.

Importance: The prevalence and baseline risk factors of post-COVID-19 condition (PCC) remain unresolved among the large number of young people who experienced mild COVID-19. Objectives: To determine the point prevalence of PCC 6 months after the acute infection, to determine the risk of development of PCC adjusted for possible confounders, and to explore a broad range of potential risk factors. Design, Setting, and Participants: This cohort study included nonhospitalized individuals from 2 counties in Norway between ages 12 and 25 years who underwent reverse transcription-polymerase chain reaction (RT-PCR) testing. At the early convalescent stage and at 6-month follow-up, participants underwent a clinical examination; pulmonary, cardiac, and cognitive functional testing; immunological and organ injury biomarker analyses; and completion of a questionnaire. Participants were classified according to the World Health Organization case definition of PCC at follow-up. Association analyses of 78 potential risk factors were performed. Exposures: SARS-CoV-2 infection. Main Outcomes and Measures: The point prevalence of PCC 6 months after RT-PCR testing in the SARS-CoV-2-positive and SARS-CoV-2-negative groups, and the risk difference with corresponding 95% CIs. Results: A total of 404 individuals testing positive for SARS-CoV-2 and 105 individuals testing negative were enrolled (194 male [38.1%]; 102 non-European [20.0%] ethnicity). A total of 22 of the SARS-CoV-2-positive and 4 of the SARS-CoV-2-negative individuals were lost to follow-up, and 16 SARS-CoV-2-negative individuals were excluded due to SARS-CoV-2 infection in the observational period. Hence, 382 SARS-CoV-2-positive participants (mean [SD] age, 18.0 [3.7] years; 152 male [39.8%]) and 85 SARS-CoV-2-negative participants (mean [SD] age, 17.7 [3.2] years; 31 male [36.5%]) could be evaluated. The point prevalence of PCC at 6 months was 48.5% in the SARS-CoV-2-positive group and 47.1% in the control group (risk difference, 1.5%; 95% CI, -10.2% to 13.1%). SARS-CoV-2 positivity was not associated with the development of PCC (relative risk [RR], 1.06; 95% CI, 0.83 to 1.37; final multivariable model utilizing modified Poisson regression). The main risk factor for PCC was symptom severity at baseline (RR, 1.41; 95% CI, 1.27-1.56). Low physical activity (RR, 0.96; 95% CI, 0.92-1.00) and loneliness (RR, 1.01; 95% CI, 1.00-1.02) were also associated, while biological markers were not. Symptom severity correlated with personality traits. Conclusions and Relevance: The persistent symptoms and disability that characterize PCC are associated with factors other than SARS-CoV-2 infection, including psychosocial factors. This finding raises questions about the utility of the World Health Organization case definition and has implications for the planning of health care services as well as for further research on PCC.

Neurological Involvement in COVID-19 Among Non-Hospitalized Adolescents and Young Adults.

Introduction: Coronavirus disease 2019 (COVID-19) is prevalent among young people, and neurological involvement has been reported. We investigated neurological symptoms, cognitive test results, and biomarkers of brain injury, as well as associations between these variables in non-hospitalized adolescents and young adults with COVID-19. Methods: This study reports baseline findings from an ongoing observational cohort study of COVID-19 cases and non-COVID controls aged 12-25 years (Clinical Trials ID: NCT04686734). Symptoms were charted using a standardized questionnaire. Cognitive performance was evaluated by applying tests of working memory, verbal learning, delayed recall, and recognition. The brain injury biomarkers, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAp), were assayed in serum samples using ultrasensitive immunoassays. Results: A total of 405 COVID-19 cases and 111 non-COVID cases were prospectively included. Serum Nfl and GFAp concentrations were significantly elevated in COVID-19 cases as compared with non-COVID controls (p = 0.050 and p = 0.014, respectively). The COVID-19 cases reported more fatigue (p < 0.001) and post-exertional malaise (PEM) (p = 0.001) compared to non-COVID-19 controls. Cognitive test performance and clinical neurological examination did not differ across the two groups. Within the COVID-19 group, there were no associations between symptoms, cognitive test results, and NfL or GFAp levels. However, fatigue and PEM were strongly associated with older age and female sex. Conclusions: Non-hospitalized adolescents and young adults with COVID-19 reported more fatigue and PEM and had slightly elevated levels of brain injury markers, but showed normal cognitive performance. No associations were found between symptoms, brain injury markers, and cognitive test results, but fatigue and PEM were strongly related to female sex and older age.

Inflammatory Markers, Pulmonary Function, and Clinical Symptoms in Acute COVID-19 Among Non-Hospitalized Adolescents and Young Adults.

Summary: Mild, subacute COVID-19 in young people show inflammatory enhancement, but normal pulmonary function. Inflammatory markers are associated with age and male sex, whereas clinical symptoms are associated with age and female sex, but not with objective disease markers. Background: Coronavirus Disease 2019 (COVID-19) is widespread among adolescents and young adults across the globe. The present study aimed to compare inflammatory markers, pulmonary function and clinical symptoms across non-hospitalized, 12 - 25 years old COVID-19 cases and non-COVID-19 controls, and to investigate associations between inflammatory markers, clinical symptoms, pulmonary function and background variables in the COVID-19 group. Methods: The present paper presents baseline data from an ongoing longitudinal observational cohort study (Long-Term Effects of COVID-19 in Adolescents, LoTECA, ClinicalTrials ID: NCT04686734). A total of 31 plasma cytokines and complement activation products were assayed by multiplex and ELISA methodologies. Pulmonary function and clinical symptoms were investigated by spirometry and questionnaires, respectively. Results: A total of 405 COVID-19 cases and 111 non-COVID-19 controls were included. The COVID-19 group had significantly higher plasma levels of IL-1ß, IL-4, IL-7, IL-8, IL-12, TNF, IP-10, eotaxin, GM-CSF, bFGF, complement TCC and C3bc, and significantly lower levels of IL-13 and MIP-1α, as compared to controls. Spirometry did not detect any significant differences across the groups. IL-4, IL-7, TNF and eotaxin were negatively associated with female sex; eotaxin and IL-4 were positively associated with age. Clinical symptoms were positively associated with female sex and age, but not with objective disease markers. Conclusions: Among non-hospitalized adolescents and young adults with COVID-19 there was significant alterations of plasma inflammatory markers in the subacute stage of the infection. Still, pulmonary function was normal. Clinical symptoms were independent of inflammatory and pulmonary function markers, but positively associated with age and female sex.

Inflammatory markers and pulmonary function in adolescents and young adults 6 months after mild COVID-19.

Introduction: Both public and scientific attention have shifted from the acute COVID-19 illness to the chronic disability experienced by a proportion of COVID-19 convalescents. Post COVID-19 condition, a term used for long-lasting symptoms after COVID-19, can affect individuals across all disease severity and age groups. Data on post-COVID-19 symptomatology, epidemiology and pathophysiology in adolescents and young adults are scarce. To date, little is known on the immunological and pulmonary trends in these patients after COVID-19. This study investigated immunological markers and pulmonary function in non-hospitalized patients in this group at 6 months after initial mild COVID-19 infection. Methods: Non-hospitalized SARS-CoV-2 positive (n = 405) and SARS-CoV-2 negative (n = 111) adolescents and young adults (aged 12-25 years) were followed prospectively for six months after SARS-CoV-2 PCR testing. At baseline and at six months follow-up, all participants underwent an assessment including clinical examination, questionnaires, spirometry, and blood sampling. Cross-sectional comparisons of blood biomarkers; including white blood cell counts, CRP, GDF-15, a 27-multiplex cytokine assay, complement activation products and SARS-CoV-2 antibodies; and spirometry measures were performed after classification of all participants according to their COVID-19 status and adherence to post-COVID-19 case criteria. Associations between biomarkers and COVID-19 symptoms were explored. Results: No difference in pulmonary function was detected between the groups. COVID-19 convalescents had higher levels of chemokines eotaxin, MCP-1 and IP-10 than non-infected controls. The increase was modest and not associated with long-lasting COVID-19 symptoms. Discussion: Elevated inflammatory mediators were found in adolescents and young adults six months after mild COVID-19, but there was no association with post-COVID-19 condition.

Rapid diagnosis and reduced workload for urinary tract infection using flowcytometry combined with direct antibiotic susceptibility testing.

BACKGROUND: We evaluated if flowcytometry, using Sysmex UF-5000, could improve diagnosis of urinary tract infections by rapid identification of culture negative and contaminated samples prior to culture plating, thus reducing culture plating workload and response time. We also evaluated if it is possible to reduce the response time for antibiotic susceptibility profiles using the bacteria information flag on Sysmex UF-5000 to differentiate between Gram positive and negative bacteria, followed by direct Antibiotic Susceptibility Testing (dAST) on the positive urine samples. METHODS: One thousand urine samples were analyzed for bacteria, white blood cells and squamous cells by flowcytometry before culture plating. Results from flowcytometric analysis at different cut-off values were compared to results of culture plating. We evaluated dAST on 100 urine samples that were analyzed as positive by flowcytometry, containing either Gram positive or Gram negative bacteria. RESULTS: Using a cut-off value with bacterial count ≥100.000/mL and WBCs ≥10/µL, flowcytometry predicted 42,1% of samples with non-significant growth. We found that most contaminated samples contain few squamous cells. For 52/56 positive samples containing Gram negative bacteria dAST was identical to routine testing. Overall, there was concordance in 555/560 tested antibiotic combinations. CONCLUSION: Flowcytometry offers advantages for diagnosis of urinary tract infections. Screening for negative urine samples on the day of arrival reduces culture plating and workload, and results in shorter response time for the negative samples. The bacteria information flag predicts positive samples containing Gram negative bacteria for dAST with high accuracy, thus Antibiotic Susceptibility Profile can be reported the day after arrival. For the positive samples containing Gram negative bacteria the concordance was very good between dAST and Antibiotic Susceptibility Testing in routine. For positive samples containing Gram positive bacteria the results were not convincing. We did not find any correlation between epithelial cells and contamination.

Clinical symptoms and markers of disease mechanisms in adolescent chronic fatigue following Epstein-Barr virus infection: An exploratory cross-sectional study.

INTRODUCTION: Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue (CF) and Chronic Fatigue Syndrome (CFS). The aim of this cross-sectional study was to explore clinical symptoms as well as markers of disease mechanisms in fatigued and non-fatigued adolescents 6 months after EBV-infection, and in healthy controls. MATERIALS AND METHODS: A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed 6 months after the initial infectious event and divided into fatigued (EBV CF+) and non-fatigued (EBV CF-) cases based on questionnaire score. The EBV CF+ cases were further sub-divided according to case definitions of CFS. In addition, a group of 70 healthy controls with similar distribution of sex and age was included. Symptoms were mapped with a questionnaire. Laboratory assays included EBV PCR and serology; detailed blood leukocyte phenotyping and serum high-sensitive C-reactive protein; and plasma and urine cortisol and catecholamines. Assessment of autonomic activity was performed with continuous, non-invasive monitoring of cardiovascular variables during supine rest, controlled breathing and upright standing. Differences between EBV CF+ and EBV CF- were assessed by simple and multiple linear regression adjusting for sex as well as symptoms of depression and anxiety. A p-value ≤ 0.05 was considered statistically significant. This study is part of the CEBA-project (Chronic fatigue following acute Epstein-Barr virus infection in adolescents). RESULTS: The EBV CF+ group had significantly higher scores for all clinical symptoms. All markers of infection and most immune, neuroendocrine and autonomic markers were similar across the EBV CF+ and EBV CF- group. However, the EBV CF+ group had slightly higher serum C-reactive protein (0.48 vs 0.43 mg/L, p = 0.031, high-sensitive assay), total T cell (CD3+) count (median 1573 vs 1481 × 106 cells/L, p = 0.012), plasma norepinephrine (1420 vs 1113 pmol/L, p = 0.01) and plasma epinephrine (363 vs 237 nmol/L, p = 0.032); lower low-frequency:high frequency (LF/HF) ratio of heart rate variability at supine rest (0.63 vs 0.76, p = 0.008); and an attenuated decline in LF/HF ratio during controlled breathing (-0.11 vs -0.25, p = 0.002). Subgrouping according to different CFS diagnostic criteria did not significantly alter the results. Within the EBV CF+ group, there were no strong correlations between clinical symptoms and markers of disease mechanisms. In a multiple regression analysis, serum CRP levels were independently associated with serum cortisol (B = 4.5 × 10-4, p < 0.001), urine norepinephrine (B = 9.6 × 10-2, p = 0.044) and high-frequency power of heart rate variability (B = -3.7 × 10-2, p = 0.024). CONCLUSIONS: In adolescents, CF and CFS 6 months after acute EBV infection are associated with high symptom burden, but no signs of increased viral load and only subtle alterations of immune, autonomic, and neuroendocrine markers of which no one is strongly correlated with symptom scores. A slight sympathetic over parasympathetic predominance is evident in CF and might explain slightly increased CRP levels.

Fatigue in Epstein-Barr virus infected adolescents and healthy controls: A prospective multifactorial association study.

OBJECTIVE: Acute Epstein-Barr virus (EBV) infection is a known trigger of both acute and chronic fatigue. The aim of this study was to investigate associations to fatigue in adolescents with EBV infection during the initial stage and six months after, as well as in healthy controls. METHODS: 200 adolescents (12-20 years old) with EBV infection were assessed as soon as possible after the onset of symptoms (EBVbaseline) and six months later (EBVsix months, 5 drop-outs). Also, 70 healthy controls (HC) were included. Associations between current fatigue and 148 different variables (including symptoms, functional abilities and biomarkers) were investigated separately for EBVbaseline, EBVsix months and HC using linear regression modelling. RESULTS: Fatigue was associated with symptoms of sleeping difficulties, negative emotions, and quality of life under all circumstances. Fatigue was independently associated with markers of immune response at EBVsix months and in HC, not at EBVbaseline. An association between fatigue and markers of autonomic cardiovascular control was only present at EBVsix months. Cognitive functioning shifted from a positive association to fatigue at EBVbaseline to a negative trend at EBVsix months. Markers of infection were not associated with fatigue at EBVbaseline, EBVsix months nor in HC. CONCLUSION: Irrespective of the cause, fatigue is important for quality of life and is highly associated with negative emotions. Markers of infection and immune response had respectively none and barely any association to fatigue. Autonomic alterations and cognitive dysfunction were exclusively associated with fatigue long after infection, corroborating findings from studies of the Chronic Fatigue Syndrome.

Lifestyle factors during acute Epstein-Barr virus infection in adolescents predict physical activity six months later.

AIM: Acute Epstein-Barr virus (EBV) infection is a trigger of prolonged fatigue. This study investigated baseline predictors of physical activity six months after an acute EBV infection. METHODS: A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed for 149 possible baseline predictors and followed prospectively. In this exploratory study, we performed linear regression analysis to assess possible associations between baseline predictors and steps per day at six months. RESULTS: In the final multiple linear regression model, physical activity six months after acute EBV infection was significantly and independently predicted by baseline physical activity (steps per day), substance use (alcohol and illicit drugs) and human growth hormone (adjusted R2  = 0.20). CONCLUSION: Baseline physical activity, substance use and plasma growth hormone are independent predictors of physical activity six months after an acute EBV infection in adolescents, whereas markers of the infection and associated immune response do not seem to be associated with physical activity six months later.

Predictors of chronic fatigue in adolescents six months after acute Epstein-Barr virus infection: A prospective cohort study.

INTRODUCTION: Acute Epstein-Barr virus (EBV) infection is a trigger of chronic fatigue and Chronic Fatigue Syndrome (CFS). This study investigated baseline predictors of chronic fatigue six months after an acute EBV infection. MATERIALS AND METHODS: A total of 200 adolescents (12-20 years old) with acute EBV infection were assessed for 149 possible baseline predictors and followed prospectively. We performed linear regression to assess possible associations between baseline predictors and fatigue (Chalder Fatigue Questionnaire total score) six months after the acute EBV infection. A total of 70 healthy controls were included for cross-sectional reference. This study is part of the CEBA-project (Chronic fatigue following acute Epstein-Barr virus infection in adolescents). RESULTS: In the final multiple linear regression model, fatigue six months after acute EBV infection was significantly and independently predicted by the following baseline variables (regression coefficient B[95% CI]): Sensory sensitivity (0.8[0.09-1.6]), pain severity (0.2[0.02-0.3]), functional impairment (1000 steps/day) (-0.3[-0.5 to -0.08]), negative emotions (anxiety) (0.4[0.2-0.6]), verbal memory (correct word recognition) (1.7[0.1-3.3]), plasma C-reactive protein (2.8[1.1-4.4] for CRP values >0.86) and plasma Vitamin B12 (-0.005[-0.01 to -0.001]). CONCLUSIONS: Development of fatigue after acute EBV infection is to a larger extent predicted by baseline variables related to symptoms and functions than to baseline variables reflecting infectious and immune processes. TRIAL REGISTRATION: ClinicalTrials, ID: NCT02335437, https://clinicaltrials.gov/ct2/show/NCT02335437.

Serum adiponectin concentration prior to clinical onset of preeclampsia.

OBJECTIVE: This study assesses whether the adipokine adiponectin is a useful marker in pregnant women who subsequently develop preeclampsia (PE). METHODS: A retrospective case-control study was conducted to measure the total serum levels of adiponectin, measured by radioimmunoassay kit, in serum samples stored in serological biobanks. RESULTS: Total serum adiponectin concentrations between the groups were not significantly different (p = 0.22). There were no obvious clinical signs of the preeclamptic inflammatory process at the time when samples were drawn. CONCLUSION: Using this design, total adiponectin appeared not be a useful pre-clinical marker of PE.