Symptom trajectories of post-COVID sequelae in patients with acute Delta or Omicron infection in Bergen, Norway.

Introduction: A substantial proportion of the over 700 million COVID-19 cases world-wide experience long-term symptoms. The objectives of this study were to compare symptom trajectories and risk factors for post-COVID-19 condition after Delta and Omicron infection. Methods: This study consecutively recruited patients with SARS-CoV-2 infection from November 2021 to March 2022. We recorded demographics, comorbidities, vaccination status, sick leave, and 18 symptoms during acute infection and after 4 months. The primary outcome measures were symptoms during acute infection and after 4 months. Secondary outcome measures were work and school absenteeism. Results: We followed a cohort of 1,374 non-hospitalized COVID-19 patients in Bergen, Norway, at three time points. The median age was 39.8 years and 11% were children <16 years. Common acute upper respiratory symptoms waned during follow-up. Fatigue remained common from acute infection (40%) until after 4 months (37%). Four months post-infection, patients reported increased frequencies of dyspnea (from 15% during acute illness to 25% at 4 months, p < 0.001), cognitive symptoms (from 9 to 32%, p < 0.001) and depression (from 1 to 17%, p < 0.001). Patients infected with Omicron reported less dyspnea (22% versus 27%, p = 0.046) and smell/taste problems (5% versus 19%, p < 0.001) at 4 months follow-up than those with Delta infection. Comorbidities and female sex were risk factors for persistent dyspnea and cognitive symptoms. Ten percent reported sick leave after acute illness, and vaccination reduced the risk of absenteeism (adjusted risk ratio: 0.36, 95% confidence interval: 0.15, 0.72, p = 0.008). Conclusion: At 4 months, home-isolated patients infected with Omicron reported overall comparable symptom burden, but less dyspnea and smell/taste problems than Delta infected patients. Several acute symptoms waned during follow-up. It is worrying that dyspnea, neurocognitive symptoms, and particularly depression, increased significantly during the first 4 months after acute infection. Previous vaccination was protective against prolonged sick leave.

SARS-CoV-2 specific immune responses in overweight and obese COVID-19 patients.

Obesity is a known risk factor for severe respiratory tract infections. In this prospective study, we assessed the impact of being obese or overweight on longitudinal SARS-CoV-2 humoral and cellular responses up to 18 months after infection. 274 patients provided blood samples at regular time intervals up to 18 months including obese (BMI ≥30, n=32), overweight (BMI 25-29.9, n=103) and normal body weight (BMI 18.5-24.9, n=134) SARS-CoV-2 patients. We determined SARS-CoV-2 spike-specific IgG, IgA, IgM levels by ELISA and neutralising antibody titres by neutralisation assay. RBD- and spike-specific memory B cells were investigated by ELISpot, spike- and non-spike-specific IFN-γ, IL-2 and IFN-γ/IL-2 secreting T cells by FluoroSpot and T cell receptor (TCR) sequencing was performed. Higher BMI correlated with increased COVID-19 severity. Humoral and cellular responses were stronger in overweight and obese patients than normal weight patients and associated with higher spike-specific IgG binding titres relative to neutralising antibody titres. Linear regression models demonstrated that BMI, age and COVID-19 severity correlated independently with higher SARS-CoV-2 immune responses. We found an increased proportion of unique SARS-CoV-2 specific T cell clonotypes after infection in overweight and obese patients. COVID-19 vaccination boosted humoral and cellular responses irrespective of BMI, although stronger immune boosting was observed in normal weight patients. Overall, our results highlight more severe disease and an over-reactivity of the immune system in overweight and obese patients after SARS-CoV-2 infection, underscoring the importance of recognizing overweight/obese individuals as a risk group for prioritisation for COVID-19 vaccination.

Prevalence and predictors of post-COVID-19 symptoms in general practice - a registry-based nationwide study.

BACKGROUND: With Norwegian national registry data, we assessed the prevalence of post-COVID-19 symptoms at least 3 months after confirmed infection, and whether sociodemographic factors and pre-pandemic health problems were risk factors for these symptoms. METHODS: All persons with a positive SARS-CoV-2 PCR test from February 2020 to February 2021 (exposed) were compared to a group without a positive test (unexposed) matched on age, sex, and country of origin. We used Cox regression to estimate hazard ratios (HR) for 18 outcome symptoms commonly described as post-COVID-19 related, registered by GPs. We compared relative risks (RR) for fatigue, memory disturbance, or shortness of breath among exposed and unexposed using Poisson regression models, assessing sex, age, education, country of origin, and pre-pandemic presence of the same symptom and comorbidity as possible risk factors, with additional analyses to assess hospitalisation for COVID-19 as a risk factor among exposed. RESULTS: The exposed group (N = 53 846) had a higher prevalence of most outcome symptoms compared to the unexposed (N = 485 757), with the highest risk for shortness of breath (HR 2.75; 95%CI 2.59-2.93), fatigue (2.08; 2.00-2.16) and memory disturbance (1.41;1.26-1.59). High HRs were also found for disturbance of smell/taste and hair loss, but frequencies were low. Concerning risk factors, sociodemographic factors were at large similarly associated with outcome symptoms in both groups. Registration of the outcome symptom before the pandemic increased the risk for fatigue, memory disturbance and shortness of breath after COVID-19, but these associations were weaker among exposed. Comorbidity was not associated with fatigue and shortness of breath in the COVID-19 group. For memory disturbance, the RR was slightly increased with the higher comorbidity score both among exposed and unexposed. CONCLUSION: COVID-19 was associated with a range of symptoms lasting more than three months after the infection.

Post COVID-19 condition after delta infection and omicron reinfection in children and adolescents.

BACKGROUND: The burden of COVID-19 in children and adolescents has increased during the delta and omicron waves, necessitating studies of long-term symptoms such as fatigue, dyspnoea and cognitive problems. Furthermore, immune responses in relation to persisting symptoms in younger people have not been well characterised. In this cohort study, we investigated the role of antibodies, vaccination and omicron reinfection upon persisting and long-term symptoms up to 8 months post-delta infection. METHODS: SARS-CoV-2 RT-PCR positive participants (n = 276, aged 10-20 years) were prospectively recruited in August 2021. We recorded the major symptoms of post COVID-19 condition and collected serum samples 3- and 8-months post delta infection. Binding antibodies were measured by spike IgG ELISA, and surrogate neutralising antibodies against Wuhan and delta variants by the hemagglutination test (HAT). FINDINGS: After delta infection, persisting symptoms at 3 months were significantly associated with higher delta antibody titres (OR 2.97, 95% CI 1.57-6.04, p = 0.001). Asymptomatic acute infection compared to symptomatic infection lowered the risk of persisting (OR 0.13, 95% CI 0.02-0.55, p = 0.013) and long-term (OR 0.28 95% CI 0.11-0.66, p = 0.005) symptoms at 3 and 8 months, respectively. Adolescents (16-20 years) were more likely to have long-term symptoms compared to children (10-15 years) (OR 2.44, 95% CI 1.37-4.41, p = 0.003). INTERPRETATION: This clinical and serological study compares long-term symptoms after delta infection between children and adolescents. The association between high antibody titres and persisting symptoms suggest the involvement of an immune mechanism. Similarly to adults, the dominant long-term symptoms in children are fatigue, dyspnoea and cognitive problems. FUNDING: This work was funded by the Ministry of Health and Care Services, Norway, the University of Bergen, Norway and Helse Vest, Norway (F-12621).

Symptom Burden and Immune Dynamics 6 to 18 Months Following Mild Severe Acute Respiratory Syndrome Coronavirus 2 Infection (SARS-CoV-2): A Case-control Study.

BACKGROUND: The burden and duration of persistent symptoms after nonsevere coronavirus disease 2019 (COVID-19) remains uncertain. This study aimed to assess postinfection symptom trajectories in home-isolated COVID-19 cases compared with age- and time- matched seronegative controls, and investigate immunological correlates of long COVID. METHODS: A prospective case-control study included home-isolated COVID-19 cases between February 28 and April 4, 2020, and followed for 12 (n = 233) to 18 (n = 149) months, and 189 age-matched severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-naive controls. We collected clinical data at baseline, 6, 12, and 18 months postinfection, and blood samples at 2, 4, 6, and 12 months for analysis of SARS-CoV-2-specific humoral and cellular responses. RESULTS: Overall, 46% (108/233) had persisting symptoms 12 months after COVID-19. Compared with controls, adult cases had a high risk of fatigue (27% excess risk, sex, and comorbidity adjusted odds ratio [aOR] 5.86; 95% confidence interval [CI], 3.27-10.5), memory problems (21% excess risk; aOR 7.42; CI, 3.51-15.67), concentration problems (20% excess risk; aOR 8.88; 95% CI, 3.88-20.35), and dyspnea (10% excess risk; aOR 2.66; 95% CI, 1.22-5.79). The prevalence of memory problems increased overall from 6 to 18 months (excess risk 11.5%; 95% CI, 1.5-21.5; P = .024) and among women (excess risk 18.7%; 95% CI, 4.4-32.9; P = .010). Longitudinal spike immunoglobulin G was significantly associated with dyspnea at 12 months. The spike-specific clonal CD4+ T-cell receptor ß depth was significantly associated with both dyspnea and number of symptoms at 12 months. CONCLUSIONS: This study documents a high burden of persisting symptoms after mild COVID-19 and suggests that infection induced SARS-CoV-2-specific immune responses may influence long-term symptoms.

Neuronal Dysfunction Is Linked to the Famine-Associated Risk of Proliferative Retinopathy in Patients With Type 2 Diabetes.

Persons with type 2 diabetes born in the regions of famine exposures have disproportionally elevated risk of vision-threatening proliferative diabetic retinopathy (PDR) in adulthood. However, the underlying mechanisms are not known. In the present study, we aimed to investigate the plausible molecular factors underlying progression to PDR. To study the association of genetic variants with PDR under the intrauterine famine exposure, we analyzed single nucleotide polymorphisms (SNPs) that were previously reported to be associated with type 2 diabetes, glucose, and pharmacogenetics. Analyses were performed in the population from northern Ukraine with a history of exposure to the Great Ukrainian Holodomor famine [the Diagnostic Optimization and Treatment of Diabetes and its Complications in the Chernihiv Region (DOLCE study), n = 3,583]. A validation of the top genetic findings was performed in the Hong Kong diabetes registry (HKDR, n = 730) with a history of famine as a consequence of the Japanese invasion during WWII. In DOLCE, the genetic risk for PDR was elevated for the variants in ADRA2A, PCSK9, and CYP2C19*2 loci, but reduced at PROX1 locus. The association of ADRA2A loci with the risk of advanced diabetic retinopathy in famine-exposed group was further replicated in HKDR. The exposure of embryonic retinal cells to starvation for glucose, mimicking the perinatal exposure to famine, resulted in sustained increased expression of Adra2a and Pcsk9, but decreased Prox1. The exposure to starvation exhibited a lasting inhibitory effects on neurite outgrowth, as determined by neurite length. In conclusion, a consistent genetic findings on the famine-linked risk of ADRA2A with PDR indicate that the nerves may likely to be responsible for communicating the effects of perinatal exposure to famine on the elevated risk of advanced stages of diabetic retinopathy in adults. These results suggest the possibility of utilizing neuroprotective drugs for the prevention and treatment of PDR.

Perinatal famine is associated with excess risk of proliferative retinopathy in patients with type 2 diabetes.

PURPOSE: Intrauterine undernutrition is associated with increased risk of type 2 diabetes. Children born premature or small for gestational age were reported to have abnormal retinal vascularization. However, whether intrauterine famine act as a trigger for diabetes complications, including retinopathy, is unknown. The aim of the current study was to evaluate long-term effects of perinatal famine on the risk of proliferative diabetic retinopathy (PDR). METHODS: We studied the risk for PDR among type 2 diabetes patients exposed to perinatal famine in two independent cohorts: the Ukrainian National Diabetes Registry (UNDR) and the Hong Kong Diabetes Registry (HKDR). We analysed individuals born during the Great Famine (the Holodomor, 1932-1933) and the WWII (1941-1945) famine in 101 095 (3601 had PDR) UNDR participants. Among 3021 (251 had PDR) HKDR participants, we studied type 2 diabetes patients exposed to perinatal famine during the WWII Japanese invasion in 1942-1945. RESULTS: During the Holodomor and WWII, perinatal famine was associated with a 1.76-fold (p = 0.019) and 3.02-fold (p = 0.001) increased risk of severe PDR in the UNDR. The risk for PDR was 1.66-fold elevated among individuals born in 1942 in the HKDR (p < 0.05). The associations between perinatal famine and PDR remained statistically significant after corrections for HbA1c in available 18 507 UNDR (padditive interaction < 0.001) and in 3021 HKDR type 2 diabetes patients (p < 0.05). CONCLUSION: In conclusion, type 2 diabetes patients, exposed to perinatal famine, have increased risk of PDR compared to those without perinatal famine exposure. Further studies are needed to understand the underlying mechanisms and to extend this finding to other diabetes complications.

Starvation to Glucose Reprograms Development of Neurovascular Unit in Embryonic Retinal Cells.

Perinatal exposure to starvation is a risk factor for development of severe retinopathy in adult patients with diabetes. However, the underlying mechanisms are not completely understood. In the present study, we shed light on molecular consequences of exposure to short-time glucose starvation on the transcriptome profile of mouse embryonic retinal cells. We found a profound downregulation of genes regulating development of retinal neurons, which was accompanied by reduced expression of genes encoding for glycolytic enzymes and glutamatergic signaling. At the same time, glial and vascular markers were upregulated, mimicking the diabetes-associated increase of angiogenesis-a hallmark of pathogenic features in diabetic retinopathy. Energy deprivation as a consequence of starvation to glucose seems to be compensated by upregulation of genes involved in fatty acid elongation. Results from the present study demonstrate that short-term glucose deprivation during early fetal life differentially alters expression of metabolism- and function-related genes and could have detrimental and lasting effects on gene expression in the retinal neurons, glial cells, and vascular elements and thus potentially disrupting gene regulatory networks essential for the formation of the retinal neurovascular unit. Abnormal developmental programming during retinogenesis may serve as a trigger of reactive gliosis, accelerated neurodegeneration, and increased vascularization, which may promote development of severe retinopathy in patients with diabetes later in life.

Reduced expression of OXPHOS and DNA damage genes is linked to protection from microvascular complications in long-term type 1 diabetes: the PROLONG study.

Type 1 diabetes is a chronic autoimmune disease requiring insulin treatment for survival. Prolonged duration of type 1 diabetes is associated with increased risk of microvascular complications. Although chronic hyperglycemia and diabetes duration have been considered as the major risk factors for vascular complications, this is not universally seen among all patients. Persons with long-term type 1 diabetes who have remained largely free from vascular complications constitute an ideal group for investigation of natural defense mechanisms against prolonged exposure of diabetes. Transcriptomic signatures obtained from RNA sequencing of the peripheral blood cells were analyzed in non-progressors with more than 30 years of diabetes duration and compared to the patients who progressed to microvascular complications within a shorter duration of diabetes. Analyses revealed that non-progressors demonstrated a reduction in expression of the oxidative phosphorylation (OXPHOS) genes, which were positively correlated with the expression of DNA repair enzymes, namely genes involved in base excision repair (BER) machinery. Reduced expression of OXPHOS and BER genes was linked to decrease in expression of inflammation-related genes, higher glucose disposal rate and reduced measures of hepatic fatty liver. Results from the present study indicate that at transcriptomic level reduction in OXPHOS, DNA repair and inflammation-related genes is linked to better insulin sensitivity and protection against microvascular complications in persons with long-term type 1 diabetes.

Novel Reclassification of Adult Diabetes Is Useful to Distinguish Stages of ß-Cell Function Linked to the Risk of Vascular Complications: The DOLCE Study From Northern Ukraine.

BACKGROUND: Presently, persons with diabetes are classified as having type 1 (T1D) or type 2 diabetes (T2D) based on clinical diagnosis. However, adult patients exhibit diverse clinical representations and this makes treatment approaches challenging to personalize. A recent Scandinavian study proposed a novel classification of adult diabetes into five clusters based on disease pathophysiology and risk of vascular complications. The current study aimed to characterize new subgroups of adult diabetes using this strategy in a defined population from northern Ukraine. METHODS: We analyzed 2,140 patients with established diabetes from the DOLCE study (n = 887 with new-onset diabetes and n = 1,253 with long duration). We used the k-means approach to perform clustering analyses using BMI, age at onset of diabetes, HbA1c, insulin secretion (HOMA2-B), and insulin resistance (HOMA2-IR) indices and glutamic acid decarboxylase antibodies (GADA) levels. Risks of macro- (myocardial infarction or stroke) and microvascular [retinopathy, chronic kidney disease (CKD) and neuropathy] complications and associations of genetic variants with specific clusters were studied using logistic regression adjusted for age, sex, and diabetes duration. RESULTS: Severe autoimmune diabetes (SAID, 11 and 6%) and severe insulin-deficient diabetes (SIDD, 25 and 14%) clusters were twice as prevalent in patients with long-term as compared to those with new-onset diabetes. Patients with long duration in both SAID and SIDD clusters had highest risks of proliferative retinopathy, and elevated risks of CKD. Long-term insulin-resistant obese diabetes 1 (IROD1) subgroup had elevated risks of CKD, while insulin-resistant obese diabetes 2 (IROD2) cluster exhibited the highest HOMA2-B, lowest HbA1c, and lower prevalence of all microvascular complications as compared to all other clusters. Genetic analyses of IROD2 subgroup identified reduced frequency of the risk alleles in the TCF7L2 gene as compared to all other clusters, cumulatively and individually (p = 0.0001). CONCLUSION: The novel reclassification algorithm of patients with adult diabetes was reproducible in this population from northern Ukraine. It may be beneficial for the patients in the SIDD subgroup to initiate earlier insulin treatment or other anti-diabetic modalities to preserve ß-cell function. Long-term diabetes cases with preserved ß-cell function and lower risk for microvascular complications represent an interesting subgroup of patients for further investigations of protective mechanisms.

Liver nucleotide biosynthesis is linked to protection from vascular complications in individuals with long-term type 1 diabetes.

Identification of biomarkers associated with protection from developing diabetic complications is a prerequisite for an effective prevention and treatment. The aim of the present study was to identify clinical and plasma metabolite markers associated with freedom from vascular complications in people with very long duration of type 1 diabetes (T1D). Individuals with T1D, who despite having longer than 30 years of diabetes duration never developed major macro- or microvascular complications (non-progressors; NP) were compared with those who developed vascular complications within 25 years from diabetes onset (rapid progressors; RP) in the Scandinavian PROLONG (n = 385) and DIALONG (n = 71) cohorts. The DIALONG study also included 75 healthy controls. Plasma metabolites were measured using gas and/or liquid chromatography coupled to mass spectrometry. Lower hepatic fatty liver indices were significant common feature characterized NPs in both studies. Higher insulin sensitivity and residual ß-cell function (C-peptide) were also associated with NPs in PROLONG. Protection from diabetic complications was associated with lower levels of the glycolytic metabolite pyruvate and APOCIII in PROLONG, and with lower levels of thiamine monophosphate and erythritol, a cofactor and intermediate product in the pentose phosphate pathway as well as higher phenylalanine, glycine and serine in DIALONG. Furthermore, T1D individuals showed elevated levels of picolinic acid as compared to the healthy individuals. The present findings suggest a potential beneficial shunting of glycolytic substrates towards the pentose phosphate and one carbon metabolism pathways to promote nucleotide biosynthesis in the liver. These processes might be linked to higher insulin sensitivity and lower liver fat content, and might represent a mechanism for protection from vascular complications in individuals with long-term T1D.